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, biodegradability, minimal immunogenicity, subcellular localization, anticancer activity, enhanced permeability and retention, increased apoptosis, lipid peroxidation, DNA damage, and reduced nonspecific toxicity. 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. 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, biodegradability, subcellular localization, anticancer activity, enhanced permeability and retention, and reduced nonspecific toxicity. 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.

Synergetic anticancer effect of combined gemcitabine and photodynamic therapy on pancreatic cancer in vivo

“…PDT in combination with surgery [15] , radiotherapy [16] or chemotherapy [17] , has become a subject of research. New photosensitizers with improved spectroscopic, photochemical and tissue-localizing properties and improved laser instrumentation have stimulated attempts to establish clinical protocols for incorporation of PDT into multi-treatment modalities [18][19][20][21][22][23][24] . Most studies on PDT to date have been on lesions of the skin or in the wall of hollow organs, but recent interest is more in its potential for treating lesions of solid organs such as the pancreas [10,11,20] .…”

Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis

“…High-molecular-mass compounds as drug delivery vehicles recently attracted special attention because tumors can selectively accumulate these molecules by the enhanced permeability and retention (EPR) effect. It was observed in tumor tissue for macromolecules [7][8][9] and is used for cancer drug delivery. Tumor vasculature can be targeted with a synthetic polymer, N-(2-hydroxypropyl)methacrylamide [8], conjugated with O-(chloracetyl-carbamoyl) fumagillol (TNP-470) [10].…”

“…It was observed in tumor tissue for macromolecules [7][8][9] and is used for cancer drug delivery. Tumor vasculature can be targeted with a synthetic polymer, N-(2-hydroxypropyl)methacrylamide [8], conjugated with O-(chloracetyl-carbamoyl) fumagillol (TNP-470) [10]. Another promising drug carrier used here is β-poly(L-malic acid) (PMLA), a natural product of Physarum polycephalum [11][12][13].…”

The Development of Targeted Drug Delivery Systems for Rheumatoid Arthritis Treatment

“…Although initial research focused on the use of N-(2-hydroxypropyl) methacrylamide (HPMA) based upon similarity to Ringsdorf's Model, polymers with a variety of architectures and structural elements are currently being explored, including linear mono-and di-functional polymers, star polymers, and dendrimers ( Fig. 3) (Kopecek et al, 2000;Peterson et al, 2003). Dendrimers can alternatively be classified as nanoparticulate carriers when drug molecules are entrapped within the interior rather than covalently linked to the surface functional groups (Gillies & Frechet, 2005;M.…”