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Pharmacokinetics of plasmid DNA

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Title:
Pharmacokinetics of plasmid DNA
Creator:
Houk, Brett Edward, 1969-
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Language:
English
Physical Description:
xv, 165 leaves : ill. ; 29 cm.

Subjects

Subjects / Keywords:
Administered dose ( jstor )
DNA ( jstor )
Dosage ( jstor )
Drug design ( jstor )
Liposomes ( jstor )
Pharmacokinetics ( jstor )
Plasmas ( jstor )
Plasmids ( jstor )
Rats ( jstor )
Standard deviation ( jstor )
DNA -- pharmacokinetics ( mesh )
Department of Pharmaceutics thesis Ph.D ( mesh )
Dissertations, Academic -- College of Pharmacy -- Department of Pharmaceutics -- UF ( mesh )
Plasmids -- pharmacokinetics ( mesh )
Research ( mesh )
Genre:
bibliography ( marcgt )
non-fiction ( marcgt )

Notes

Thesis:
Thesis (Ph.D.)--University of Florida, 2000.
Bibliography:
Bibliography: leaves 159-165.
General Note:
Typescript.
General Note:
Vita.
Statement of Responsibility:
by Brett Edward Houk.

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University of Florida
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University of Florida
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Copyright [name of dissertation author]. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
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PHARMACOKINETICS OF PLASMID DNA


By

BRETT EDWARD HOUK










A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA


2000































Copyright 2000

by

Brett Edward Houk

























This work is dedicated to my parents Nancy and Ronald Houk for all of their guidance
throughout my life.














ACKNOWLEDGMENTS

I would like to acknowledge Dr. Jeffrey A. Hughes who, aside from my parents,

has been the biggest influence in my life thus far. I would also like to acknowledge Dr.

Guenther Hochhaus for his invaluable insight and guidance in this work.













TABLE OF CONTENTS
page


ACKNOW LEDGM ENTS ............................................................................................ iv

LIST OF TABLES ............................................................................................................ vii

LIST OF FIGURES ........................................................................................................ ix

ABSTRACT ..................................................................................................................... xiv

INTRODUCTION .............................................................................................................. 1

The Use of Naked pDNA as a Therapeutic Agent .................................................... 2
Effectiveness of Naked Plasmid DNA after Local Administration .................... 3
Effectiveness of Naked Plasmid DNA after IV Administration ......................... 6
Anatomical Factors Potentially Involved in the Pharmacokinetics of Plasmid DNA.. 9
Degradation of pDNA in the Bloodstream ............................................................ 16
Pharm acokinetics of Liposom al Delivery Vehicles ............................................... 17
Pharmacokinetics of Naked Plasmid DNA and Liposome: Plasmid DNA Complexes
................................................................................. ......................................... ......... 17
Pharmacokinetics of Naked Plasmid DNA in the Blood after IV Injection ......... 17
Distribution of Plasmid DNA in Tissues after IV Injection ............................. 20
Conclusions ................................................................................................................. 21

PHARMACOKINETICS OF PLASMID DNA IN ISOLATED RAT PLASMA ..... 23

Introduction ................................................................................................................. 23
M ethods ....................................................................................................................... 25
Theoretical .................................................................................................................. 35
R esu lts ......................................................................................................................... 3 6
Conclusions ................................................................................................................. 46

PHARMACOKINETICS OF PLASMID DNA AFTER IV BOLUS ADMINISTRATION
IN THE RAT ..................................................................................................................... 52

Introduction ................................................................................................................. 52
M ethods ....................................................................................................................... 53
Theoretical .................................................................................................................. 57
R esu lts ......................................................................................................................... 6 0
Conclusions ................................................................................................................. 61








DOSE DEPENDENCY OF PLASMID DNA PHARMACOKINETICS .................... 71

Introduction ................................................................................................................. 71
M ethods ....................................................................................................................... 73
Results ......................................................................................................................... 78
Conclusions ................................................................................................................. 90

PHARMACOKINETIC MODELING OF PLASMID DNA AFTER IV BOLUS
ADM IN ISTRA TION IN TH E RA T ............................................................................... 102

Introduction ............................................................................................................... 102
Theoretical ................................................................................................................ 104
Results ....................................................................................................................... 106
Conclusions ............................................................................................................... 114

PHARMACOKINETICS OF LIPOSOME: PLASMID DNA COMPLEXES .............. 122

Introduction ............................................................................................................... 122
M ethods ..................................................................................................................... 125
Results ....................................................................................................................... 127
Pharmacokinetics of Liposome:pDNA Complex Degradation in Rat Plasma ... 127
Pharmacokinetics of Liposome:pDNA Complex Degradation in Rat Whole Blood
............................................................................................................................. 12 8
Pharmacokinetics of Liposome:pDNA Complexes after IV Bolus Administration
in the Rat ........................................................................................................ 129
Conclusions ............................................................................................................... 130

CON CLU SION S AND IM PLICATION S ...................................................................... 145

Sum m ary of Results .................................................................................................. 145
Implications of Plasmid DNA Degradation in Isolated Plasma .......................... 145
Com parison of In Vitro and In Vivo Pharm acokinetics ...................................... 146
Effects of Increasing Dose of Plasm id DN A ...................................................... 148
Results of the Curve Fitting Experim ents ........................................................... 151
Liposom e: pDN A Com plex Conclusions ........................................................... 152
Future Directions ...................................................................................................... 155
Concluding Rem arks ................................................................................................. 157

LIST OF REFEREN CES ................................................................................................ 159

BIOGRA PHICA L SKETCH .......................................................................................... 166














LIST OF TABLES


Table pag

2-1. Method parameters for pDNA analysis ................................................................... 34

2-2. Pharmacokinetic parameters for pDNA in isolated rat plasma ................................ 41

2-3. Noncompartmental parameters for pDNA after incubation in isolated plasma ..... 42

2-4. Pharmacokinetic parameters for pDNA after incubating the pGE150 plasmid in
isolated rat plasm a ................................................................................................. 49

3-1. Pharmacokinetic parameters calculated after 500 .tg dose of SC pDNA ................. 65

3-2. Comparison of in vivo and in vitro pharmacokinetic parameters for pDNA ............ 66

3-3. Comparison of OC and L pDNA parameters after administration of SC pGL3,
pG E 150, and pG eneM ax ...................................................................................... 69

4-1. Pharmacokinetic parameters estimated for supercoiled pDNA based upon the fit t=0
concentration of SC pDN A ................................................................................... 81

4-2. Noncompartmental analysis of OC pDNA after IV bolus administration of SC
p D N A ......................................................................................................................... 84

4-3. Noncompartmental analysis of L pDNA after IV bolus administration of SC pDNA..85

4-4. Noncompartmental analysis of OC pDNA after IV bolus administration of OC
pDNA at 2500 and 250 tg doses .......................................................................... 89

4-5. Noncompartmental analysis of L pDNA after IV bolus administration of L pDNA at
2500 and 250 tg doses .......................................................................................... 93

5-1. Pharmacokinetic parameters for pDNA based upon the model presented in the text... 112

5-2. Overall pharmacokinetic parameters for pDNA when all doses are fit
sim ultan eously ........................................................................................................... 113








5-3. Pharmacokinetic parameters calculated after administration of OC pDNA at 2500
and 250 g g doses ........................................................................................................ 118

5-4. Pharmacokinetic parameters calculated after administration of L pDNA at 2500 and
250 ptg doses .............................................................................................................. 119

6-1. Noncompartmental analysis of pDNA after administration of liposome: SC pDNA
com p lex es .................................................................................................................. 137

6-2. Comparison of SC pDNA pharmacokinetic parameters after administration of SC
pDNA either in free form (naked) at 2500 [tg dose or after administration as
liposome: pDNA complexes at 500 ptg dose ............................................................. 138

6-3. Comparison of OC pDNA pharmacokinetic parameters after administration of SC
pDNA either in free form (naked) or after administration as liposome: pDNA
com plexes at 500 jig pDN A dose .............................................................................. 139

6-4. Comparison of L pDNA pharmacokinetic parameters after administration of SC
pDNA either in free form (naked) or after administration as liposome: pDNA
com plexes at 500 jtg pD N A dose .............................................................................. 140














LIST OF FIGURES


Figure p

1-1. Potential sights for nicking of the phosphodiester backbone of DNA ...................... 10

1-2. Model of plasmid DNA degradation in the bloodstream .......................................... 11

1-3. Schematic representation of pDNA (.) passing through a continuous capillary: (1)
pinocytosis, (2) through intercellular junctions, and (3) passing through
endothelial channels ............................................................................................... 12

1-4. Schematic representation of pDNA (.) passing through a fenestrated capillary: (1)
pinocytosis, (2) passing through a diaphragm fenestrae, and (3) passing through
and open fenestrae ................................................................................................. 13

1-5. Schematic representation of pDNA (e) passing through a discontinuous capillary.
(1) pinocytosis and (2) passing through large pores in the endothelium .............. 14

2-1. Plasm id m ap of pGL3 Control ................................................................................. 26

2-2. Plasmid map of the pGeneMax-Luciferase ............................................................ 27

2-3. Plasm id m ap of pG E150 .......................................................................................... 28

2-4. Standard curve for supercoiled pDNA. Abcissa represents total ng estimated by UV
absorbance at 260 nm. Ordinate represents ng calculated by the KDS ID
software. Error bars represent 1 standard deviation .......................................... 31

2-5. Standard curve for OC pDNA. Abcissa represents total ng estimated by UV
absorbance at 260 nm. Ordinate represents ng calculated by the KDS ID
software. Error bars represent 1 standard deviation .......................................... 32

2-6. Standard curve for Linear pDNA. Abcissa represents total ng estimated by UV
absorbance at 260 nm. Ordinate represents ng calculated by the KDS ID
software. Error bars represent 1 standard deviation .......................................... 33

2-7. Pharmacokinetic model of plasmid DNA degradation in rat plasma. The model is
considered to be a unidirectional process. SC, OC, and L represent the amounts
of supercoiled, open circular, and linear plasmid, respectively, in each








compartment. The rate constants k,, ko, and k, represent the degradation constants
for supercoiled, open circular, and linear plasmid, respectively ........................... 37

2-8. Agarose gel analysis of pDNA degradation in isolated rat plasma. Lane 1; size
standard, lane 2; 30 sec, lane 3; 1 min, lane 4; 2 min, lane 5; 3 min, lane 6; 5 min,
lane 7; 10 min, lane 8; 20 min, lane 9; 30 min, lane 10; 45 min, lane 11; 60 min,
lane 12; 80 m in ...................................................................................................... 39

2-9. Experimental and fitted data based on the pharmacokinetic model described in the
text. Data points represent actual experimental data. Lines represent values
predicted by the model. Data represents mean of n-3 1 standard deviation.
Key: U supercoiled, open circular, A linear .................................................. 40

2-10. Analysis of rate constants in dilute plasma. Degradation rate constants were
modeled in PBS diluted rat plasma. Rate constants represent the fitted values of
n=6 rats/ time point. Key: *ks in dilute plasma, Sk0 in dilute plasma. The value
of k, is not reported due to the prolonged stability of linear plasmid in dilute
p lasm a ........................................................................................................................ 44

2-11. Degradation of supercoiled pDNA in 25% rat plasma after (A) incubating the
plasma at 90'C for 10 min (B) the addition of 0.1 mM EDTA ............................ 45

2-12. Comparison of concentrations of OC pDNA using (*) pGE150 concentrations of
OC pDNA using (0) pGL3 in isolated rat plasma. Data represents mean of n=3
1 standard deviation ............................................................................................. 47

2-13. Comparison of concentrations of L pDNA using (*) pGE 150 versus
concentrations of L pDNA using (0) pGL3 in isolated rat plasma. Data
represents mean of n=3 1 standard deviation ..................................................... 48

3-1. Photograph of the jugular cannula placement used for blood sampling ................... 55

3-2. Photograph of the femoral vein isolation and injection procedure used for IV bolus
adm inistration ............................................................................................................ 56

3-3. A representative gel from which plasmid amounts were quantified as described in
the methods section. Lane 1: size standard, lane 2: 1 min, lane 3: 2 min, lane 4:
3.5 min, lane 5: 5 min, lane 6:10 min, lane 7: 20 min, lane 8: 30 min, lane 9: 45
m in, lane 10: 60 m in ............................................................................................ 59

3-4. Experimental and fitted data based on the pharmacokinetic model described in the
text. Data points represent actual experimental data. Lines represent values
predicted by the model. Data represents mean of n=6 I standard devaition.
K ey: 0 open circular, A linear ............................................................................ 62

3-5. Concentrations of OC pGL3 after 0: IV bolus administration of a 500 [-tg dose of
SC pGL3, and *: Incubation of SC pGL3 in isolated plasma at 37'C ................. 63








3-6. Concentrations of L pGL3 after 0: IV bolus administration of a 500 jIg dose of SC
pGL3, and *: Incubation of SC pGL3 in isolated plasma at 37'C ..................... 64

3-7. Concentrations of OC pDNA in the bloodstream after IV bolus administration of
500 [tg of pCMV-Luc, pGE150, or pGL3. Data represents mean of n=3 I
standard deviation ................................................................................................. 67

