POLY(HYDROXYETHYLASPARTAMIDE) DERIVATIVES AS COLLOIDAL DRUG CARRIER SYSTEMS

Poly(hydroxyethylaspartamide) (PHEA) derivatives bearing at the polyaminoacidic backbone poly(ethyleneglycol) (2000 or 5000 Da) or both poly(ethyleneglycol) and hexadecylalkylamine as pendant moieties were investigated as polymeric colloidal drug carriers. The ability of the PHEA derivatives to solubilize hydrophobic drugs was investigated using paclitaxel, amphotericin B and methotrexate. The results demonstrated that the drug solubility depends on both macromolecule composition and drug physicochemical properties. In particular, PEG/hexadecylalkylamine co-grafting increased significantly the solubilization properties of PHEA for the considered drugs while the conjugation of PEG only did not endow PHEA with drug carrier properties. A stability study carried out with paclitaxel/PHEA-PEG(5000)-hexadecylalkylamine demonstrated that the drug/carrier system is characterized by physicochemical instability, which is strictly related to the incubation pH. However, the carrier was found to partially prevent drug degradation. Investigations performed using murine myeloid leukaemia NFS-60 cell line showed that paclitaxel loaded PHEA-PEG(5000)-hexadecylalkylamine possesses high pharmacological activity with IC(50) value of 22.3 ng/ml. Pharmacokinetic studies carried out by intravenous administration of paclitaxel loaded PHEA-PEG(5000)-hexadecylalkylamine to Balb/c mice demonstrated that the carrier modifies the in vivo paclitaxel fate. In particular, PHEA-PEG(5000)-hexadecylalkylamine prolonged the drug distribution and elimination phase of 6 and 17 times, respectively; in addition, it increased the systemic availability (AUC) by about 30 times.