title: A polyphosphoester conjugate of melphalan as antitumoral agent.
abstract: The low molecular weight of many chemotherapeutics causes their untargeted distribution in the body and fast renal clearance, which leads to a loss of therapeutic activity and to unspecific toxic side effects. Therefore, there is a growing interest in conjugating anticancer drugs to water soluble polymers and thus, take advantage of the 'enhanced permeability and retention' (EPR) effect in tumors. In this study, water soluble polyphosphoesters were used as polymer carriers of melphalan hydrochloride (hydrochloride of p-bis(2-chloroethyl)amino-L-phenylalanine), which is a multifunctional alkylating agent. Melphalan was chemically immobilized by covalent bonding to poly(oxyethylene H-phosphonate) under Atherton-Todd reaction conditions. Novel polymer-melphalan complexes with ionic and hydrogen bonds were designed as controls, basing on two other biodegradable polyphosphoesters: poly(hydroxyoxyethylene phosphate) and poly(methyloxyethylene phosphate). The structure of the formed products was elucidated by (1)H, (13)C, (31)P NMR and FT-IR spectroscopy. The cytotoxic effect of the melphalan formulations was evaluated on different tumor cell lines. The novel polymer formulations showed a concentration dependent antitumoral activity, comparable to the effect of unmodified melphalan. The polymer-melphalan conjugate was also evaluated in vivo in the human hepatocellular carcinoma HuH7 xenograft mouse model. It improved the therapeutic efficacy of pure melphalan without causing side effects.
authors: Institute of Polymers, Bulgarian Academy of Sciences, "Acad. G. Bonchev" Str., 1113 Sofia, Bulgaria. Electronic address: anitabogomilova@abv.bg.
authors: Anita
authors: A
authors: Bogomilova
authors: Miriam
authors: M
authors: Höhn
authors: Michael
authors: M
authors: Günther
authors: Annika
authors: A
authors: Herrmann
authors: Kolio
authors: K
authors: Troev
authors: Ernst
authors: E
authors: Wagner
authors: Laura
authors: L
authors: Schreiner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D008558:Melphalan / Q000008:administration & dosage / Q000737:chemistry*; D051379:Mice; D016513:Mice, SCID; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011108:Polymers; D008558:Melphalan
keywords: Chemotherapeutics; EPR effect; Polymer-drug conjugate; Polyphosphoesters