3-8. Concentrations of L pDNA in the bloodstream after IV bolus administration of 500
jig of pCMV-Luc, pGE150, or pGL3. Data represents mean of n=3 1 standard
d ev iation ..................................................................................................................... 6 8

4-1 Agarose gel analysis of pDNA after conversion to the OC form of the plasmid. Lane
1: Prior to treatment plasmid is predominately SC. Lane 2: After treatment
plasmid is completely converted to to OC form ................................................... 75

4-2. Absorbance of pDNA before and after conversion to the OC form. Data represents
averages of n=3 I standard deviation ............................................................... 76

4-3. Agarose gel analysis of pDNA before and after conversion to the L form of the
plasmid. Lane 1: Size standard, Lane 2: before treatment the plasmid is
predominately in the SC and OC form, Lane 3: Mixture of SC, OC, and L
plasmid for reference, Lane 4: after treatment the plasmid is completely converted
to th e L form .............................................................................................................. 77

4-4. Concentrations of SC pDNA in the bloodstream after 2500 jig dose. SC pDNA
remained detectable through 1 minute after administration. Data points represent
averages of n=3 1 standard deviation. Lines represent a least squares fit of the
data using the model described in the Methods section ........................................ 80

4-5. Concentrations of OC pDNA after IV bolus administration of: U 2500 jig, A 500
pg, O 333 jig, or 250 jig of SC pDNA. Data represents mean of n=3 ............ 82

4-6. Concentrations of L pDNA after IV bolus administration of: N 2500 pig, A 500 [1g,
333 pjg, or 250 jig of SC pDNA. Data represents mean of n=3 .................. 83

4-7. Superposition of OC pDNA concentrations normalized for dose after administration
of 0: 2500 jig, A: 500 jig, +: 333 jig, or 0:250 jtg dose. Data represents mean
of n=3 I standard deviation .............................................................................. 86

4-8. Concentrations of OC pDNA in the bloodstream after administration of OC pDNA
at a 2500 jig dose. Data represents mean of n=3 1 standard deviation ............. 87

4-9. Concentrations of OC pDNA in the bloodstream after administration of OC pDNA
at a 250 pg dose. Data represents mean of n=3 I standard deviation ............... 88

4-10. Concentrations of L pDNA in the bloodstream after administration of L pDNA at a
2500 jig dose. Data represents averages of n=3 1 standard deviation .............. 91








4-11. Concentrations of L pDNA in the bloodstream after administration of L pDNA at a
250 jag dose. Data represents averages of n=3 1 standard deviation ................ 92

4-12. Area under the curve of OC pDNA after administration of a 2500 jIg dose of SC or
OC pDNA. Data represents mean of n-3 1 standard deviation. Indicates
statistical significance by one way ANOVA (p<0.05) ....................................... 94

4-13. Area under the curve of OC pDNA after administration of a 250 jig dose of SC or
OC pDNA. Data represents mean of n=3 1 standard deviation. Indicates
statistical significance by one way ANOVA (p<0.05) ......................................... 95

4-14. Area under the curve of L pDNA after administration of a 2500 jig dose of SC or
OC pDNA. Data represents mean of n=3 1 standard deviation. Indicates
statistical significance by one way ANOVA (p<0.05) ......................................... 96

4-15. Area under the curve of L pDNA after administration of a 250 jig dose of SC or
OC pDNA. Data represents mean of n=3 1 standard deviation. AUC
differences were not statistically significant by one way ANOVA ...................... 97

5-1. M odel for pDNA clearance from the bloodstream ........................................................ 105

5-2. Concentrations of(A) OC and (B) L pDNA in the bloodstream after 2500 lag dose
of SC pDNA. Data points represent the averages of n=3 1 standard deviation.
Lines represent concentrations predicted by the model ............................................. 108

5-3. Concentrations of(A) OC and (B) L pDNA in the bloodstream after 500 jig dose of
SC pDNA. Data points represent the averages of n=3 1 standard deviation.
Lines represent concentrations predicted by the model ............................................. 109

5-4. Concentrations of(A) OC and (B) L pDNA in the bloodstream after 333 jig dose of
SC pDNA. Data points represent the averages of n=3 1 standard deviation.
Lines represent concentrations predicted by the model ............................................. 110

5-5. Concentrations of (A) OC and (B) L pDNA in the bloodstream after 250 jig dose of
SC pDNA. Data points represent the averages of n=3 1 standard deviation.
Lines represent concentrations predicted by the model ............................................. 111

5-6. Concentrations of OC pDNA in the bloodstream after (A) 2500 jig and (B) 250 jig
dose of OC pDNA. Data points represent the averages of n=3 1 standard
deviation. Lines represent concentrations predicted by the model ........................... 115

5-7. Concentrations of L pDNA in the bloodstream after (A) 2500 jig and (B) 250 jig
dose of OC pDNA. Data points represent the averages of n=3 1 standard
deviation. Lines represent concentrations predicted by the model ........................... 116








5-8. Concentrations of L pDNA in the bloodstream after (A) 2500 jIg and (B) 250 jIg
dose of L pDNA. Data points represent the averages of n=3 1 standard
deviation. Lines represent concentrations predicted by the model ........................... 117

6-1. Liposome-pDNA complexes were incubated in rat plasma for various time points.
10 j.1 of sample was loaded in each lane as described in the methods section.
Lane 1; size standard, lane 2; 1 min, lane 3; 2 min, lane 4; 5 min, lane 5; 10 min,
lane 6; 20 min, lane7; 30 min, lane 8; 60 min, lane9; 2 h, lane 10; 3 h, lane 11; 5.5
h .................................................................................................................................. 13 1

6-2. Agarose gel analysis of liposome/pDNA complexes. (A) 1:1 lipid:pDNA ratio,
through 4 hours. (B) 3:1 lipid:pDNA ratio, through 6 hours. (C) 6:1 lipid:pDNA
ratio, through 6 hours. *Indicates the 3 hour time point ........................................... 132

6-3. Lane 1: high molecular weight size standard, lane 2:1:1 lipid:pDNA complexes,
lane 3: 3:1 lipid:pDNA ratio (w/w), lane 4: 6:1 lipid:pDNA ratio ............................ 133

6-4. (A)Degradation of SC pDNA in rat blood versus plasma. (B)Degradation of
supercoiled pDNA in 3:1 and 6:1 (w/w) liposome/pDNA complexes incubated in
heparinized rat whole blood. Error bars indicate standard deviation of n=3 rats .... 134

6-5. Agarose gel analysis of pDNA after administration of liposome: pDNA complexes.
Lane 1: 15 sec, lane 2: 30 sec, lane 3: 45 sec, lane 4: 1 min, lane 5: 1.5 min, lane
6:2 min, lane 7:2.5 min, lane 8:3 min, lane 9:4 min, lane 10:5 min ..................... 135
6-6. Plasma concentrations of SC, OC, and L pDNA after 500 jig IV bolus

administration of SC pDNA: liposome complexes. Key: *: SC, U: OC, A: L ....... 136

7-1. Schematic representation of pDNA degradation in isolated plasma ............................. 147

7-2. Schematic representation of pDNA pharmacokinetic parameters after IV bolus
adm inistration of SC pDN A in the rat ....................................................................... 154

7-3. Schematic representation of liposome pDNA clearance from the bloodstream. In
this model, removal from the bloodstream of the lipid: pDNA complexes is
assumed to be larger than the degradation of the complex ........................................ 156














Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

PHARMACOKINETICS OF PLASMID DNA

By

Brett E. Houk

May 2000

Chairman: Dr. Jeffrey A. Hughes
Cochairman: Dr. Guenther Hochhaus
Major Department: Pharmaceutics

We sought to construct a complete pharmacokinetic model to describe the

degradation of all three topoforms, supercoiled (SC), open circular (OC), and linear (L),

of pDNA in vivo and in vitro. SC pDNA was incubated in isolated rat plasma at 37C in

vitro. At various time points, the plasma was assayed by electrophoresis for the amounts

of SC, OC, and L pDNA remaining. The calculated amounts remaining were fit to linear

differential equations describing this process. The calculated pharmacokinetic

parameters suggested that SC pDNA degrades in isolated rat plasma with a half-life of

1.2 min, OC pDNA degrades with a half-life of 21 min, and L pDNA degrades with a

half-life of 11 min. Complexation of pDNA with cationic liposomes resulted in a portion

of the supercoiled plasmid remaining detectable through 5.5 h in vitro. We next

investigated the pharmacokinetics of SC plasmid DNA after IV bolus administration in

the rat by following SC, OC, and L pDNA. SC pDNA was detectable in the bloodstream

only after the highest, 2500 tg, dose and had a clearance of 390(10) ml/min and volume








of distribution of 148(26) ml. The pharmacokinetics of OC pDNA exhibited non-linear

characteristics with clearance ranging from 8.3(0.8) to 1.3(0.2) ml/min and a volume

of distribution of 39(19) ml. L pDNA exhibited linear kinetics and was cleared at

7.6(2.3) ml/min with a volume of distribution of 37(17) ml. AUC analysis revealed

60(10) % of the SC was converted to the OC form, and nearly complete conversion of

the OC pDNA to L pDNA. Clearance of SC pDNA was decreased after liposome

complexation to 87(30) ml/min. However, the clearance of OC and L pDNA was

increased relative to naked pDNA at an equivalent dose to 37(9) ml/min and 95(37)

m/min, respectively. We conclude that SC pDNA is rapidly cleared from the circulation.

OC pDNA displays non-linear pharmacokinetics. L pDNA exhibits first order kinetics.

Liposome complexation protects the SC topoform, but the complexes are more rapidly

cleared than the naked pDNA.













CHAPTER 1
INTRODUCTION

Biotechnology is one of the most rapidly growing areas in the pharmaceutical

sciences today. However, biotechnology products (e.g. proteins and peptides) suffer

from poor stability, low absorption, and difficulties in delivery. It would therefore be

ideal if the protein could be made in vivo, utilizing the body's own mechanisms to

produce the competent protein. Gene therapy is one potential route by which to

accomplish this goal. Gene therapy also offers the potential treatment of genetic

diseases. The replacement of mutated, missing, or deleted DNA via gene therapy can

result in the production of a competent protein. These potentials make gene therapy one

of the most exciting and rapidly advancing areas of biotechnology.

Early studies have revealed that systemically administered plasmid DNA (pDNA)

can be expressed in animals (Kawabata et al. 1995; Mahato et al. 1995; Osaka et al. 1996;

Song et al. 1997; Thierry et al. 1997) and humans (Valere 1999). Intravenous (IV)

administration of DNA offers the potential advantage of allowing a wide distribution of

activity in the body (Lew et al. 1995; Thierry 1995; Osaka et al. 1996; Thierry et al.

1997). This route of administration allows the treatment of non-localized and systemic

diseases. Previous research on the pharmacokinetics of non-viral gene therapies have

only been observational citing that plasmid DNA degrades within 5 minutes after

incubation in whole blood in vitro or after IV injection (Kawabata et al. 1995; Thierry et

al. 1997).








Plasmid DNA exists as three major topoforms. The native structure of non-

damaged pDNA is supercoiled (SC). Single strand nicks to the phosphodiester backbone

of pDNA yield an open circular (OC) form (Figure 1-1). This metabolite of SC pDNA is

associated with significant transcriptional activity (-90-100%) (Adami et al. 1998; Niven

et al. 1998). Further single strand nicks to the OC pDNA yield linear (L) pDNA,

associated with a significant loss of activity (-90%). This process is schematically

illustrated in Figure 1-2.

In order to properly dose and achieve the desired levels of gene expression it will

be necessary to understand the pharmacokinetics of pDNA. In initial human clinical

trials with viral gene therapy, at least one study was terminated due to a patient death

(Press 1999). This death was later attributed to the high doses utilized in the trails. Thus,

the pharmacokinetics of pDNA is an essential area to be considered as gene therapy

approaches clinical use.

The Use of Naked pDNA as a Therapeutic Agent

The use of naked pDNA as a drug after intravenous (IV) administration has been

intensely investigated (Wang et al. 1995; Takeshita et al. 1996; Zhang et al. 1997; Budker

et al. 1998; Song et al. 1998; Wang et al. 1998; Witzenbichler et al. 1998; Liu 1999;

Zhang et al. 1999). The use of naked pDNA in vivo was initially reported after

intramuscular (IM) or intradermal (SQ) administration in mammals (Wolff et al. 1991;

Fazio et al. 1994; Katsumi et al. 1994; Bright et al. 1995; Donnelly et al. 1995; Lopez-

Macias et al. 1995; Ulmer et al. 1995; Bright et al. 1996; Corr et al. 1996; Casares et al.

1997; Danko et al. 1997; Lawson et al. 1997; Ragno et al. 1997; Haensler et al. 1999;

Noll et al. 1999; Osorio et al. 1999). These studies have definitively shown efficient

expression of a transgene can be achieved after administration of naked pDNA. The








successes in these studies suggest that pharmacokinetic modeling of pDNA in the

bloodstream after IV administration, or pDNA appearing in the bloodstream after local

administration, is an area that must be more clearly defined in order to optimize gene

therapy for clinical use.

