Steric stabilization of poly(2-(dimethylamino)ethyt methacrytate)-based polyplexes mediates prolonged circulation and tumor targeting in mice

Background Efficient tumor targeting of polymeric gene transfer systems (polyplexes) represents a major challenge. To establish tumor targeting after intravenous (IV) administration, the circulation lifetime of these systems should be sufficiently long. Since naked polyplexes are rapidly eliminated from the circulation after IV adminstration, strategies have to be developed to improve their pharmacokinetics. Methods Complexes of plasmid DNA and poly(2-(dimethylamino) ethyl methacrylate) (pDMAEMA)-graft-PEG or AB di-block copolymers of pDMAEMA and PEG, as well as PEGylated complexes prepared via PEGylation of preformed complexes (postPEGylation), were evaluated for their physicochemical properties (size and charge) their interactions with blood constituents and transfection activity in vitro. The pharmacokinetics and biodistribution of PEG-polyplexes were studied in mice after IV administration. The degree of accumulation in two subcutaneous (SC) mouse tumors after IV administration was evaluated for the system with the longest circulation time. Results It is shown that the surface charge of the pDMAEMA-polyplexes was effectively shielded by two PEGylation methods (i.e. the use of pDMAEMA-graft-PEG polymers and postPEGylation). The shielding effect was the highest for the postPEGylation method with PEG(20000), yielding polyplexes that hardly show interactions with blood components (i.e. albumin and erythrocytes) and show substantially prolonged circulation time in mice after IV administration. The superior colloidal stability and circulation kinetics of the postPEGylated polyplexes translated into tumor accumulation which amounted to about 3.5% of the injected dose per gram tumor tissue in a SC Neuro2A tumor model and to about 4.2% of the injected dose per gram tumor tissue in a SC C26 tumor model. Conclusions This study shows that postPEGylation of pDMAEMA-based polyplexes is the most attractive method to prepare polyplexes with long circulating properties. Tumor targeting capacity after intravenous administration was demonstrated in two subcutaneous tumor models. Copyright (C) 2004 John Wiley Sons, Ltd.