Polyacetal−Doxorubicin Conjugates Designed for pH-Dependent Degradation

Abstract

Terpolymerization of poly(ethylene glycol) (PEG), divinyl ethers, and serinol can be used to synthesize water soluble, hydrolytically labile, amino-pendent polyacetals (APEGs) suitable for drug conjugation. As these polyacetals display pH-dependent degradation (with faster rates of hydrolysis at acidic pH) and they are not inherently hepatotropic after intravenous (iv) injection, they have potential for development as biodegradable carriers to facilitate improved tumor targeting of anticancer agents. The aim of this study was to synthesize a polyacetal-doxorubicin (APEG-DOX) conjugate, determine its cytotoxicity in vitro and evaluate its potential for improved tumor targeting in vivo compared to an HPMA copolymer-DOX conjugate in clinical development. Amino-pendent polyacetals were prepared, and following succinoylation (APEG-succ), the polymeric intermediate conjugated to DOX via one of three methods using carbodiimide mediated coupling (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in aqueous solution was the most successful). The resultant APEG-DOX conjugates had a DOX content of 3.0-8.5 wt %, contained <1.2% free DOX (relative to total DOX content) and had a M(w) = 60000-100000 g/mol and M(w)/M(n) = 1.7-2.6. In vitro cytotoxicity studies showed APEG-DOX to be 10-fold less toxic toward B16F10 cells than free DOX (IC(50) = 6 microg/mL and 0.6 microg/mL respectively), but confirmed the serinol-succinoyl-DOX liberated during main-chain degradation to be biologically active. When administered iv to C57 black mice bearing subcutaneous (sc) B16F10 melanoma, APEG-DOX of M(w) = 86000 g/mol, and 5.0 wt % DOX content exhibited significantly (p < 0.05) prolonged blood half-life and enhanced tumor accumulation compared to an HPMA copolymer-GFLG-DOX conjugate of M(w) = 30000 g/mol and 6.2 wt % DOX content. Moreover, APEG-DOX exhibited lower uptake by liver and spleen. These observations suggest that APEG anticancer conjugates warrant further development as novel polymer therapeutics for improved tumor targeting.

Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid

“…To improve the stability in the systemic circulation and the tumor accumulation, various groups have devised non-viral gene carriers with PEG. [13][14][15][16][17][18][19][30][31][32] Recently, cleavable PEG systems were developed, which are cleaved in response to an intracellular environment (e.g. low pH in endosome/ lysosomes, thiolytically small molecules, etc.…”

“…low pH in endosome/ lysosomes, thiolytically small molecules, etc. [14][15][16][17][18][19] ) and an extracellular environment 33 (e.g. low pH in tumor tissue 34 ) to enhance endosomal escape and cellular Systemic gene delivery system for cancer therapy H Hatakeyama et al association, respectively.…”

“…Most of the current cleavable PEG devices have been designed to be cleaved in response to the intracellular microenvironment, such as low pH or a specific enzyme in the endosome/lysosome and the reductive conditions in the cytoplasm. [14][15][16][17][18][19] Here, we report the development of a novel gene delivery system for cancer gene therapy, using a MEND modified with an enzymatically cleavable PEG-lipid. The cleavable PEG-lipid is composed of a PEG/matrix metalloproteinase (MMP)-substrate peptide 20 /1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) ternary conjugate (PPD), which is specifically cleaved by MMP in the extracellular space in tumor tissues.…”

Polymer–drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

“…Our recent studies have explored dextrin, a natural polymer degraded by amylase (Hreczuk-Hirst et al 2001), and pendant chain functionalised polyacetals that display pH-dependent degradation after internalisation into the endosomal or lysosomal compartment (Tomlinson et al 2002(Tomlinson et al , 2003. These polymers can incorporate the drug (e.g.…”

Doxorubicin Loaded pH-sensitive Micelle: Antitumoral Efficacy against Ovarian A2780/DOXR Tumor

“…Other examples include the polymer-drug conjugate with pH-induced cleavable bonds such as acetal (23,24), hydrozone (25,26), and N-ethoxybenzylimidazole bonds (27). These have been used for cytoplasmic drug delivery.…”