Effectiveness of Naked Plasmid DNA after Local Administration

Fazio and coworkers (Fazio et al. 1994) demonstrated that a transgene could be

efficiently secreted into the circulation after IM administration. Plasma accumulation of

human Apo-E2 was demonstrated for at least 45 days after injection. After

administration of pDNA encoding for an interferon transgene, interferons were detected

from days 7 to 28 post-DNA innoculation (Lawson et al. 1997). Administration of

plasmid DNA encoding the chloramphenicol acetyltransferase gene (CAT) in sterile

water lead to CAT transgene expression that peaked between 1 and 3 days and was

detected up to 28 days after DNA administration. Together these results indicate that

sustained expression can be obtained.

Efficient immunization of monkeys, mice, dogs, and cats has been demonstrated

using naked pDNA (Katsumi et al. 1994; Lopez-Macias et al. 1995; Ulmer et al. 1995;

Bright et al. 1996; Ragno et al. 1997; Haensler et al. 1999; Noll et al. 1999; Osorio et al.

1999). After injection of naked pDNA encoding for influenza hemagglutinin into the

skin of mice and monkeys, induction of significant ELISA antibody titers and

hemagglutination (HA) inhibition titers that were above the usual threshold values

predictive of protection against influenza were demonstrated (Haensler et al. 1999). Mice

immunized by various mucosal routes with a pDNA carrying the HA gene (pVlj- HA)

induced a HA-specific cytotoxic T lymphocyte (CTL) response. Similarly, nasal








immunization with the DNA vaccine induced primary CTLs against measles virus HA

(Etchart et al. 1997).

Plasmid DNA may also serve as an attractive means by which immunization to

parasitic infection may be achieved. After injection of pDNA encoding for heat shock

protein 65, T cell proliferation and antibodies to this protein were found to be elevated in

rats when compared with both an arthritic control and nafve animals (Ragno et al. 1997).

A single immunization with pDNA encoding for Yersinia enterocolitica 60-kDa heat

shock protein (Y- HSP60) was used for vaccination and induced significant Y-HSP60-

specific T cell responses after 1 week (Noll et al. 1999). Induction of antibodies against

Salmonella typhi OmpC porin by naked DNA immunization has also been demonstrated

(Lopez-Macias et al. 1995).

A pDNA expression vector encoding human factor IX as an example of

immunogen was injected into mice three times at 10-day intervals (Katsumi et al. 1994).

This resulted in production of antibodies to human factor IX. Spleen cells from

inoculated mice also showed significant cytotoxic T lymphocyte response to target cells

expressing human factor IX. Thus, IM and SQ injection of pDNA can induce immune

responses against the encoded protein without an exposure to virus particles, and this

approach may serve as the basis for immunotherapy in the treatment of cancer and

infectious diseases in humans.

Plasmid DNA encoding for viral proteins is also an attractive means by which

immunization to viral infection may be achieved. The applicability of pDNA

immunization technology for vaccine development was also investigated by immunizing

dogs and cats by the IM and SQ routes with a pDNA vector encoding the rabies virus








glycoprotein G (Osorio et al. 1999). The results demonstrated that non-facilitated, naked

pDNA vaccines can elicit strong, antigen-specific immune responses in dogs and cats,

and DNA immunization may be a useful tool for future development of novel vaccines

for these species. Plasmid DNA encoding for the large tumor antigen (T- Ag) of SV40

was used to actively immunize mice to assess the induction of SV40 T-Ag-specific

immunity (Bright et al. 1996). Direct injection of the recombinant SV40 T-Ag protein

alone failed to induce SV40 T-Ag-specific CTL responses, whereas the pDNA encoding

SV40 T-Ag elicited CTL activity specific for SV40 T-Ag. Naked pDNA induced

immune responses that were protective against a lethal challenge with SV40-transformed

cells.

Naked pDNA has also been successful in the treatment of cancer by local

administration. Direct intratumoral injection of free pDNA into mouse melanoma BL6

solid tumor can also result in a high level of transfection. The average amount of

chloramphenicol acetyltransferase (CAT) expressed by injecting 30 Ig pDNA containing

a CAT gene into a single BL6 tumor was 1.9 +/- 1.0 ng, which is comparable to that

reported in the skeletal muscle (Yang and Huang 1996). An intratumoral injection of

naked pDNA containing the HSV-TK gene (pAGO) resulted in tumor weight reduction

(40-50%) in treated animals versus control groups. Moreover, histopathological analysis

on tumors showed large areas of cavitary necrosis (85%) in treated groups compared to

controls (10%) (Soubrane et al. 1996). Thus direct injection of free pDNA may offer a

simple and effective approach and might be a potential method for cancer gene therapy.








Effectiveness of Naked Plasmid DNA after IV Administration

Naked pDNA administration by IV injection has also been shown to be an

effective means by which high levels of gene expression can be obtained (Wang et al.

1995; Takeshita et al. 1996; Zhang et al. 1997; Budker et al. 1998; Song et al. 1998;

Wang et al. 1998; Witzenbichler et al. 1998; Liu 1999; Zhang et al. 1999). Budker and

coworkers demonstrated that pDNA can be delivered to and expressed within skeletal

muscle of rats when injected rapidly, in a large volume (2 to 3 ml) (Budker et al. 1998).

Liu and coworkers also showed naked pDNA can be efficiently expressed in mice

(Liu 1999). As high as 45 tg of luciferase protein per gram of liver could be recovered

by a single tail vein injection of 5 ig of naked pDNA. Approximately 45% of

hepatocytes expressed the transgene. Peak expression was obtained at 8 hours after

administration and could be retained with repeated injections.

Efficient naked pDNA expression has been obtained following delivery via the

portal vein, hepatic vein, bile duct or direct IV administration via the tail vein in mice,

rats, and dogs (Zhang et al. 1997; Zhang et al. 1999). The highest levels of expression

were achieved after IV administration by rapidly injecting the pDNA in large volumes,

approximately 2.5 ml. Over 15 jig of luciferase protein/liver was produced in mice and

over 50 gg in rats. Equally high levels of beta-galactosidase (beta-Gal) expression were

obtained, in over 5% of the hepatocytes that had intense blue staining. Expression of

luciferase or beta-Gal was evenly distributed in hepatocytes throughout the entire liver

when either of the three routes were injected. Peri-acinar hepatocytes were preferentially

transfected when the portal vein was injected in rats. These levels of foreign gene

expression are among the highest levels obtained with nonviral vectors. Repetitive








pDNA administration through the bile duct led to sustianed foreign gene expression.

This study demonstrates that high levels of pDNA expression in hepatocytes can be

easily obtained by IV injection.

Takeshita and coworkers (Takeshita et al. 1996) investigated the hypothesis that

naked pDNA encoding for vascular endothelial growth factor (VEGF) could be used in a

strategy of arterial gene therapy to stimulate collateral artery development. Plasmid

DNA encoding each of the three principle human VEGF isoforms (phVEGF121,

phVEGF165, or phVEGF189) was applied to the hydrogel polymer coating of an

angioplasty balloon and delivered percutaneously to one iliac artery of rabbits with

operatively induced hindlimb ischemia. Compared with control animals transfected with

LacZ, site-specific transfection of phVEGF resulted in augmented collateral vessel

development documented by serial angiography, improvement in calf blood pressure

ratio (ischemic to normal limb), resting and maximum blood flow, and capillary to

myocyte ratio (suggesting increased vascularization). Similar results were obtained with

phVEGF121, phVEGF165, and phVEGF189. This suggests that these isoforms are

biologically equivalent with respect to in vivo angiogenesis. The potential for VEGF-C

to promote angiogenesis in vivo was then tested in a rabbit ischemic hindlimb model

(Witzenbichler et al. 1998). Ten days after ligation of the external iliac artery, VEGF-C

was administered as naked pDNA (pcVEGF-C; 500 [ig) from the polymer coating of an

angioplasty balloon or as recombinant human protein (rhVEGF-C; 500 [tg) by direct

intra-arterial infusion. Physiological and anatomical assessments of angiogenesis 30 days

later showed evidence of therapeutic angiogenesis for both pcVEGF-C and rhVEGF-C.

Hindlimb blood pressure ratio (ischemic/normal) after pcVEGF-C increased after








pcVEGF-C versus controls and after rhVEGF-C versus control rabbits receiving rabbit

serum albumin. Doppler- derived iliac flow reserve was increased for pcVEGF-C versus

controls and increased for rhVEGF-C versus albumin controls. Neovascularity was

documented by angiography in vivo after administration of pcVEGF-C and capillary

density was measured at necropsy increased. Arterial gene transfer of naked pDNA

encoding for a secreted angiogenic cytokine, thus, represents a potential alternative to

recombinant protein administration for stimulating collateral vessel development.

Naked pDNA constructs encoding for the human kallikrein protein delivered to

spontaneously hypertensive rats via IV injection have been shown to be efficient at

controlling hypertension (Wang et al. 1995). The expression of human tissue kallikrein in

rats was identified in the heart, lung, and kidney by reverse transcription polymerase

chain reaction followed by Southern blot analysis and an ELISA specific for human

tissue kallikrein. A single injection of both human kallikrein pDNA constructs caused a

sustained reduction of blood pressure, which began 1 week after injection and continued

for 6 weeks. A maximal effect of blood pressure reduction of 46 mm Hg in rats was

observed 2-3 weeks after injection with kallikrein pDNA as compared to rats with vector

pDNA. These results show that direct gene delivery of human tissue kallikrein causes a

sustained reduction in systolic blood pressure in genetically hypertensive rats and

indicate that the feasibility of kallikrein gene therapy for treating human hypertension

should be studied.

Collectively, these results suggest that IV administration of naked pDNA is an

attractive means to treat a large range of diseases. However, complete pharmacodynamic

modeling of pDNA will has not been achieved. This will allow correlation of the








administered dose with the desired levels of gene expression at the site of activity.

Because of the plasmids high molecular weight, anatomical factors must be considered in

the movement of these molecules within the body.

Anatomical Factors Potentially Involved in the Pharmacokinetics of Plasmid DNA

Plasmid DNA is a macromolecule having a molecular weight of 3.5 million for a

typical plasmid of 5.5 kilobase pairs. This large molecular weight results in an increased

likelihood of clearance processes being a function of size and its resulting abitily to pass

through capillary endothelia. After IV administration, distribution of macromolecules is

limited by the structure of the vascular endothelium. The structure of capillaries is

diverse among organs. There are 3 main types of blood capillaries: continuous,

fenestrated, and discontinuous (Hwang et al. 1997; Takakura et al. 1996).

These 3 types of capillaries are represented in Figures 1-3, 1-4, and 1-5. The

diameter of the free plasmid varies from between 8 to 22 rum (Yarmola 1985). The

passage of pDNA through a continuous capillary would be limited to the 50 nm

pinocytotic vesicles, 2 to 6 nm intracellular junctions, and 50 nm transendothelial

channels (Figure 1-3) (Hwang et al. 1997). The basal lamina presents a barrier of

collagen, glycoproteins, and fibronectin, macromolecules greater than 11 Im can be

retained by the basal lamina. Thus, this may present a barrier for diffusion of the plasmid

(Hwang et al. 1997). Continuous capillaries are the most widely distributed in

mammalian tissue and are found in skeletal, cardiac, and smooth muscles, as well as lung,

skin, subcutaneous tissues, serous membranes, and mucus membranes (Takakura et al.

1996).











































Figure 1-1. Potential sights for nicking of the phosphodiester backbone of DNA.

























Endonuclease action: Endonuclease action:
Single strand nick to Single strand nick
the plasmid adjacent to previous


Endonuclease or
exonuclease action


Figure 1-2. Model of plasmid DNA degradation in the bloodstream.


10'





















0
50 nm


2
2-6 nm


0
50 nm


---I


Figure 1-3. Schematic representation of pDNA (.) passing through a continuous
capillary: (1) pinocytosis, (2) through intercellular junctions, and (3) passing through
endothelial channels.





















50 nm


40-60 nm


40-60 nm


S S


Figure 1-4. Schematic representation of pDNA (.) passing through a fenestrated
capillary: (1) pinocytosis, (2) passing through a diaphragm fenestrae, and (3) passing
through and open fenestrae.


-j


















1


50 nm


2

0
10'-10' nm


Figure 1-5. Schematic representation of pDNA (.) passing through a discontinuous
capillary. (1) pinocytosis and (2) passing through large pores in the endothelium.


F---










Fenestrated capillaries (Figure 1-4) are more likely to allow passage of pDNA

into tissues. The pDNA may be transported through mechanisms similar to those

involved in the continuous capillary, in addition to transport through 20 to 60 ram

fenestrae (Hwang et al. 1997; Takakura et al. 1996). These fenestrae may or may not be

closed by a diaphragm. The diameter of the closed diaphragm has not been reported.

This type of capillary is generally found in the intestinal mucosa, endocrine glands,

exocrine glands, glomerulus, and peritubular capillaries (Takakura et al. 1996).

Discontinuous capillaries are characterized by endothelial gaps and large pores

with diameters ranging from 100 to 1000 nm (Figure 1-5) (Hwang et al. 1997; Takakura

et al. 1996). In these capillaries there is little restriction of diffusion of macromolecules.

