Introduction-The treatment of prostate cancer using a radiotherapeutic 90 Y labeled N-(2-hydroxypropyl)methacrylamide (HPMA)copolymer can be enhanced with localized tumor hyperthermia. An 111 In labeled HPMA copolymer system for single photon emission computerized tomography (SPECT) was developed to observe the biodistribution changes associated with hyperthermia. Efficacy studies were conducted in prostate tumor bearing mice using the 90 Y HPMA copolymer with hyperthermia.

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Polymer architecture can influence biodistribution and the mode of presentation of bioactive agents to cells. Herein, we examined delivery, loading efficiency and mode of cellular entry of polymer conjugates of the photosensitizer Meso-Tetra (4-Carboxyphenyl) Porphyrine (MTCP) when attached to hyper-branched amine terminated poly(amido amine) (PAMAM) dendrimer or random coil linear N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer containing free amines in the side chains. The in vitro dark cytotoxicity and phototoxicity of MTCP and related conjugates were assessed on mouth epidermal carcinoma (KB) and human adenocarcinoma alveolar basal epithelial (A549) cells. Phototoxicity of polymeric conjugates increased by approximately 100 and 4,000 fold in KB and A549 cells compared with non-conjugated MTCP. The increase in phototoxicity activity was shown to result from increased rate of cellular uptake, whereas, cellular internalization of MTCP was negligible in comparison with the conjugated forms. Our results suggest the superiority of amine-terminated HPMA copolymer vs PAMAM dendrimer under study for delivery of MTCP. Treatment with various pharmacological inhibitors of endocytosis showed that polymer architecture influenced the mechanism of cellular uptake of the conjugated photosensitizer. Results show that polymeric conjugates of MTCP improved solubility, influenced the route and the rate of cellular internalization and drastically enhanced the uptake of the photosensitizer.

This study describes the synthesis, characterization, and in vitro evaluation of a combination therapy utilizing HPMA copolymer-RGDfK conjugates. HPMA copolymer-RGDfK conjugates bearing either aminohexylgeldanamycin or docetaxel were synthesized and characterized. Stability was evaluated in physiologically relevant media. Binding to αvβ3 integrins on the surface of ovarian cancer cells was assessed. Cytotoxicity towards ovarian cancer cells was evaluated and the ability of the conjugates in combination to induce cell death was assessed by combination index analysis. Conjugates bearing aminohexylgeldanamycin were more stable and exhibited slower drug release than those bearing docetaxel. Both conjugates demonstrated the ability to bind specifically to αvβ3 integrins. In combination, HPMA copolymer-RGDfK conjugates demonstrated marked synergism as compared to their non-targeted counterparts and free drug controls. HPMA copolymer-RGDfK conjugates bearing aminohexylgeldanamycin and docetaxel induce cytotoxicity in vitro in a synergistic manner, suggesting their potential as a promising combination therapy for ovarian cancer.