Combination chemotherapy and photodynamic therapy of targetable N-(2-hydroxypropyl)methacrylamide copolymer–doxorubicin/mesochlorin e6-OV-TL 16 antibody immunoconjugates

Enhanced antitumor activity of combinations of free and HPMA copolymer-bound drugs

“…Several HPMA copolymer drug conjugates underwent clinical testing, including DOX (Vasey et al, 1999) and platinates (Rademaker-Lakhai et al, 2004). The advantages of combination therapy using HPMA copolymer conjugates have been demonstrated on animal models of ovarian carcinoma (Krinick et al, 1994;Peterson et al, 1996;Shiah et al, 1999Shiah et al, , 2000Shiah et al, , 2001b. The results presented here highlight the potential applications of synergistic combinations and dose reduction for combination therapy for renal carcinoma.…”

“…Common side effects are prolonged cutaneous and systemic photosensitivities, which remain a problem in patients treated with low-molecular weight photosensitizers (Dougherty et al, 1990;Chiarello, 2004). Binding Mce 6 to HPMA copolymers containing a targeting moiety can also limit its distribution in the body and reduce side effects (Krinick et al, 1990;Goff et al, 1991;Shiah et al, 2001b).…”

“…The advantages of polymer-bound drugs (when compared to low-molecular weight drugs) are (reviewed in Putnam and Kopeèek, 1995;Kopeèek et al, 2000;Duncan, 2003): a) active uptake by fluid-phase pinocytosis (non-targeted polymer-bound drug) or receptor-mediated endocytosis (targeted polymer-bound drug), b) increased active accumulation of the drug at the tumor site using targeting (Lu et al, 1999;Shiah et al, 2001b) c) increased passive accumulation of the drug at the tumor site by the enhanced permeability and retention (EPR) effect (Shiah et al, 2001a), d) long-lasting circulation in the bloodstream (Seymour et al, 1987(Seymour et al, , 1990), e) decreased non-specific toxicity of the conjugated drug (Øíhová et al, 1988), f) decreased immunogenicity of the targeting moiety (Øíhová et al, 1988), f) immunoprotecting and immunomobilizing activities (Øíhová et al, 2001), g) modulation of the cell signaling and apoptotic pathways (Minko et al, 1999(Minko et al, , 2001Nishiyama et al, 2003;Malugin et al, 2006), h) enhanced solubility of hydrophobic drugs, and i) the potential to overcome efflux pump-mediated mechanism of drug resistance (Minko et al, 1998(Minko et al, , 1999.…”

“…In vivo combination chemotherapy and PDT studies on two cancer models, Neuro 2A neuroblastoma induced in A/J mice (Krinick et al, 1994) and human ovarian carcinoma heterotransplanted in nude mice (Peterson et al, 1996;Shiah et al, 2000Shiah et al, , 2001b, demonstrated that combination therapy with HPMA copolymer-bound DOX and HPMA copolymer-bound Mce 6 (mesochlorin e 6 monoethylene diamine) produced tumor cures which could not be obtained with either chemotherapy or PDT alone. Additionally, significantly lower nonspecific toxicities were observed when compared to low-molecular weight drugs.…”

Polymeric Micelles: Nanocarriers for Cancer-Targeted Drug Delivery

“…For example, the combination of PGA-paclitaxel conjugate with cisplatin (57) or carboplatin (58) has shown improved therapeutic benefits or reduced toxicity in Phase I clinical trial. In addition, the anticancer effect of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin conjugate in combination with HPMA copolymer-mesochlorin e6 was shown to be more efficacious than either conjugate alone (59).…”