Another characteristic of this type of capillary is the lack of a basal lamina (Hwang et al.

1997). The mucopolysaccharide rich interstitial Spaces of Disse have pore diameters

ranging from 36 to 50 nrm and are unlikely to present a major barrier for the transport of

pDNA. The discontinuous capillary is more limited in its distribution than the other

types and is found only in the liver, spleen, and bone marrow (Takakura et al. 1996).

These anatomical features can play an important role in the distribution of IV

administered pDNA, and other macromolecules. In addition, capillary permeability can

be further enhanced in pathophysiological states such as cancer and inflammation

(Takakura et al. 1996). Thus the fate of IV administered pDNA is determined not only

by physio-chemical properties such as molecular weight, but also by anatomical features

of the capillary endothelium present in each tissue.








Degradation of pDNA in the Bloodstream

Early studies suggested that serum nucleases play a major role in the clearance of

DNA from the bloodstream of injected animals (Gosse et al. 1965). Investigations by

Chused and coworkers suggested that nucleases may not play a major role in the

degradation of tritiated KB cell genomic DNA when IV injected in mice (Chused 1972).

However, their assay was not able to identify the true activity of nucleases given that

their assay utilized genomic DNA. Single strand cuts to the isolated genomic DNA

would not yield small fragments and would be undetectable by their method. This would

yield an underestimation of true nuclease activity. In contrast, single strand cuts to

pDNA would lead to a degradation of the native SC structure to the OC form of the

plasmid and be detectable by agarose gel analysis.

Nucleases represent two subclasses of enzymes, endonucleases and exonucleases.

Endonucleases act on the phosophodiester backbone of DNA in a continuous chain

(Lodish 1995). Whereas, endonucleases act upon the free end (5' or 3') of the

phosphodiester backbone in a linear segment of DNA. Investigations by Thierry and

coworkers, utilizing agarose gel analysis, suggested that the main nuclease activity in the

bloodstream was endonucleolytic. This was based on the finding that the linear to

supercoiled ratio increased with time and the SC: OC ratio remained identical to control

(Thierry et al. 1997). However this view fails to recognize endonucleolytic activity on

linear pDNA also generates degradation products. If endonuclease activity is the primary

route of degradation, the kinetic ratios should all remain similar, owing to the fact that

exonuclease activity would be masked by endonuclease activity. The pharmacokinetics

of this degradation remain to be determined and may serve as a valuable tool in the

understanding of the mechanisms of pDNA degradation observed in the bloodstream.








Pharmacokinetics of Liposomal Delivery Vehicles

Although few studies are available on the pharmacokinetics of liposome:pDNA

complexes, liposomal pharmacokinetics alone have been studied extensively with several

reviews published (Hwang et al. 1997; Juliano 1988; Takakura et al. 1996). Liposome

pharmacokinetics have been shown to be dependent upon size (Sato 1986), dose

(Bosworth 1982; Osaka et al. 1996), lipid composition (Gabizon 1988), and charge

(Juliano 1988). In general, liposomes larger than 60 nm in diameter are unable to access

tissues having continuous capillary endothelia, including skeletal, cardiac, and smooth

muscle, lung, skin, subcutaneous tissue, and serous and mucous membranes, and are

limited to uptake in tissues of the reticuloendothelial system (Hwang et al. 1997).

Liposomes larger than 0.5 p.m are confined to the vasculature in all tissues.

Pharmacokinetics of Naked Plasmid DNA and Liposome: Plasmid DNA Complexes

After systemic administration of pDNA alone or as liposome:pDNA complexes,

DNA rapidly disappears from the bloodstream. The processes responsible involve

degradation in the blood stream, interaction with plasma proteins, organ distribution, and

uptake by the reticuloendothelial system. The transport of DNA and liposome:pDNA

complexes into organs is roughly a unidirectional system, where distribution back into

the central compartment can be assumed to be negligible (Mahato et al. 1997).

Pharmacokinetics of Naked Plasmid DNA in the Blood after IV Injection

Plasma levels of pDNA may be measured using radiolabeled DNA or agarose gel

analysis (Kawabata et al. 1995; Lew et al. 1995; Mahato et al. 1995; Osaka et al. 1996;

Thierry et al. 1997). Using agarose gel analysis, Thierry and coworkers found that SC

plasmid DNA is not detectable in either murine plasma or cell fractions 1 minute after

injection of naked plasmid DNA in mice (Thierry et al. 1997). OC and L forms have








been detected through 30 minutes post-injection by Southern blot analysis (Lew et al.

1995). The half-life of intact (OC or L) plasmid DNA is less than 5 minutes. Degraded

plasmid fragments remain detectable in the blood at 30 minutes post injection. By 60

minutes even degraded plasmid is cleared. This elimination has been shown to be

independent of the DNA sequence (Lew et al. 1995).

When plasmid DNA was administered to mice in the form of liposome:pDNA

complexes, SC DNA was detected in the blood between 1 and 60 minutes after injection

(Thierry et al. 1997). OC DNA degrades with a half-life of approximately 10 to 20

minutes. Uptake of pDNA in blood cells reaches a maximum as early as 1 minute after

injection of liposome:pDNA complexes.

A major problem associated with these studies is that the analysis of samples was

done only qualitatively. No attempt was made to quantitate the amounts and types of

plasmid present in the bloodstream at various times. This information is critical for an

evaluation of the predictive value of pharmacokinetic parameters associated with gene

delivery.

Quantitative analysis of gene delivery has been done using IV injected

radiolabeled pDNA, [32p] or [33P], in mice. In these studies, the half-life of naked pDNA

is approximately 10 minutes (Kawabata et al. 1995; Osaka et al. 1996). The total plasma

radioactivity displays a degradation pattern consistent with a two compartment body

model (Mahato et al. 1995). Total body clearance of naked pDNA is estimated at 102

ml/hr, and plasma AUC is estimated at 0.98 (% of dose*hr/ml). Urinary radioactivity

increases with time, indicating the degradation products are excreted via the kidney.

Similar results were obtained following injection of radiolabeled liposome:pDNA








complexes with AUC's of 0.57 to 0.7 (% dose*hr/ml) and total clearance ranging from

175.8 to 142.7 (ml/hr) (Mahato et al. 1995). Half-life for radiolabeled pDNA:

dimethyldioctadecylammonium bromide: dioleoylphosphatidylethanolamine complexes

was shorter ranging from 4 to 8 minutes (Osaka et al. 1996) suggesting rapid tissue

entrapment of the liposome:pDNA complexes relative to naked plasmid. Twenty-four

hours after injection, blood cell and plasma radioactivity for naked pDNA and

liposome:pDNA complexes were similar (Osaka et al. 1996).

Between these 3 analysis methods (agarose gel, Southern blotting, and

radiolabeling) agarose gel analysis can determine more detailed information on the

degradation of different structures of plasmid, (SC, OC, and L). This method is easy to

apply and can be done under normal conditions without the limitations associated with

radioactivity. The disadvantage of this method is that it is traditionally a semi-

quantitative method. The advantage of the [33P] and [32P] methods is that these are

quantitative methods and are more sensitive than agarose gel analysis. The disadvantages

are that radiolabeling yields OC pDNA and thus, this method gives no information on the

pharmacokinetics of SC pDNA. OC plasmid can also not be differentiated from L

pDNA. The radioactivity is also counted without discriminating the degraded DNA

fragments or the free label. Furthermore, special conditions and precautions are needed

to handle radioactive materials. The difference between [32p] and [33p] is that [33P] has

less personal danger and offers greater ease of handling than [32p] (Song et al. 1997;

Niven et al. 1998).

Overall, when pDNA is injected in mice, SC pDNA has not been detected when

administered as naked pDNA, but is after the injection of liposome:pDNA complexes.








After administration as naked pDNA, OC and L pDNA degrades with a half-life of

between 5 and 10 minutes. The half-life of OC or L pDNA after administration of

liposome:pDNA complexes ranges from 4 to 20 minutes. OC pDNA is available for

transcription if taken up by cells. (Adami et al. 1998; Niven et al. 1998) Thus,

administering pDNA in the form of liposome:pDNA complexes may offer a slight

increase in the availability of IV administered pDNA.

Distribution of Plasmid DNA in Tissues after IV In-jection

Tissue distribution of pDNA may be measured using radioactivity, Southern

analysis, or whole body autoradiography. Using Southern analysis, pDNA has been

detected in the bone marrow, heart, kidney, liver, lung, spleen, and muscle as early as I

hour after injection (Lew et al. 1995; Niven et al. 1998). No plasmid was detectable in

the brain, intestine, and ovaries.

Sub-picogram levels may be detected using polymerase chain reaction (PCR).

Using this method, Lew and coworkers showed that at 7 days after IV injection, the range

of residual plasmid was 1 fg/tg in the brain, intestine, and gonads, and was 64 fg/ptg in

the marrow, heart, liver, spleen, and muscle (translating to approximately 250-16,000

copies/genome (Lew et al. 1995). By 28 days post-injection, levels of detectable plasmid

had decreased 128 fold. Using PCR, residual plasmid remained detectable 6 months post

injection at 2 to 8 fg/lag genomic DNA and was predominantly in the muscle.

After injection of radiolabeled plasmid, distribution may be measured by isolating

tissues and measuring homogenates in a scintillation counter (Kawabata et al. 1995;

Mahato et al. 1995). Alternatively, the entire carcass may be measured by whole body

sectioning and autoradiography (Osaka et al. 1996; Niven et al. 1998).








After injection of radiolabeled naked pDNA, accumulation of radioactivity occurs

initially in the lung, but declines rapidly through 1 minute post-injection (Kawabata et al.

1995). Osaka and coworkers found that by 2 minutes after injection of naked pDNA,

organ distribution is liver>spleen>lung, blood (Osaka et al. 1996). Whereas, Niven and

coworkers found the time to reach maximum levels in the lungs is as long as 5 minutes

versus 2 hours in the liver (Niven et al. 1998). Thus, there appears to be an initial rapid

entrapment and transient accumulation in the lungs with accumulation occurring in the

liver after a short period of time. Plasmid DNA was preferentially recovered in the non-

parenchymal cells in the liver suggesting that the liver is acting in a scavenger role in

uptake (Kawabata et al. 1995).

When compared to naked pDNA, IV injection of liposome:pDNA complexes

shows a higher accumulation of radioactivity in the lung 2 minutes after injection, Osaka

and coworkers showed the major organs exhibit a distribution of

lung>liver>spleen>kidney (Osaka et al. 1996). One hour after injection, a slight rise is

seen in most organs, which is probably related to continuous uptake by the

reticuloendothelial system. By 24 hours after injection of liposome:pDNA complexes,

lung radioactivity dropped approximately 70 fold, with a distribution in major organs of

spleen>liver>lung, kidney.

Conclusions

A complete understanding of the classical pharmacokinetic parameters of gene

delivery is necessary to move genetic agents forward as clinical therapeutics. Problems

include the rapid clearance of naked pDNA and liposome:pDNA complexes without

expression of the gene products, poor target tissue specificity, and degradation in the

plasma. After systemic administration in mice, plasmid DNA is rapidly eliminated from





22


the circulation by extensive uptake by the reticuloendothelial system and degradation by

plasma nucleases. Hepatic uptake is almost identical to liver blood flow suggesting

highly efficient uptake. A complete pharmacokinetic model of all 3 forms of plasmid

DNA (SC, OC, and L) has not been proposed. As the products of the biotechnology

industry begin to move towards more clinical applications, the pharmacokinetic modeling

of gene delivery will likely become an intensely investigated area.













CHAPTER 2
PHARMACOKINETICS OF PLASMID DNA IN ISOLATED RAT PLASMA

Introduction

In vivo delivery of plasmid DNA (pDNA) encoding for therapeutic proteins to

patients via parenteral administration is an attractive means by which to target the gene to

a wide variety of tissues. Early studies revealed that endogenous enzymes present in the

plasma play a role in the clearance of nucleotides from the bloodstream (Chused 1972;

Whaley 1972; Chia 1979; Piva 1998). These early studies have displayed that pDNA

incubated in the presence of 10 % fetal bovine serum shows initial degradation by 15 min

and is completely degraded by 60 min (Piva 1998). Similar results have been displayed

in the presence of 90% human serum (Piva 1998).

Nucleases will convert the native supercoiled (SC) pDNA topoform to the open

circular (OC) and linear (L) forms of the plasmid (Lodish 1995). Changes in topoform

have been associated with alterations in transcriptional activity. The significance of this

change has been the matter of some debate. For example, the OC form of the plasmid

has been shown to express similar levels of chloramphenicol acetyl transferase and

luciferase proteins (Adami et al. 1998; Niven et al. 1998) to 2 to 4 times less (Hirose

1993; Cherng 1999; Ramsey 1999) levels of transcribed luciferase and lac-Z, proteins.

Increases in the amount of supercoiling serves to further increase the percent maximal

transcription (Ramsey 1999). Furthermore, the time required for formation of the

transcription preinitiation complex has been shown to be decreased with a SC template

(Hirose 1993). Degradation to the L form of pDNA is associated with significant losses








in transcriptional activity (90-100%) (Hirose 1993; Adami et al. 1998; Niven et al. 1998;

Cherng 1999; Ramsey 1999). Differences in transcriptional activity may need to be

accounted for in future pharamcodynamic studies.

