Controlled release of the camptothecins from a novel in situ forming hydrogel

The camptothecins (CPTs) are potent cell-cycle specific anticancer drugs that exhibit maximum cell-kill in the S phase. Despite the investigation of various delivery systems, the systemic uptake of the CPTs is erratic and may result in either subtherapeutic efficacy or toxicity.; The objective of the current study was to design and evaluate a novel delivery system for the controlled release of the CPTs. An in situ forming PEG-based hydrogel was synthesized and characterized in vitro. The pore size of the hydrogel was determined experimentally. Hydrophilic linear compounds (40–70 kDa) and spherical particles (40–100 nm) were released from the hydrogel in a controlled manner. CPT, which is lipophilic, was released slowly since dissolution was the rate-limiting step. The water-soluble analogs (TPT and CPT-11) were rapidly released from the hydrogel due to their small size. Therefore, the hydrogel was found to be unsuitable for the controlled delivery of low molecular weight drugs.; This limitation was overcome by encapsulating TPT in liposomes, which were subsequently entrapped in the hydrogel. The release period of TPT from the hydrogel was prolonged 60-fold by loading TPT-liposomes in the hydrogel. Therefore, a two-phase system achieved controlled delivery of small, hydrophilic compounds from the hydrogel.; The release behavior of this two-phase system was evaluated in vivo in rats. The C_max was reduced significantly compared to i.v. administration of TPT, possibly preventing toxicity due to high drug-plasma levels. Drug appearance in the systemic circulation was continuous over a prolonged period since release of TPT from the liposomes and subsequently the hydrogel into the s.c. site occurred prior to absorption. Constant plasma levels of TPT were achieved (10 ng/mL) over several days.; The in vivo efficacy of the drug delivery system was evaluated to assess tumor growth reduction in rats innoculated with Mat B-III breast cancer cells. For small tumors, the continuous release of TPT was more successful than free TPT. However, for large tumors, the slow release rate prevented adequate tumor growth inhibition. In summary, controlled delivery of TPT was achieved over prolonged periods using the novel in situ forming hydrogel containing a multi-component system.