Evaluation of pharmacokinetics of bioreducible gene delivery vectors by real-time PCR

Qing Hui Zhou, Chao Wu, Devika Soundara Manickam, David Oupicky

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Purpose: To investigate pharmacokinetics of reversibly stabilized DNA nanoparticles (rSDN) using a single-step lysis RT-PCR. Methods: rSDN were prepared by coating bioreducible polycation/DNA polyplexes with multivalent N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. Targeted polyplexes were formulated by linking cyclic RGD ligand (c(RGDyK)) to the HPMA surface layer of rSDN. The pharmacokinetic parameters in tumor-bearing mice were analyzed by PKAnalyst®. Results: The pharmacokinetics of naked plasmid DNA, simple DNA polyplexes, rSDN, and RGD-targeted rSDN exhibited two-compartment model characteristics with area under the blood concentration-time curve (AUC) increasing from 1,102 ng·ml-1·min-1 for DNA to 3,501 ng·ml-1·min-1 for rSDN. Non-compartment model analysis revealed increase in mean retention time (MRT) from 4.5 min for naked DNA to 22.9 min for rSDN. Conclusions: RT-PCR is a sensitive and convenient method suitable for analyzing pharmacokinetics and biodistribution of DNA polyplexes. Surface stabilization of DNA polyplexes can significantly extend their MRT and AUC compared to naked DNA. DNA degradation in rSDN in blood circulation, due to a combined effect of disulfide reduction and competitive reactions with charged molecules in the blood, contributes to DNA elimination.

Original languageEnglish (US)
Pages (from-to)1581-1589
Number of pages9
JournalPharmaceutical Research
Volume26
Issue number7
DOIs
StatePublished - Jul 1 2009

Fingerprint

Pharmacokinetics
Real-Time Polymerase Chain Reaction
Genes
DNA
Nanoparticles
Area Under Curve
Blood
Bearings (structural)
Polymerase Chain Reaction
Blood Circulation
Hemodynamics

Keywords

  • Gene delivery
  • Pharmacokinetics
  • Real-time PCR
  • Tumor targeting

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

Cite this

Evaluation of pharmacokinetics of bioreducible gene delivery vectors by real-time PCR. / Zhou, Qing Hui; Wu, Chao; Manickam, Devika Soundara; Oupicky, David.

In: Pharmaceutical Research, Vol. 26, No. 7, 01.07.2009, p. 1581-1589.

Research output: Contribution to journalArticle

Zhou, Qing Hui ; Wu, Chao ; Manickam, Devika Soundara ; Oupicky, David. / Evaluation of pharmacokinetics of bioreducible gene delivery vectors by real-time PCR. In: Pharmaceutical Research. 2009 ; Vol. 26, No. 7. pp. 1581-1589.
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N2 - Purpose: To investigate pharmacokinetics of reversibly stabilized DNA nanoparticles (rSDN) using a single-step lysis RT-PCR. Methods: rSDN were prepared by coating bioreducible polycation/DNA polyplexes with multivalent N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. Targeted polyplexes were formulated by linking cyclic RGD ligand (c(RGDyK)) to the HPMA surface layer of rSDN. The pharmacokinetic parameters in tumor-bearing mice were analyzed by PKAnalyst®. Results: The pharmacokinetics of naked plasmid DNA, simple DNA polyplexes, rSDN, and RGD-targeted rSDN exhibited two-compartment model characteristics with area under the blood concentration-time curve (AUC) increasing from 1,102 ng·ml-1·min-1 for DNA to 3,501 ng·ml-1·min-1 for rSDN. Non-compartment model analysis revealed increase in mean retention time (MRT) from 4.5 min for naked DNA to 22.9 min for rSDN. Conclusions: RT-PCR is a sensitive and convenient method suitable for analyzing pharmacokinetics and biodistribution of DNA polyplexes. Surface stabilization of DNA polyplexes can significantly extend their MRT and AUC compared to naked DNA. DNA degradation in rSDN in blood circulation, due to a combined effect of disulfide reduction and competitive reactions with charged molecules in the blood, contributes to DNA elimination.

AB - Purpose: To investigate pharmacokinetics of reversibly stabilized DNA nanoparticles (rSDN) using a single-step lysis RT-PCR. Methods: rSDN were prepared by coating bioreducible polycation/DNA polyplexes with multivalent N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. Targeted polyplexes were formulated by linking cyclic RGD ligand (c(RGDyK)) to the HPMA surface layer of rSDN. The pharmacokinetic parameters in tumor-bearing mice were analyzed by PKAnalyst®. Results: The pharmacokinetics of naked plasmid DNA, simple DNA polyplexes, rSDN, and RGD-targeted rSDN exhibited two-compartment model characteristics with area under the blood concentration-time curve (AUC) increasing from 1,102 ng·ml-1·min-1 for DNA to 3,501 ng·ml-1·min-1 for rSDN. Non-compartment model analysis revealed increase in mean retention time (MRT) from 4.5 min for naked DNA to 22.9 min for rSDN. Conclusions: RT-PCR is a sensitive and convenient method suitable for analyzing pharmacokinetics and biodistribution of DNA polyplexes. Surface stabilization of DNA polyplexes can significantly extend their MRT and AUC compared to naked DNA. DNA degradation in rSDN in blood circulation, due to a combined effect of disulfide reduction and competitive reactions with charged molecules in the blood, contributes to DNA elimination.

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