Early studies revealed that serum nucleases play a role in the rapid clearance of

genomic DNA from the circulation of injected animals (Gosse et al. 1965). Recent

studies on the pharmacokinetics of pDNA have attempted to use radiolabeled pDNA for

detection (Osaka et al. 1996; Niven et al. 1998). However, the radiolabeling procedure

involves nick translation, thereby eliminating the possibility of maintaining the SC

topoform. Furthermore, this method does not discriminate the degraded pDNA from the

intact plasmid, thus yielding an overestimation of the true half-life of the intact pDNA.

Other studies on the pharmacokinetics of SC and OC pDNA have been only qualitative

citing the presence of pDNA topoforms at various time points (Kawabata et al. 1995;

Osaka et al. 1996; Thierry et al. 1997).

Thierry and coworkers studied the stability of pDNA in the bloodstream of mice

after IV injection (Thierry et al. 1997). Their results indicated that SC plasmid was not

detectable in the plasma or red blood cell fractions 1 min after injection of pDNA. The

true half-life was unable to be calculated using their method due to this rapid degradation.

Kawabata and coworkers found that the SC pDNA was completely converted to the OC

topoform within 5 min when incubated in mouse whole blood (Kawabata et al. 1995).

Little other information on the pharmacokinetics of pDNA is available. The exact

pharmacokinetics underlying this rapid degradative process is not fully understood. To

properly dose and reach the desired therapeutic endpoints, a thorough understanding of

the pharmacokinetics of pDNA is a necessity.








It is necessary to study the effects of plasma on pDNA in order to begin

understanding the importance of the degradation of pDNA in the blood and allow a

foundation upon which comparisons of delivery vehicles can be made. Naked pDNA has

been shown to remain in the plasma fraction of blood (Osaka et al. 1996). For these

reasons, we sought to investigate the pharmacokinetic processes underlying the stability

of pDNA in a rat plasma model. We further sought to construct a complete

pharmacokinetic model to describe the degradation of all three topoforms of pDNA in

plasma. This model will allow a prediction of the time course of potential tissue

exposure to the transcriptionally active SC and OC pDNA topoforms.

Methods

Phenol: chloroform: isoamyl alcohol (25: 24: 1, v/v/v), Tris, boric acid, EDTA,

and agarose were purchased from Sigma Chemical Company (St. Louis, MO). Ethidium

bromide (electrophoresis grade) was purchased from Fisher Biotech (Fair Lawn, NJ).

Competent JM 109 bacteria (Promega, Madison, WI) were transformed according to the

manufacturers directions with the pGL3 control plasmid (Promega, Madison, WI),

pGeneMax-Luciferase (Gene Therapy Systems, San Francisco, CA) or pGE 150 plasmid

(a generous gift of Dr. G. Elliot, Marie Curie Research Institute, The Chart, Oxted,

Surrey, UK). Representative plasmid maps are presented in Figures 2-1, 2-2, and 2-3 for

the pGL3, pGeneMax-Luciferase, and pGE150 plasmids, respectively. Plasmid DNA

was isolated from overnight cultures using the Plasmid Maxi-Prep kit (Quiagen,

Valencia, CA), and was >95% SC by agarose gel analysis.

Blood was isolated from male Sprague-Dawley rats (300-350 g) by cardiac

puncture, and immediately placed in heparinized test tubes (Vacutainer, Becton
















































Figure 2-1. Plasmid map of pGL3 Control.












































Figure 2-2. Plasmid map of the pGeneMax-Luciferase.














































Figure 2-3. Plasmid map ofpGE150.








Dickinson, Franklin Lakes, NJ) on ice at the times indicated. Blood samples were

centrifuged at 6,000 g for 5 min. For dilution experiments, plasma was diluted to 25 and

50% with PBS or PBS containing 0.1 mM EDTA. To analyze the effects of heat, plasma

samples were incubated at 90'C for 10 min in sealed tubes before assay. Plasma (600 p)

was removed and placed on ice until assay. Plasma samples were warmed to 370 C in a

water bath and maintained at 370 C for the duration of the experiment. Plasmid DNA (12

tl/17 jtg) in TE buffer was incubated in the 370 C plasma and 50 p.1 samples were taken

at various times. Phenol: chloroform: isoamyl alcohol (25: 24: 1, v/v/v) (80 p1) was

immediately added to each sample, vortexed for 5 s at low speed, and placed on ice.

Samples were centrifuged at 20,800 x g for 10 min at room temperature. From the

supernatant, an aliquot of 15 p.1 was removed, 5 p.l of 6 x loading dye (Promega,

Madison, WI) added and placed on ice until loaded on an agarose gel.

Samples were loaded on 0.8% agarose in 0.9 M Tris-Borate and 1 mM EDTA

gels containing 0.001% ethidium bromide. Electrophoresis was carried out at 0.30 V/cm3

for 12 h. The ethidium bromide was excited on a UV light box (Model TFX-35M, Life

Technologies, Grand Island, NY) and the net fluorescence intensity captured at 590 nm

on a Kodak DC120 digital camera (Eastman Kodak, Rochester, NY). The amounts of

SC, OC, and L pDNA were calculated using Kodak Digital Science 1D Image Analysis

Software (version 3.0, Eastman Kodak Company, Rochester NY) with a Lambda Hind III

digest (Promega, Madison WI) and a High DNA Mass Ladder (Life Technologies, Grand

Island, NY) as external standards. Accuracy was 96 to 104% for SC pDNA, 98 to 108%

for OC, and 96 to 113% for L pDNA. Percent coefficient of variation was < 5%, 19%,

and 13% for SC, OC and L forms of the plasmid respectively. Standard curves for all








three forms of the plasmid (Figures 2-4, 2-5, and 2-6) were linear between 10 and 250 ng

pDNA bands (R2 = 0.9995, 0.9985, and 0.9933 for SC, OC, and L respectively). All

reported concentrations were calculated from bands within the range of the standard

curves. Lower limit of quantitation was 0.5 ng4. for all three forms of the plasmid.

Lower limit of detection was 0.25 ng/tl for all three forms of the plasmid. Method

parameters are summarized in Table 2-1. Comparisons of the relative fluorescence of SC

pDNA versus OC and L pDNA were made by analyzing equivalent amounts as described

above and comparing the resulting fluorescence. It was found that on a weight to weight

ratio, SC pDNA was only 59% as fluorescent relative to L pDNA by agarose gel analysis.

To correct for this difference, SC pDNA amounts were multiplied by 1.7 prior to

analysis. This difference has been reported previously and is likely due to the relative

inaccessibility of ethidium bromide to the SC topology (Cantor 1980). Percent recovery

using the phenol: chloroform: isoamyl alcohol method was found not to be dependent on

topoform. Recovery was 90 ( 6) % for SC and 86 ( 13) % for L pDNA. Comparisons

of the relative fluorescence of SC pDNA versus L pDNA were made by digesting SC

pDNA with the Hind III restriction enzyme (Promega, Madison, WI) which has a single

recognition site in the plasmid. Equivalent amounts of L and SC pDNA were then loaded

on agarose gels as described above and the relative fluorescence compared. Percent

recovery was calculated by comparing phenol: chloroform: isoamyl alcohol (25: 24: 1,

v/v/v) extracted versus non-extracted known amounts and analyzing on agarose gels as

described above.

















300


250


200



JIOO

100-


50


0 fI I
0 50 100 150 200 250
A260 DNA equivalents



Figure 2-4. Standard curve for supercoiled pDNA. Abcissa represents total ng estimated
by UV absorbance at 260 nm. Ordinate represents ng calculated by the KDS ID
software. Error bars represent 1 standard deviation.





















300


250-
R2 =0.9985

200


150
U




50



0-
0 50 100 150 200 250
A260 DNA Equivalents






Figure 2-5. Standard curve for OC pDNA. Abcissa represents total ng estimated by UV
absorbance at 260 nm. Ordinate represents ng calculated by the KDS ID software. Error
bars represent 1 standard deviation.

















300



250



200


150


R2 = 0.9933


100



50


0
0.I I I I I
0 50 100 150 200 250
A260 DNA equivalents




Figure 2-6. Standard curve for Linear pDNA. Abcissa represents total ng estimated by
UV absorbance at 260 nm. Ordinate represents ng calculated by the KDS ID software.
Error bars represent 1 standard deviation.


















Table 2-1. Method parameters for pDNA analysis.


Accuracy Supercoiled: 94-101 %
Open Circular: 98-108 %
Linear: 96-113 %
Precision Supercoled: 5 %
Open Cicular: 19 %
Linear: 13 %
Lower Limit of Quantitation 0.5 ng/pt
Lower Limit of Detection 0.25 ng/gl
Recovery from Plasma Supercoiled: 90 (6) %
Linear: 86 (13) %










Theoretical

The degradation of SC pDNA was assumed to follow pseudo first-order kinetics.

The model used is diagrammed in Figure 2-7. In this model, pDNA degradation is

considered to be a unidirectional process. The degradation of L pDNA is considered to

yield fragments of heterogeneous lengths, thus these products were not included in the

fitted model. No elimination from any of the compartments is assumed to occur through

routes other than degradation to the following topoform.

Based on this model the following differential equations were derived to describe

the process:


dSC k *SC
dt
dOC
-ks SC kOC
dt
= k OC- k, L
dt
The amounts of supercoiled, open circular and linear pDNA were then fit to the

integrated form of the equations:


SC = SCo e- .
o c = k,. SC o .( ,', .e -k.-, + I e-k ,t
Lo= k, SCo C(,.( 1 k.., + I .e-k, t +e-kt
-( k o(k,- ko e +ko ) (k,-kXk,-k,) (k.-kXk,-k, )
Where SC, OC, and L are the amounts of supercoiled, open circular, and linear pDNA

present at time--t, respectively. SCo is the amount of supercoiled pDNA present at time

(t)=O. The constants k, ,k,, and k, represent the rate constants for the degradation of SC,

OC, and L pDNA respectively. The constants represent the activity of all enzymes acting

in the degradation process. Non-linear curve fitting and goodness of fit, model selection








criteria (MSC) assessment was carried out using Scientist (version 4.0, Micromath, Salt

Lake City, UT) (MicroMath 1995). Area under the plasma concentration time curve

(AUC) was calculated using trapezoidal rule. Area under the terminal portion of the

plasma concentration time curve, AUCterm, was calculated by integration using the

equation:


AUT C -cast
AU'term- k
Where Cast is the last concentration point measured and k is the terminal elimination rate

constant. Clearance (Cl) was calculated from the volume (V) of rat plasma (7.8 ml) and

the terminal elimination rate constant (k) using the equation (Davies 1993):



Cl- V-k


Statistical analysis was performed using SAS (The SAS Institute, Cary, NC).

Results

For quantitative purposes, the relative fluorescence of SC pDNA was compared to

that of OC and L pDNA. It was found that on a weight to weight ratio, SC pDNA was

only 59% as fluorescent relative to L pDNA by agarose gel analysis. To correct for this

difference, SC pDNA amounts were multiplied by 1.7 prior to analysis. This difference

has been reported previously, and is likely due to the relative inaccessibility of ethidium

bromide to the SC topology (Cantor 1980). Percent recovery using the phenol:

chloroform: isoamyl alcohol method was found not to be dependent on topoform.

Recovery was 90 (6) % for SC and 86 (13) % for L pDNA.





















is iks [ko
sc oc OC___ > Linear



Figure 2-7. Pharmacokinetic model of plasmid DNA degradation in rat plasma. The
model is considered to be a unidirectional process. SC, OC, and L represent the amounts
of supercoiled, open circular, and linear plasmid, respectively, in each compartment. The
rate constants ks, k,, and k, represent the degradation constants for supercoiled, open
circular, and linear plasmid, respectively.










Figure 2-8 displays a representative gel in which the degradation of SC pDNA

and the appearance of OC and L topoforms of plasmid is observed. In addition, the

degradation products of L pDNA are visible as a light smear running below the band at

60 min. Under the conditions used in this experiment, limit of quantification was 0.5

ng/ d using the Lambda Hind III size standard. Plasmid amounts were calculated from

agarose gel analysis using Kodak Digital Science 1D image analysis software (Eastman

Kodak, Rochester, NY) as described in the methods section. The observed and predicted

values, based on the model displayed in Figure 2-8, are plotted in Figure 2-9. Plasmid

concentrations were well described the model, MSC=3.0. Pharmacokinetic parameters

calculated based on the model are summarized in Table 2-2. SC pDNA degraded rapidly

in the plasma with a half-life of 1.2 ( 0.1) min. OC plasmid however was fairly stable,

degrading with a half-life of 21 ( 1) min. L plasmid degraded more rapidly than the OC

topoform but was fairly stable, in comparison to the SC plasmid degrading with a half-

life of 11 ( 2) min. OC AUC was nearly 17 times larger than SC, and 2.3 times larger

than L pDNA (Table 2-3).

