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

Four new poly(hydroxyethylaspartamide) based copolymers bearing a. poly(ethylene glycol) 2000, b. poly(ethylene glycol) 5000, c. poly(ethylene glycol) 2000 and hexadecylalkyle, d. poly(ethylene glycol) 5000 and hexadecylalkyle, as pendant groups were synthesised. The copolymers were obtained by partial aminolysis of polysuccinimide with poly(ethylene glycol) and hexadecylalkyl amino derivatives followed by reaction with ethanolamine. Naked polyhydroxyaspartamide was obtained by polysuccinimide reaction with ethanolamine. The NMR, IR, light scattering and elemental analysis allowed for the extensive physico-chemical chemical characterisation of the carriers. The molecular weight of all the polymers was in the range of 27,000-34,000 Da, and the polydispersivity was in the range of 1.5-1.7. By intravenous injection to mice bearing a solid tumour, all the polymeric carriers 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 and in the liver. The poly(ethylene glycol)/hexadecylalkyle conjugates localised preferentially in the liver were over 30% of the dose/g of tissue was determined after 144 hours from administration. In the tumour all the polymers displayed a relevant accumulation that significantly increased throughout the time to reach high concentrations after 24 hours. In particular, the poly(ethylene glycol)/hexadecylalkyle conjugates achieved a concentration of 15-25% of the dose/g of tissue after 24 hours from administration that was maintained up to 144 hours.