Synthesis and biopharmaceutical characterisation of new poly(hydroxyethylaspartamide) copolymers as drug carriers

Four new poly(hydroxyethylaspartamide)-based copolymers bearing (a) poly(et hylene glycol) 2000, (b) poly(ethylene glycol) 5000, (C) poly(ethylene glyc ol) 2000 and hexadecylalkyl, (d) poly(ethylene glycol) 5000 and hexadecylal kyle, as pendant groups were synthesised. The copolymers were obtained by p artial aminolysis of polysuccinimide with poly(ethylene glycol) and hexadec ylalkyl an-imo derivatives followed by reaction with ethanolamine. Naked po lyhydroxyaspartamide was obtained by polysuccinimide reaction with ethanola mine. The nuclear magnetic resonance, infrared, light scattering and elemen tal analysis allowed for the extensive physico-chemical characterisation of the carriers. The molecular mass of all the polymers was in the range of 2 7 000-34 000 Da, and the polydispersivity was in the range of 1.5-1.7. By i ntravenous injection to mice bearing a solid tumour, all the polymeric carr iers displayed a bi-compartmental pharmacokinetic behaviour. Both the poly( ethylene glycol) and the hexadecylalkyle conjugation prolonged and enhanced the distribution phase of poly(hydroxyethylaspartamide). The poly(ethylene glycol) conjugation was found to promote the carrier elimination by kidney ultrafiltration and to prevent partially the accumulation in the spleen an d in the liver. The poly(ethylene glycol)/hexadecylalkyle conjugates locali sed preferentially in the liver were over 30% of the dose/g of tissue was d etermined after 144 h from administration. In the tumour all the polymers d isplayed a relevant accumulation that significantly increased throughout th e time to reach high concentrations after 24 h. In particular, the poly(eth ylene glycol)/hexadecylalkyle conjugates achieved a concentration of 15-25% of the dose/g of tissue after 24 h from administration that was maintained up to 144 h. (C) 2001 Elsevier Science B.V. All rights reserved.