No kinetics suggestive of enzyme saturation were observed under the

experimental conditions tested. However, to ensure that saturation of plasma nucleases

was not resulting in artificially low rate constant values, we analyzed the rate constants

produced in dilute plasma (dilution was chosen as decreasing the dose of pDNA quickly

results in a loss of sensitivity and sample sizes too large for loading). If saturation of


















1 2 3 4 5 6 7 8 9 10 11 12


Oc

Linear


Figure 2-8. Agarose gel analysis of pDNA degradation in isolated rat plasma. Lane 1;
size standard, lane 2; 30 sec, lane 3; 1 min, lane 4; 2 min, lane 5; 3 min, lane 6; 5 min,
lane 7; 10 min, lane 8; 20 min, lane 9; 30 min, lane 10; 45 min, lane 11; 60 min, lane 12;
80 min.






40

















15.0- I


12.5-


10.0

tM 7.5 --
5.o5
z
0. 5.0-


2.5-


0.0-
0 10 20 30 40 50 60

time (min)
Figure 2-9. Experimental and fitted data based on the pharmacokinetic model described
in the text. Data points represent actual experimental data. Lines represent values
predicted by the model. Data represents mean of n=3 1 standard deviation. Key: U
supercoiled, open circular, A linear.

















Table 2-2. Pharmacokinetic parameters for pDNA in isolated rat plasma


Topoform Rate Value (min') Standard Half-life (min)
constant Deviation
Supercoiled k, 0.6 0.03 1.2 0.1)

Open circular k, 0.03 0.002 21 (+ 1)

Linear k, 0.06 0.008 11 (2)

Data represent the fitted values of n=6 1 standard deviation.


















Table 2-3. Noncompartmental parameters for pDNA after incubation in isolated plasma.


Topoform AUC (ng/ l*min) Clearance
( I/min)
Supercoiled 18 360 (+ 9)
Open circular 310 23 (+ 1)
Linear 130 47 (5)

Data represent n=6 standard deviation. AUC was calculated from the model fitted
values using trapezoidal rule as described in the methods section. Clearance was
calculated from the fitted rate constants and volume of rat plasma as described in the
Methods section.










plasma nucleases was occurring, we expected that the rate constants in dilute plasma

should deviate from a linear relationship negatively. Thus we tested the kinetics of

pDNA degradation in 25% and 50% plasma. As displayed in Figure 2-10, no deviation

was observed in the degradation of SC and OC pDNA.

To further investigate the mechanism responsible for the observed degradation,

and further validate our assay (to ensure the assay was not causing degradation itself) we

studied the degradation of pDNA in PBS diluted 25% heated plasma (90'C for 10 min)

and PBS containing 0.1 mM EDTA. No degradation of SC pDNA was observed in either

case through 1 hr (Figure 2-11). The degradation sensitivity to heat and EDTA provides

evidence that the degradation observed in the assay is due to enzymatic processes.

We next sought to determine if the degradation observed in the previous

experiments was dependent upon pDNA sequence. We, therefore, utilized the same

model diagrammed above and replaced the pGL3 plasmid with the pGE150 plasmid.

Unlike the pGL3 plasmid, which encodes for the luciferase protein and has an SV40

promoter, this plasmid encodes for the green fluorescent protein and includes a CMV

promoter. If the degradation of pDNA in the plasma was sequence dependent, we

expected the degradation rate constants observed to differ from those observed in the

previous experiment. A comparison of plasma concentrations of OC and L pDNA is

presented in Figures 2-12 and 2-13. The resulting rate constants are presented in Table 4.

Again the model diagrammed in Figure 2-7 described the data (model selection

criteria = 3.1, R2=0.96, 0.99, and 0.92 for SC, OC, and L respectively). To determine if




















y = 0.6494x- 0.0311
R2 = 0.9361 .o


y = 0.0415x 0.0082
R2 = 0.9962


*Ks
=Ko






1.2


% plasma


Figure 2-10. Analysis of rate constants in dilute plasma. Degradation rate constants were
modeled in PBS diluted rat plasma. Rate constants represent the fitted values of n=6 rats/
time point. Key: *ks in dilute plasma, k, in dilute plasma. The value of k, is not
reported due to the prolonged stability of linear plasmid in dilute plasma.




















A B












Std O.5m lm 2m3m 5m l0m 15m 20m 30m45m lhr Std O.5m Im2m 5m 1Om 20m 30m45m Ilhr

Figure 2-11. Degradation of supercoiled pDNA in 25% rat plasma after (A) incubating
the plasma at 90'C for 10 min (B) the addition of 0.1 mM EDTA.








these rates were significantly different from those obtained using the pGL3 plasmid a

statistical analysis was carried out using a 2-tailed equal variance student's t-test. The

resulting parameters (ko, and k1) were not significantly different when judged at the

p<0.05 criteria. These results suggest that pDNA sequence is not a major factor involved

in the overall degradation of pDNA by plasma nucleases.
Conclusions

Previous reports on the pharmacokinetics of pDNA have only been qualitative, or

involved radiolabeling. These studies indicated that pDNA degrades within 5 minutes in

vitro or after IV injection (Kawabata et al. 1995; Thierry et al. 1997). In this study, we

sought to quantitatively model the pharmacokinetics underlying the stability of pDNA in

the plasma. The results revealed that SC pDNA degrades in the plasma with a half-life of

1 min. OC pDNA is more stable than the SC topoform degrading with a half-life of 20

min. L pDNA is degraded more rapidly than the OC topoform. This latter shortened

stability is likely due to the accessibility of various nucleases present in the plasma to the

L pDNA. OC plasmid must be nicked by endonucleases on each sister strand in the same

location to generate L pDNA. However L pDNA would be accessible to both

endonucleases and exonucleases, thus degrading more rapidly. The model and equations

presented successfully described the degradation of pDNA in the plasma.

Investigations by Thierry and coworkers suggested the main nuclease activity was

endonucleolytic based on the finding that the L: SC ratio increased over time and the SC:

OC ratio remained identical to control (Thierry et al. 1997). However this view fails to
















100

10

1

0.1


20


40


60


80


time (min)




Figure 2-12. Comparison of concentrations of OC pDNA using (*) pGE150
concentrations of OC pDNA using (U) pGL3 in isolated rat plasma. Data represents
mean of n=3 1 standard deviation.

















10



zO0.1
0.01

0 20 40 60 80

time (min)

Figure 2-13. Comparison of concentrations of L pDNA using (4) pGE150 versus
concentrations of L pDNA using (0) pGL3 in isolated rat plasma. Data represents mean
of n=3 1 standard deviation.




















Table 2-4. Pharmacokinetic parameters for pDNA after incubating the pGE150 plasmid
in isolated rat plasma.

Standard

Topoform Rate constant Value (min-1) Deviation Half-life (min)

Open Circular k, 0.04 0.007 21 (1)

Linear k, 0.06 0.007 11 (1)

Data represent the fitted values of n=6 rats.








recognize endonucleolytic activity on L pDNA also generates degradation products. If

endouclease activity is the primary route of degradation, the kinetic ratios should all

remain similar or decrease, owing to the fact that both exonucleases and endonucleases

are active on the L pDNA and are thus both responsible for the observed degradation.

Our results suggest that L pDNA has faster kinetics. This can be explained by

endonuclease activity generating more free ends for degradation by exonucleases,

exonucleases are more active than endonucleases, or that topoform influences the binding

of these enzymes and thus influences reaction rate. Thus the main nuclease activity

responsible for the observed kinetics remains to be answered.

Area under the curve analysis revealed that tissues would be exposed to the OC

topoform predominantly after injection of naked pDNA (Table 2-2). Blood flow through

any individual organ becomes the limiting factor in its ability to uptake a drug, which is

highly metabolized in the plasma. When compared to hepatic plasma flow in the rat

(8.14 ml/min), clearance values for the degradation of SC plasmid (4.6 ml/min) suggest

that metabolism in the bloodstream is a major pathway by which in vivo clearance of SC

pDNA can occur (Davies 1993). However, given that the clearance by degradation in the

plasma is less than the liver blood flow, it also suggests that the liver possess a perfusion

rate sufficient for uptake of SC pDNA after IV injection. This parallels the findings of

Kawabata and coworkers who observed that naked plasmid was cleared more rapidly

from the circulation after IV injection than after in vitro incubation in whole blood

(Kawabata et al. 1995). Lung, kidney, and spleen have also been shown to take up

detectable amounts of plasmid after IV injection (Kawabata et al. 1995; Osaka et al.








1996). Our model establishes not only that tissue uptake of plasmid is possible, but also

that tissue uptake of the non-nicked SC topoform is possible after IV injection.

In summary this study presents a pharmacokinetic model describing the

degradation of pDNA in rat plasma. A pharmacokinetic model is presented that can be of

use in the future as gene therapy moves toward clinical trials. Using the derived model,

we are able to conclude that naked SC pDNA degrades in rat plasma with a half-life of

1.2 ( 0.05) min, OC with a half-life of 21 ( 1) min, and L pDNA with a half-life of 11

( 2) min.













CHAPTER 3
PHARMACOKINETICS OF PLASMID DNA AFTER IV BOLUS ADMINISTRATION
IN THE RAT

Introduction

Naked pDNA is being used successfully in gene delivery by administration IM or

SQ, (Haensler et al. 1999; Noll et al. 1999; Osorio et al. 1999; Rizzuto et al. 1999) and

after IV injection (Wang et al. 1995; Budker et al. 1998; Song et al. 1998; Liu 1999;

Zhang et al. 1999) in rats and mice. The success in these studies indicates that gene

therapy is an attractive means by which to achieve therapeutic response. Thus, a

thorough understanding of the pharmacokinetics of naked pDNA is an important area to

be considered in order to move towards use in clinical trials

The pharmacokinetics of pDNA after IV bolus administration have been

investigated using radiolabeling with linearized [33p] pDNA (Osaka et al. 1996). These

investigations have led to the conclusion that the half-life of the pDNA radiolabel is 7 to

12 min after IV bolus administration of naked pDNA in mice. However, this analysis

offers no information on the other functional forms of the plasmid; supercoiled (SC),

open circular (OC), or linear (L), nor does it discriminate the free label. Other studies

have qualitatively revealed that the SC topoform of pDNA is not detectable as early as

one minute post IV injection in mice (Lew et al. 1995; Thierry et al. 1997). The OC form

of the plasmid has a half-life estimated in these studies to be in the range of 10 to 20

minutes (Thierry et al. 1997).








The purpose of this investigation was to model the pharmacokinetics of naked

pDNA in a topoform specific manner after IV bolus administration in the rat. We further

sought to determine if the observed pharmacokinetics were affected by changes in

plasmid sequence. These results were then compared to pDNA degradation in isolated

plasma in order to determine the relative importance of plasma nucleases in the

pharmacokinetics of pDNA.

Methods

Animals (male Sprague-Dawley rats 300-350 g) were purchased from Charles

River Laboratories (Wilmington, MA). Animals were housed in the University of Florida

Animal Resources Unit prior to all experiments and were given food and water ad

libitum. Animals were anesthetized by intraperitoneal injection with 0.5 ml of a cocktail

containing 13 mg/kg Xylazine, 2.15 mg/kg Acepromazine (The Butler Co., Columbus,

OH), and 66 mg/kg Ketamine (Fort Dodge Animal Health, Fort Dodge Iowa).

Phenol: chloroform: isoamyl alcohol (25: 24: 1, v/v/v), chloroform, Tris, boric

acid, EDTA, and agarose were purchased from Sigma Chemical Company (St. Louis,

MO). Ethidium bromide (electrophoresis grade) was purchased from Fisher Biotech

(Fair Lawn, NJ). Competent JM109 bacteria (Promega, Madison, WI) were transformed

according to the manufacturer's directions with the pGL3 control plasmid (Promega,

Madison, WI) or pGeneMax plasmid (Gene Therapy Systems, San Francisco, CA).

Plasmid DNA was isolated from overnight cultures using alkaline lysis and

ultracentrifugation with a CsCl gradient (Katz 1977). Isolated pDNA was resuspended in

phosphate buffered saline. Plasmid was >90% SC by agarose gel analysis.

To facilitate blood sampling, male Sprague-Dawley rats (300-350g) were

anesthetized and the jugular vein was exposed via an incision, isolated, ligated, and








nicked with ophthalmic scissors. A sterile silatstic (0.640 cm internal diameter by 0.12

cm outer diameter, 10 cm in length) filled with sterile saline was threaded 3 0-40 mm into

the jugular vein and positioned just distal to the entrance to the right atrium and secured

by 6.0 silk sutures Figure 3-1). For injections, the femoral vein was isolated, and pDNA

was injected into the femoral vein using a 27-gauge needle (Figure 3-2). Isolated blood

samples (approx. 300 tl) were drawn through the jugular vein cannula and immediately

placed in test tubes containing 0.57 ml of 0.34 M EDTA (Vacutainer, Becton Dickinson,

Franklin Lakes, NJ) on ice at the times indicated. This concentration of EDTA has

previously been shown to inhibit the degradation of pDNA in isolated rat plasma (Houk

1999).

To isolate pDNA from whole blood samples, 250 [d1 of blood was liquid/ liquid

extracted with 250 [d1 of phenol: chloroform: isoamyl alcohol (25: 24: 1, v/v/v), vortexed

for 5 s at low speed, and centrifuged at 20,800 x g for 10 min at room temperature. The

aqueous phase was removed and stored at -20'C until analysis.

