Preparation and evaluation of polyvinyl alcohol-co-oleylvinyl ether derivatives as tumor-specific cytotoxic systems.
A series of poly(vinyl alcohol) amphiphilic derivatives have been prepared to obtain polymeric aggregates in aqueous phase holding thermodynamic instability. The aim was to evaluate their ability to interact with tumor cells eliciting selective cytotoxicity. The poly(vinyl alcohol) derivatives were prepared by partial substitution of poly(vinyl alcohol) (MW 10 kDa) with both oleyl chains and poly(ethylene glycol) monoethyl ethers (PEGMEE) of different molecular weights. The substitution degree was 1.5% for the oleyl chains and 1% for the PEGMEE chains (moles of substituent per 100 mol of hydroxyvinyl monomer). The polyvinyl derivatives obtained easily dissolved in water. Dynamic and static light scattering measurements on the polymer aqueous solutions indicated the formation of polymeric aggregates characterized by low polydispersity (0.232-0.299) and mean size (218-382 nm) in the range suitable for intravenous administration. Moreover, they were characterized by different packing densities and thermodynamic instabilities driving the polymers to interact with hydrophobic membranes. Among the analyzed polymers, the poly(vinyl alcohol)-co-oleylvinyl ether substituted with triethylene glycol monoethyl ether (P10(4)) provided in solution the highest affinity for hydrophobic membranes. P10(4), moreover, was the most cytotoxic toward the tumor cell lines analyzed (neuroblastoma: SH-SY5Y, IMR-32, HTLA-230. melanoma: MZ2-MEL, RPMI7932.), while it did not appreciably alter the viability of the normal resting lymphocytes. The peculiar behavior of the P10(4) aggregates has been correlated to their high thermodynamic instability in solution due to the high packing density that triggers the polymeric aggregates to interact with hydrophobic membranes such as the tumor cell membranes, thus eliciting cytotoxicity.
Orienti
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Department of Pharmaceutical Sciences, University of Bologna, Italy. orienti@biocfarm.unibo.it
Zuccari
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Carosio
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Montaldo
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PG
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001672:Biocompatible Materials / Q000737:chemistry; D001704:Biopolymers / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D004337:Drug Carriers / Q000737:chemistry; D004987:Ethers / Q000737:chemistry; D006801:Humans; D008027:Light; D008214:Lymphocytes / Q000378:metabolism; D008956:Models, Chemical; D008970:Molecular Weight; D009369:Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D011142:Polyvinyl Alcohol / Q000737:chemistry*; D012542:Scattering, Radiation; D012995:Solubility; D013696:Temperature; D013816:Thermodynamics
D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D001704:Biopolymers; D004337:Drug Carriers; D004987:Ethers; D011108:Polymers; D011092:Polyethylene Glycols; C035053:triethylene glycol monoethyl ether; D011142:Polyvinyl Alcohol