HPMA-hydrogels containing cytostatic drugs. Kinetics of the drug release and in vivo efficacy.

Abstract

This study proposes a strategy to generate new anticancer therapy using hydrogel-based drug delivery systems to improve drug bioavailability and increase the therapeutic efficacy. We have synthesized biodegradable hydrogels based on N-(2-hydroxypropyl)methacrylamide (HPMA) with prolonged drug release. Pharmacokinetic data from in vitro studies showed that the in vitro release of hydrophilic drugs (doxorubicin, vinblastine) from HPMA-hydrogels is affected mainly by drug diffusion and only partially by hydrogel degradation. The release of hydrophobic drugs (cyclosporine A, CsA) actually copies the process of degradation and therefore it is slower. Hydrogels with degradation time of 50 h released the doxorubicin over a period of at least 96 h after s.c. implantation. Drug concentration at pharmacologically active levels was maintained in the bloodstream over a period of at least 4 days, ranging between 0.1 and 1 microg/ml. The therapeutic potential of HPMA-hydrogels in vivo was studied in Bcl1 leukemia. HPMA-hydrogels containing DOX were significantly more effective in inhibition of Bcl1 leukemia in comparison with free DOX or non-targeted polymeric drug (PK1). The efficacy of therapeutic combination using unspecific, hydrogel-based therapy with specific, antibody-targeted therapy at late stages of Bcl1 leukemia was also tested. In contrast to application of DOX alone, a cocktail of DOX with CsA as a blocker of P-glycoprotein (Pgp) incorporated into HPMA-hydrogel blocked the proliferation of Pgp-overexpressing multidrug resistant cell lines in vitro by induction of apoptosis.