Samples were loaded on 0.8% agarose in 0.9 M Tris-borate, 1 mM EDTA gels

containing 0.001% ethidium bromide. Electrophoresis was carried out at 0.30 V/cm3 for

12h. The ethidium bromide was excited on a UV light box (Model TFX-35M, Life

Technologies, Grand Island, NY) and the net fluorescence intensity captured at 590 nm

on a Kodak DC120 digital camera (Eastman Kodak, Rochester, NY). The amounts of

SC, OC, and L pDNA were calculated using Kodak Digital Science 1D Image Analysis

Software (version 3.0, Eastman Kodak Company, Rochester NY) with a Lambda Hind III

digest (Promega, Madison WI) and a High DNA Mass Ladder (Life Technologies, Grand











































Figure 3-1. Photograph of the jugular cannula placement used for blood sampling.












































Figure 3-2. Photograph of the femoral vein isolation and injection procedure used for IV
bolus administration.










Island, NY) as external standards. Accuracy was 96 to 104% for SC pDNA, 98 to 108%

for OC, and 96 to 113% for L pDNA. Percent coefficient of variation was < 5%, 19%,

and 13% for SC, OC and L forms of the plasmid respectively. Standard curves for all

three forms of the plasmid (Figures 2-1, 2-2, and 2-3) were linear between 10 and 250 ng

pDNA bands (R2 = 0.9995, 0.9985, and 0.9933 for SC, OC, and L, respectively). All

reported concentrations were calculated from bands within the range of the standard

curves. Lower limit of quantitation was 0.5 ng/[tl for all three forms of the plasmid.

Lower limit of detection was 0.25 ng/pll for all three forms of the plasmid. Method

parameters are summarized in Table 2-1. Comparisons of the relative fluorescence of SC

pDNA versus OC and L pDNA were made by analyzing equivalent amounts as described

above and comparing the resulting fluorescence. It was found that on a weight to weight

ratio, SC pDNA was only 59% as fluorescent relative to L pDNA by agarose gel analysis.

To correct for this difference, SC pDNA amounts were multiplied by 1.7 prior to

analysis. This difference has been reported previously, and is likely due to the relative

inaccessibility of ethidium bromide to the SC topology (Cantor 1980). Percent recovery

using the phenol: chloroform: isoamyl alcohol method was found not to be dependent on

topoform. Recovery was 90 ( 6) % for SC and 86 ( 13) % for L pDNA.

Theoretica

The degradation of SC pDNA was assumed to follow pseudo first-order kinetics.

The model used is diagrammed in Figure 2-3. In this model, pDNA degradation is

considered to be a unidirectional process. The degradation of L pDNA is considered to

yield fragments of heterogeneous lengths, thus these products were not included in the







fitted model. No elimination from any of the compartments is assumed to occur through

routes other than degradation to the following topoform.

Based on this model the following differential equations were derived to describe

the process:


dSC k SC
dt
dOC~k
dt= kS.SC-ko.OC
dt
dLk0
A- = ko.OC- k, .L
dt



The amounts of supercoiled, open circular and linear pDNA were then fit to the

integrated form of the equations:


SC = SC0 e-k,t
OC = ks SCo ( kIk, e kot + k,--k, .ek t )
-ko ks o ( kk e e + e -kt)
(k,-ko)(k,-ko) + (ko -k, )(k, -k,) "e + (ko kj)(k, kj)e
Where SC, OC, and L are the amounts of supercoiled, open circular, and linear

pDNA present at time=t, respectively. SC0 is the amount of supercoiled pDNA present at

time (t)=O. The constants ks ,ko, and k, represent the rate constants for the degradation of

supercoiled, open circular, and linear pDNA, respectively. The constants represent the

activity of all enzymes acting in the degradation process. Non-linear curve fitting and

statistical analysis was carried out using Scientist (version 4.0, Micromath, Salt Lake



















1 2 3 4 5 6 7 8 9 10


Figure 3-3. A representative gel from which plasmid amounts were quantified as
described in the methods section. Lane 1: size standard, lane 2: 1 min, lane 3: 2 min, lane
4: 3.5 min, lane 5: 5 min, lane 6:10 min, lane 7: 20 min, lane 8: 30 min, lane 9: 45 min,
lane 10: 60 min.








City, UT). Noncompartmental pharmacokinetic analysis was carried out using standard

parameters (Gibaldi 1982).

Result

SC pDNA was not detected as early as 30 seconds post-injection. The OC and L

forms of the pDNA remained detectable through 30 minutes post-injection of the 500 tg

dose. An agarose gel analysis of the isolated samples is presented in Figure 3-3.

An important parameter to be considered is the initial concentrations achieved

after IV administration in comparison to the initial concentrations in vitro. The initial

concentrations of SC pDNA in the in vitro experiments (i.e. the time=0 concentration)

were 10 ( 0.3) ng/ll. After IV bolus administration, the initial extrapolated SC pDNA

concentrations were 17 ( 5) ng/jul. Thus, we concluded that these concentrations were

within a range relevant for comparison. The observed and fitted concentrations of OC

and L pDNA are presented in Figure 3-4. The model again adequately described the

data, model selection criteria=4.42. Pharmacokinetic parameters calculated based upon

the model are presented in Table 3-1.

A comparison of the in vitro and in vivo concentrations of OC and L pDNA are

presented in Figures 3-5 and 3-6, respectively. Calculated pharmacokinetic parameters

are presented in Table 3-2. OC pDNA half-life was markedly shorter after IV bolus

administration than after incubation in isolated plasma, 5.3 (1.4) versus 21 (1) min. L

pDNA removal was also more rapid after IV bolus administration, 1.9 (0.8) versus 11

(2) min after incubation in isolated plasma.

In order to further investigate the importance of plasmid sequence on the observed

pharmacokinetics, we injected the pGeneMax-Luciferase, and pGE150 plasmids by IV








bolus administration at equivalent dose (500 jig). Concentrations of OC and L pDNA in

the bloodstream are presented in Figures 3-7 and 3-8 respectively. The fitted elimination

rate constants for OC and L pDNA were compared by 2-way ANOVA. The results are

displayed in Table 3-3. There were no significant differences between the terminal rate

constants of any of the 3 plasmids by 2-way ANOVA when judged at the p<0.05 criteria.

Conclusions

DNase I is a well characterized enzyme in human plasma present at

concentrations averaging 26.1 (9.2) ng/ml in the sera of normal humans (Chitrabamrung

1981). Traditionally, the presence of this enzyme has led to the conclusion that pDNA

administered IV is degraded rapidly (Gosse et al. 1965; Chused 1972). This has led to

the current view of gene delivery, where protection from plasma nucleases is a major

goal of delivery systems. The results of this study demonstrate that although the half-life

of SC and OC pDNA is remarkably short, degradation alone was not enough to explain

the rapid disappearance of pDNA from the circulation observed in vivo. After IV bolus

the rate of degradation of SC pDNA was greater than 7 times faster than in isolated

plasma (Houk 1999).

Chused and coworkers (Chused 1972) also suggested that nuclease activity was

not enough to explain the rapid clearance of KB cell DNA from the circulation in mice.

In this study, only 2 to 3 % of the radioactivity was hydrolyzed to trichloroacetic acid

(TCA) soluble fragments in 30 min, which was several half-lives longer than in the

circulation. Tsumita and Iwanga (Tsumita and Iwanga 1963) also found that less than 5

% of the total radioactivity was found in the TCA soluble fraction after 4.5 hours in

mouse serum.





62













20-



15 +



10
z



5



0-
0 10 20 30 40 50
time (min)

Figure 3-4. Experimental and fitted data based on the pharmacokinetic model described
in the text. Data points represent actual experimental data. Lines represent values
predicted by the model. Data represents mean of n=6 1 standard devaition. Key: 0
open circular, A linear.
















20


20 40 60


time (min)




Figure 3-5. Concentrations of OC pGL3 after 0: IV bolus administration of a 500 [tg
dose of SC pGL3, and *: Incubation of SC pGL3 in isolated plasma at 37'C.




64









5

3

<2
z
CL

0 20 40 60 80
time (min)

Figure 3-6. Concentrations of L pGL3 after U: IV bolus administration of a 500 [tg dose
of SC pGL3, and *: Incubation of SC pGL3 in isolated plasma at 37*C.



















Table 3-1. Pharmacokinetic parameters calculated after 500 ptg dose of SC pDNA.

Topoform Rate Value Standard Half-life

constant (min-1) Deviation (min)
Supercoiled k, 3.4 0.4 0.2 ( 0.03)
Open circular ko 0.14 0.04 5.3(+ 1.4)
Linear k 0.41 0.18 1.9(+ 0.8)
Parameters represent averages of n=6 rats.




















Table 3-2. Comparison of in vivo and in vitro pharmacokinetic parameters for pDNA.


Topoform Terminal Half-life AUCco (ng/Jil*min) Cl/f (gl/min)
(min)

In vitro In vivo In vitro In vivo In vitro In vivo

Supercoiled 1.2 (0.1) ? 17( 5) N/A 360 ( 9) N/A




Open Circular 21 ( 1) 5.3 (1.4) 280 128 ( 52) 23 (+ 1) 4800
(150) (2000)



Linear 11( 2) 1.9 (0.8) 103 ( 47) 49 ( 28) 47 (5) 11000
(5000)


Parameters represent averages of n=3 (I 1 standard deviation).















100

pCMV-Luc:i
0)
pGE150
,< pGL3
z 1
a

0. 1
0 5 10 15
time (min)
Figure 3-7. Concentrations of OC pDNA in the bloodstream after IV bolus
administration of 500 Lg of pCMV-Luc, pGE150, or pGL3. Data represents mean of n=3
1 standard deviation.
















pCMV-Luc
-IS- pGEI 50
pGL3


0.01


time (min)


Figure 3-8. Concentrations of L pDNA in the bloodstream after IV bolus administration
of 500 [tg of pCMV-Luc, pGE150, or pGL3. Data represents mean of n=3 1 standard
deviation.


1

0.1




















Table 3-3. Comparison of OC and L pDNA parameters after administration of SC pGL3,
pGE150, and pGeneMax.


Plasmid Parameter OC Value L Value
pGL3 AUCJ. 120 (50) 52 (25)
(ng/jtl*min)
Cmax (ng/gl) 13 (4) 3.2 (1.0)
pGE150 AUC.C 160 (30) 55 (12)
(ng/!tl*min)
Cmx (ng/ d) 14 (3) 3.3 (0.9)
pGeneMax AUC.O 121 (25) 59 (3)
(ng/gl*min)
C., (ng/.l) 12 (5) 3.7 (0.3)
Parameters represent averages of n=3 (_ 1 standard deviation).








Alternatively, Gosse and coworkers suggested a major role for nucleases in the

initial degradation of DNA after IV administration in rabbits and mice (Gosse et al.

1965). This finding was based upon the proportionality between the initial rate of

depolymerization and the plasma DNase activity level. Also, a rapid decrease in

viscosity of isolated blood was discovered indicating a depolymerization of DNA.

Finally, a markedly slower disappearance of DNA-methyl green complex (a non-specific

DNase inhibitor) than after native DNA.

The reason for this disparity in results deserves further investigation. Gosse

utilized much higher doses of pDNA than Chused and coworkers in their investigations,

200 p.g versus 5 jtg pDNA in Chused and coworkers 's investigations. This disparity

may be due to saturation of a scavenger receptor, allowing nuclease activity to become

increasingly important. The effect of increasing dose on the clearance of DNA deserves

further investigation.

The results presented in the present study indicate that SC pDNA was

undetectable after IV bolus administration, whereas SC pDNA was readily detectable in

isolated plasma, and remained detectable through 3 min of incubation. Similar results

were seen for the OC and L forms of the plasmid. The half-lives of OC and L pDNA

decreased from 21 (1) to 5.3 (1.4) and 11 (2) to 1.9 (0.8) min, respectively. Thus

indicating that nuclease activity alone is not sufficient to describe the rapid clearance of

pDNA from the bloodstream in rats. The observed kinetics were found not to be

dependent upon plasmid sequence.













CHAPTER 4
DOSE DEPENDENCY OF PLASMID DNA PHARMACOKINETICS

Introduction

The studies presented in Chapters 2 and 3 have shown that degradation in the

plasma alone was not sufficient to describe the pharmacokinetics of pDNA. After IV

bolus administration SC pDNA was undetectable as early as 30 sec. This was in contrast

to isolated plasma when SC pDNA was detectable 3 minutes after the start of incubation

in isolated plasma. OC and L pDNA terminal half-life also decreased from 21 (1) to 5.3

(1.4) and 11 (2) to 1.9 (0.8) min, respectively.

Other investigators have suggested variable importance of plasma nucleases in the

degradation of genomic DNA after IV bolus administration. For example, Chused and

coworkers (Chused 1972), Whaley and Webb (Whaley 1972), and Tsumita and Iwanaga

(Tsumita 1963) all suggested a minimal role for plasma nucleases in the clearance of

DNA. This was based upon the observed fragmentation rate of genomic DNA in isolated

plasma versus the fragmentation rate after IV bolus administration, and the diffuse high

level of distribution of the DNA to tissues immediately after administration. This finding

was accompanied by the suggestion of extensive uptake of intact DNA molecules by the

reticuloendothelial system.

