Regional drug delivery with radiation for the treatment of Ewing's sarcoma- In vitro development of a taxol release system

Recently, several studies have suggested the radiosensitizing effect of tax ol. a microtubular inhibitor. Our overall hypothesis is that a combination of radiation and taxol may demonstrate therapeutic efficacy over doses of e ither individually. Studies examining taxol use have mostly focused on syst emic administration, which can lead to undesired effects. To circumvent the se side effects, we propose a locally administered polymeric microsphere de livery system combined with radiation therapy for the treatment of Ewing's sarcoma. The present study focuses on the in vitro ability of taxol when pr esent as a microencapsulated drug delivery system, and delivered locally at the site of the sarcoma/tumor. to block cells in the G2/M phase of the cel l cycle and potentially enhance the radiation sensitivity of cells. Using t he bioresorbable poly(anhydride-co-imide). poly[pyromellityl-imidoalanine-1 ,6-bis(carboxy-phenoxy)hexane] (PMA-CPH), and the radiosensitizing agent ta xol, a microsphere based delivery system was fabricated. A solvent evaporat ion technique was used to encapsulate taxol at doses of 1%, 5%, and 10% in PMA-CPH microspheres. Release kinetics studies demonstrated that the total amount of taxol released and the release rate were directly dependent on lo ading percentage. Taxol's bioactivity and radiosensitizing ability were mea sured using flow cytometry. Go-culture of Ewing's sarcoma cells with and wi thout taxol-loaded microspheres demonstrated that released taxol retained i ts bioactivity and effectively blocked cells in the radiosensitive G2/M pha se of mitosis. The taxol-radiation delivery system studied achieved an 83% decrease in tumor cell count compared to control. Taxol effectively sensiti zed Ewing's sarcoma cells to radiation with radiosensitivity shown to be in dependent of radiation dose at levels of dosages studied. This work has dem onstrated that taxol can be effectively released from a biodegradable PMA-C PH microsphere delivery system while maintaining potent combined cytotoxic and radiosensitizing abilities. (C) 2001 Elsevier Science B.V. All rights r eserved.