Polymeric anticancer drugs: design, characterization and activity against human ovarian carcinoma in nude mice

N-(2-hydroxypropy)methacrylamide (HPMA) copolymer conjugates containing the antineoplastic agents, adriamycin (ADR) and meso chlorine e-6 monoethylene diamine (Mce-6), may increase the safety regimen, improve the targeting efficiency, and decrease the nonspecific toxicity of the parent drugs. This research was to evaluate the bioactivity of HPMA copolymer-Mce-6 and ADR conjugates toward human ovarian OVCAR-3 carcinoma. HPMA copolymer-Mce-6 conjugates were synthesized with various numbers of Mce-6 molecules conjugated to the copolymer via either non-biodegradable G or biodegradable GFLG side-chain termini. The solution and photoproperties of these conjugates were studied by dynamic light scattering, UV/VIS and fluorescence spectroscopy, time-resolved fluorescence spectroscopy and fluorescence quenching techniques. The results of these studies revealed that Mce-6 formed intra-molecular aggregates within HPMA copolymer. The degree of aggregation and photosensitizing efficiency MCe-6 were influenced by the side-chain hydrophobicity, solvent pH, presence of detergents or organic solvent, and loading Mce-6 to copolymer. The bio-distribution of free Mce-6 and ADR (P-mce-6 and P-ADR) in nude mice were examined. The results revealed that the bio-distribution of P-Mce-6/P-ADR in mice was significantly different from that of Mce-6/ADR. In particular, the drug conjugates accumulated to essentially higher levels in tumors; probably attributed to the enhanced permeability and retention (EPR) effect. The bioactivity of P-Mce-6 in photodynamic therapy (PDT) and P-ADR in chemotherapy in nude mice with s.c. OVCAR-3 carcinoma xenografts were examined. Drug conjugates showed improved safety regimens when compared to the free drugs. No significant weight loss or toxic death occurred to the mice receiving chemotherapy with P-ADR and PDT with P-Mce-6 at a dose of up to 2.2 mg/kg (ADR equivalent) and 8.7 mg/kg (Mce-6 equivalent), respectively. Only mice which received the latter combination doses achieved complete tumor regression. This combination therapy was more effective in tumor destruction than chemotherapy or PDT alone. The split light dose PDT achieved better therapeutic efficacy than a single light dose PDT at the same drug and total light dose. The mice receiving multiple chemotherapy and PDT treatments achieved complete tumor regression and exhibited greater therapeutic efficacy than those receiving treatments of multiple chemotherapy or multiple PDT.