Design of poly(α‐malic acid)‐5FU conjugate exhibiting antitumor activity

Abstract

Since poly(α‐malic acid) is a biodegradable and bioabsorbable lactic acid type polyester having pendent carboxylic acid groups, it is of interest for application as the polymer carrier to covalently attach both a parent drug and a targeting agent. In order to provide a macromolecular prodrug of 5‐fluorouracil (5FU) with reduced side‐effects and exhibiting high antitumor activity, the covalent attachment of 5FU to poly(α‐malic acid) through hydrophobic spacer groups, ester or amide and carbamoyl groups was carried out. In order to estimate the release behavior of 5FU from poly(α‐malic acid)‐5FU conjugates, the hydrolysis of the pendent ester or amide and carbamoyl groups in the conjugates obtained was investigated in vitro using various kinds of aqueous solution at 37°C. The effect on prolongation of life was tested in vivo against p‐388 lymphocytic leukemia in female CDF1 mice by intraperitoneal (i.p.) i.p. injection. These poly(α‐malic acid) 5FU conjugates gave a high survival rate and did not display acute toxicity in the high dose range of 200–800 mg/kg.

Thermo-Sensitive Release Behavior of 5-Fluorouracil from Chitosan-Gel Microspheres Coated with Lipid Multilayers

“…Structure of I-[N-(5-annnopentyl)ureal-5-fluorouracil: Ap-5FU. [25]. Toluene, chloroform, methanol and other organic solvents were purified by distillation.…”

Synthesis of New Polyamides from Natural Monomers:L-Malic acid andL-Lysine

“…l-Lysine has often been polycondensed as a diamine with various diacids, and in particular with Omethyl-protected l-tartaric acid. [27] Poly(a-malic acid)s, [38] poly(b-malic acid)s [39] and poly(a,b-malic acid)s [40] have been synthesized, but to our knowledge no polyamide based on l-malic acid has been described. Moreover, poly(a-malic acid)-5-fluorouracil conjugate revealed to have interesting antitumor activity.…”

“…Moreover, poly(a-malic acid)-5-fluorouracil conjugate revealed to have interesting antitumor activity. [38] Experimental Part l-Malic acid, 99%, (Acros); l-lysine, 99%, purum, (Fluka); pentachlorophenol, 99%, (Aldrich); pentafluorophenol, 99%, (Acros); isobutene, (Praxair); p-nitrobenzyl bromide, 99%, (Aldrich); palladium/carbon 10 wt.-%, (Aldrich) were used as received.…”

Synthesis and characterization of novel ABA triblock copolymers from L-lactide, glycolide, and PEG

“…1 Presently, polylactide, polyglycolide, and poly(-caprolactone) homo-and copolymers constitute the most promising bioresorbable materials in the field of surgery and pharmaceutics. Polymers derived from these ␣-hydroxy acids are biocompatible and biodegradable, and their degradation products are nontoxic.…”