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 taxol, a microtubular inhibitor. Our overall hypothesis is that a combination of radiation and taxol may demonstrate therapeutic efficacy over doses of either individually. Studies examining taxol use have mostly focused on systemic administration, which can lead to undesired effects. To circumvent these side effects, we propose a locally administered polymeric microsphere delivery system combined with radiation therapy for the treatment of Ewing's sarcoma. The present study focuses on the in vitro ability of taxol when present 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 cell cycle and potentially enhance the radiation sensitivity of cells. Using the bioresorbable poly(anhydride-co-imide), poly[pyromellityl-imidoalanine-1,6-bis(carboxy-phenoxy)hexane] (PMA-CPH), and the radiosensitizing agent taxol, a microsphere based delivery system was fabricated. A solvent evaporation 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 loading percentage. Taxol's bioactivity and radiosensitizing ability were measured using flow cytometry. Co-culture of Ewing's sarcoma cells with and without taxol-loaded microspheres demonstrated that released taxol retained its bioactivity and effectively blocked cells in the radiosensitive G2/M phase of mitosis. The taxol-radiation delivery system studied achieved an 83% decrease in tumor cell count compared to control. Taxol effectively sensitized Ewing's sarcoma cells to radiation with radiosensitivity shown to be independent of radiation dose at levels of dosages studied. This work has demonstrated that taxol can be effectively released from a biodegradable PMA-CPH microsphere delivery system while maintaining potent combined cytotoxic and radiosensitizing abilities.
Center for Advanced Biomaterials and Tissue Engineering, Department of Chemical Engineering, Drexel University, Philadelphia, PA 19104, USA.
M A
MA
Attawia
M D
MD
Borden
K M
KM
Herbert
D S
DS
Katti
F
F
Asrari
K E
KE
Uhrich
C T
CT
Laurencin
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use; D001672:Biocompatible Materials / Q000737:chemistry; D001859:Bone Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D002453:Cell Cycle / Q000187:drug effects; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005434:Flow Cytometry; D006586:Hexanes / Q000737:chemistry; D006801:Humans; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D010316:Particle Size; D011108:Polymers / Q000737:chemistry; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000532:radiotherapy*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000972:Antineoplastic Agents, Phytogenic; D001672:Biocompatible Materials; D006586:Hexanes; D011108:Polymers; D011838:Radiation-Sensitizing Agents; C115154:poly(pyromellitylimidoalanine-co-1,6-bis(carboxyphenoxy)hexane); D017239:Paclitaxel