Activity of doxorubicin covalently bound to a novel human serum albumin microcapsule

Doxorubicin is widely used in the treatment of human malignancies, however is associated with significant cardiac, bone marrow and gastro-intestinal t oxicity. Delivery systems may ameliorate this toxicity and increase treatme nt specificity by increasing the proportion of drug delivered to sites of d isease. We have developed a novel preparation of doxorubicin (Dox) covalent ly linked to a heat stabilised human serum albumin microparticle (HSAM) car rier (median particle diameter of 4 mu m) and assessed its activity in 4 ma lignant cell lines. Materials and methods. Doxorubicin microcapsules were compared with free do xorubicin in the rat carcinoma cell line, WRC256, and the human lines, OVCA R3, MCF7 and the Dox resistant MCF7/Dox, using a cell counting technique. I C50 were calculated from regression analysis of the resulting survival curv es. Endocytosis of the microcapsules by cells in culture was observed. The rate of microcapsule uptake was assessed using dual wavelength filtered flu orescence microscopy and flow cytometry. Results. The mean IC50 following incubation with the Dox microcapsules was around 5 times greater than Dox for WRC256 (p < 0.001), MCF7 (p < 0.01) and for OVCAR3 (p < 0.01). MCF7/Dox was significantly more sensitive to Dox mi crocapsules than free Dox (p = 0.034). A negative correlation between the r ate of microcapsule uptake and the IC50 values for each cell line in cultur e exists (r = -0.96, p = 0.04). Conclusions. We conclude that: 1) Doxorubicin microcapsules retain activity in vitro and appear to overcome p-glycoprotein mediated Dox resistance. 2) The observed activity of Dox microcapsules correlates with the rate of par ticle uptake. Further studies in animal tumour models are in progress.