Abstract
To investigate pharmacokinetics of reversibly stabilized DNA nanoparticles (rSDN) using a single-step lysis RT-PCR. 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. 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 x ml(-1) x min(-1) for DNA to 3,501 ng x ml(-1) x 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. 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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