Alternatively, Gosse and coworkers (Gosse et al. 1965) found that "the plasma

DNases play a fundamental and probably exclusive role in the initial degradation of

DNA". This was based upon 3 observations. First was a rapid decrease in viscosity of








the blood within 3 minutes after administration. Second, this was based upon the

proportionality between the initial rate of degradation and the DNase activity level.

Third, this was also based upon the markedly slower disappearance of the DNA-methyl

green complex (a non-specific DNase inhibitor).

The disparity between the results presented here and the previous studies deserves

further investigation. Chused and coworkers, and Whaley and Webb, utilized smaller

doses of DNA in their experiments versus Gosse and coworkers (5 versus 200 jtg/

mouse). If this large dose had temporarily saturated an alternative clearance mechanism,

this would increase the observed importance of nucleases. Thus, nonlinear processes

may provide an explanation for the observed disparity.

Nonlinear clearance of pDNA has previously been suggested using

pharmacokinetic analysis of outflow patterns from rat perfused liver studies with

radiolabeled OC pDNA(Yoshida 1996). In this study, Vd increased and extraction ratio

decreased as perfusion dose was increased from 1.33 to 13.3 Pg/liver.

The purpose of this investigation was to model the pharmacokinetics of increasing

doses of naked pDNA in a topoform specific manner after IV bolus administration in the

rat. This information may provide an explanation for the disparity between the results

presented here and in previous studies. Furthermore, we sought to determine the

metabolite (OC and L) pharmacokinetics independently, by direct injection of each of the

metabolites. This information will provide a basis upon the percent conversion of the SC

to the OC form and the OC form to the L form of the plasmid.








Methods

Animals (male Sprague-Dawley rats 300-350 g) were purchased from Charles

River Laboratories (Wilmington, MA). Animals were housed in the University of Florida

Animal Resources Unit prior to all experiments and were given food and water ad

libitum. Animals were anesthetized by intraperitoneal injection with 0.5 ml of a cocktail

containing 13 mg/kg Xylazine, 2.15 mg/kg Acepromazine (The Butler Co., Columbus,

OH), and 66 mg/kg Ketamine (Fort Dodge Animal Health, Fort Dodge Iowa).

Phenol: chloroform: isoamyl alcohol (25: 24: 1, v/v/v), chloroform, Tris, boric

acid, EDTA, and agarose were purchased from Sigma Chemical Company (St. Louis,

MO). Ethidium bromide (electrophoresis grade) was purchased from Fisher Biotech

(Fair Lawn, NJ). Competent JM109 bacteria (Promega, Madison, WI) were transformed

according to the manufacturers directions with the pGL3 control plasmid (Promega,

Madison, WI) or pGeneMax plasmid (Gene Therapy Systems, San Francisco, CA).

Plasmid DNA was isolated from overnight cultures using alkaline lysis and

ultracentrifugation with a CsCl gradient (Katz 1977). Isolated pDNA was resuspended in

phosphate buffered saline. Plasmid was >90% SC by agarose gel analysis.

OC pDNA was produced by incubation of the SC pDNA, in phosphate buffered

saline, at 70'C for 16h. This procedure resulted in >90% OC plasmid (Figure 4-1). UV

absorbance at 260 nm and the A260/A280 ratio of the pDNA solution did not change

after this treatment (Figure 4-2).

L pDNA was produced by digestion with BamHI restriction enzyme (Promega,

Madison, WI) in separate reaction mixtures containing 173 utl of DI H20, 27 p.1 1 Ox

Buffer (Promega, Madison, WI) 56 p1 (100 ptg) pGL3, and 10 p.1 of BamHI (10 U/p.l).








The reaction mixture was incubated at 37C for 3 h. Plasmid was then isolated from the

reaction mixture by extraction with 1 volume of phenol: chloroform: isoamyl alcohol (25:

24: 1), followed by extraction with 1 volume of chloroform. Plasmid was then

concentrated by precipitation with 0.3 M Na Acetate, and 1 volume of isopropanol,

followed by centrifugation at 13K g for 30 min at 4C, and resuspended in 50 JAI of

phosphate buffered saline. This method routinely produced >90% L pDNA (Figure 4-3).

Concentration of pDNA was measured by monitoring UV absorbance at 260 nm, purity

was measured by A260/A280 ratio. A resulting purity of less than 1.7 was re-extracted

with 1 volume of chloroform until purity >1.7 was achieved.

For blood sampling, male Sprague-Dawley rats (300-350g) were anesthetized and

the jugular vein was exposed via an incision, isolated, ligated, and nicked with

ophthalmic scissors. A sterile silatstic (0.64 cm internal diameter by 0.12 cm outer

diameter, 10 cm in length) filled with sterile saline was threaded 30-40 mm into the

jugular vein and positioned just distal to the entrance to the right atrium and secured by

6.0 silk sutures. For injections, the femoral vein was isolated, and pDNA was injected

into the femoral vein using a 27-gauge needle. This method is graphically illustrated in

Figure 3-1 and 3-2. Isolated blood samples (approx. 300 tl) were drawn through the

jugular vein cannula and immediately placed in test tubes containing 0.57 ml of 0.34 M

EDTA (Vacutainer, Becton Dickinson, Franklin Lakes, NJ) on ice at the times indicated.

This concentration of EDTA has previously been shown to inhibit the degradation of

pDNA in isolated rat plasma (Houk 1999).








2

















E-OC





: +SC











Figure 4-1 Agarose gel analysis of pDNA after conversion to the OC form of the plasmid.
Lane 1: Prior to treatment plasmid is predominately SC. Lane 2: After treatment plasmid
is completely converted to to OC form..





76
















3500


o 3000
0

z 2500
a.

2000


1500


1000
E
0

CL 500
0

C. 0
Supercoiled Open Circular

Figure 4-2. Absorbance of pDNA before and after conversion to the OC form. Data
represents averages of n=3 I standard deviation.








2 3 4















4-OC

-L






4-SC









Figure 4-3. Agarose gel analysis of pDNA before and after conversion to the L form of
the plasmid. Lane 1: Size standard, Lane 2: before treatment the plasmid is
predominately in the SC and OC form, Lane 3: Mixture of SC, OC, and L plasmid for
reference, Lane 4: after treatment the plasmid is completely converted to the L form.








To isolate pDNA from whole blood 250 il of blood was liquid/ liquid extracted

with 250 lal of phenol: chloroform: isoamyl alcohol (25: 24: 1, v/v/v), vortexed for 5 s at

low speed, and centrifuged at 20,800 g for 10 min at room temperature. The aqueous

phase was removed and stored at -20'C until analysis. Samples analyzed and quantitated

as described in Chapter 2.
Results

SC pDNA was detectable in the bloodstream only after a 2500 plg dose, no SC

pDNA was detectable in the bloodstream at lower doses as early as 30 sec after

administration. Because of this, the pharmacokinetic parameters reported for this form of

pDNA relied only on data acquired from this dose. SC pDNA remained detectable in the

plasma through 1 min after administration. Using the limited available data we

approximated that SC pDNA degraded with a half-life of 0.15 (0.01) min. The

degradation of SC pDNA was fit to a one-compartment body model with central

elimination and uptake (Figure 4-4). We extrapolated a least squares fit of the data to an

initial, t=0, concentration which was necessary as this area accounted for a major portion

of the AUC... Clearance of SC pDNA was calculated to be 390 (10) ml/min, and

volume of distribution was 148 (26) ml. (Table 4-1).

Concentrations of OC and L pDNA in the bloodstream after IV bolus

administration are displayed in Figure 4-5 and 4-6 respectively. Noncompartmental

analysis of all four doses is displayed in Table 4-2 for OC and Table 4-3 for L pDNA. A

decrease in terminal slope is observable with increasing dose for the OC form of the

plasmid (Figure 4-5). Clearance of the OC form of the plasmid decreased with increasing

dose (Table 4-2). Formation clearance values for the OC form of the plasmid after the








administration of SC pDNA ranged from 1.3 ( 0.2) to 8.3 ( 0.8) ml/min for the 2500,

and 250 jig doses respectively. Formation clearance of the L form of the pDNA

remained constant at an average of 6.7 ( 0.2) ml/min for all doses. The 250 jlg dose L

concentrations close to limits of quantitation, and thus required a large amount of

extrapolation for AUC calculation. For this reason, the 250 jig dose L analysis was

excluded from the noncompartmental analysis. Corresponding plots of OC pDNA

plasma concentrations, normalized for dose, were not superimposable (Figure 4-7)

(Gibaldi 1982).

To investigate the percent of SC plasmid that becomes OC as well as the percent

OC plasmid that becomes L, we compared the AUC obtained after IV bolus

administration of the OC and L forms of plasmid independently at 2500 and 250 lag

doses. Plasma concentrations of OC pDNA obtained after administration of 2500 and

250 lag doses are displayed in Figure 4-8 and 4-9 respectively. Noncompartmental

analysis of the OC form of the plasmid at each dose is displayed in Table 4-4. Clearance

again decreased between the 250 and 2500 jig doses 8.8 (2.4) to 1.3 (0.2) ml/min.

Clearance also remained consistent with that observed after administration of SC pDNA

at each dose, 8.8 ( 2.4) versus 8.3 (0.8) ml/ min at the 250 lag dose, and 1.3 ( 0.2)

versus 1.3 ( 0.2) at the 2500 jig dose. Volume of distribution of the OC form was 43

(15) ml.

Concentrations of L pDNA after administration of 2500 and 250 gig doses of L

pDNA are presented in Figure 4-10 and 4-11 respectively. Noncompartmental analysis is


















12


10-


8-

CD
-S.- 6T

z
CL4-


2

0T

0.0 0.5 1.0 1.5 2.0 2.

time (min)
Figure 4-4. Concentrations of SC pDNA in the bloodstream after 2500 lag dose. SC
pDNA remained detectable through 1 minute after administration. Data points represent
averages of n=3 I standard deviation. Lines represent a least squares fit of the data
using the model described in the Methods section.




















Table 4-1. Pharmacokinetic parameters estimated for supercoiled pDNA
fit t=0 concentration of SC pDNA


based upon the


Parameter Value

AUC (ng/ l*min) 6.4 (0.2)

MRT(min) 0.21 (0.02)

Cl (ml/min) 390 (10)

Vdss (ml) 148 (26)

Half-life (min) 0.15 (0.02)


Parameters represent averages of n=3 1 standard deviation.
















100

10


a
0.1
0 10 20 30 40 50 60
time (min)


Figure 4-5. Concentrations of OC pDNA after IV bolus administration of: U 2500 p.g, A
500 gg, @ 333 jtg, or 250 jtg of SC pDNA. Data represents mean of n=3.


















10




z
0
CL

0.1

0 10 20 30 40 50 60

time (min)
Figure 4-6. Concentrations of L pDNA after IV bolus administration of: U 2500 lg, A
500 lg, 0 333 gig, or 250 jig of SC pDNA. Data represents mean of n=3.



















Table 4-2. Noncompartmental analysis of OC pDNA after IV bolus administration of SC
pDNA.

Parameter 2500 tg 500 ptg 333 tg 250 Lg

Dose Dose Dose Dose

AUC 1200 120 (50) 59 (3) 18 (2)

(ng/jtl*min) (200)

AUC % extrapolated 1 (0.4) 9 (4) 10 (6) 24 (2)

AUMC 20000 1900 400 (20) 130 (20)

(ng/i1*min2) (6000) (1200)

MRT (min) 16 (3) 14 (3) 6.8 (0.4) 7.2 (0.3)

Cl/f (ml/min) 2.1 (0.4) 4.8 (2.0) 5.7 (0.3) 14 (1)

C1 (ml/min) 1.3 (0.2) 3.0 (1.2) 3.5 (0.2) 8.3 (0.8)

C. (ng/ tl) 49 (4) 13 (4) 6.5 (0.3) 2.2 (0.2)

tmax (min) 1 1 0.7 ( 0.3) 0.8 ( 0.3)


Parameters represent averages of n=3 ( 1 standard deviation).



















Table 4-3. Noncompartmental analysis of L pDNA after IV bolus administration of SC
pDNA.

Parameter 2500 [tg 500 pg 333 pg

Dose Dose Dose

AUC 240 (40) 52 (25) 32 (5)

(ng/jtl*min)

AUC % extrapolated 12 (7) 15 (5) 13 (7)

AUMC 7500 570 300 (20)

(ng/pl*min2) (2700) (370)

MRT (min) 31 (6) 10 (2) 9.6 (1.7)

Cl/f (ml/min) 10.6 (2.0) 11 (5) 11 (1)

Cl (ml/min) 6.5 (1.2) 6.9 (2.8) 6.6 (0.9)

Cmax (ng/tl) 5.4 ( 0.6) 3.2 (1.0) 2.4 (0.5)

t,,x (min) 22 ( 3) 5.3 ( 4.0) 6.0 ( 3.6)


Parameters represent averages of n=3 ( 1 standard deviation).




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