HPMA copolymer delivery of chemotherapy and photodynamic therapy in ovarian cancer

Abstract

Our studies document a unique and unexpected advantage of the combination of HPMA copolymer bound doxorubicin with mesochlorin e6 /photodynamic therapy in the treatment of ovarian cancer. Each drug's activity is individually enhanced when compared with free (low molecular weight) drugs, furthermore, in combination these HPMA copolymer bound agents act synergistically to create an unexpected biological effect. Figure 8 depicts the known activities of each agent which may play synergistic roles. HPMA copolymer-doxorubicin has been widely evaluated in preclinical and clinical studies. It demonstrates marked advantages over free doxorubicin: control of biodistribution and accumulation via molecular weight restrictions [10,16,35,37,45], biodegradability [16-19,24,25,39,42], minimal immunogenicity [17-19, 25,38-44], subcellular localization [15-20], anticancer activity [33-36,43-46,54,55,57], enhanced permeability and retention [9,14,57,58], increased apoptosis [36], lipid peroxidation [57], DNA damage [57], and reduced nonspecific toxicity [14,33-35,43-46]. Recent clinical trials in the UK provide "proof of principle" of the "enhanced permeability and retention effect" for solid tumors and the unique advantages of this novel drug delivery system for the treatment of ovarian cancer. [35,43-46] With regards to photodynamic therapy using the photosensitizer mesochlorin e6, the preclinical evaluations thus far document: control of biodistribution and accumulation via molecular weight restrictions [10,11,16,33], biodegradability [14,43], subcellular localization [15-19], anticancer activity [33,55,56], enhanced permeability and retention [55], and reduced nonspecific toxicity [33]. Ongoing microarray studies document unique cellular pathways and new pharmaceutical properties which are initiated by the HPMA copolymer delivery delivery of these agents, and predict an exciting future for this novel drug delivery system.