In vitro investigation of ionic polysaccharide microspheres for simultaneous delivery of chemosensitizer and antineoplastic agent to multidrug-resistant cells.
Insufficient intratumoral concentration of therapeutic agents and multidrug resistance are major factors responsible for failure of treatment of solid tumors. Simultaneous delivery of chemosensitizing and antineoplastic agents by microspheres could lead to enhanced chemotherapy of multidrug-resistant (MDR) tumors. Ionic polysaccharide microspheres derived from dextran were used to load chemosensitizers (e.g., verapamil) and anticancer drugs such as vinblastine. High drug loading was achieved for both a single agent and dual agents. The equilibrium drug loading was dependent on the ratio of the microspheres (MS) to the drug, as well as the relative affinity of the agents to the MS in the case of dual agents. The drug release from drug-MS involved hydration and swelling of the MS in addition to ion exchange. The effectiveness of MS-delivered chemosensitizers in the reversal of drug resistance was evaluated by measuring the uptake of [3H]vinblastine by MDR cells (CHRC5). The concomitant delivery of verapamil with vinblastine by the MS led to a 6-7-fold increase in the uptake of vinblastine, a level similar to the uptake obtained with free drug solutions. The results suggest that the antineoplastic and chemosensitizing agents were released effectively from the MS and the bioactivity of the chemosensitizer was preserved during the process.
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Faculty of Pharmacy, 19 Russell Street, University of Toronto, Toronto, Ontario, Canada M5S 2S2.
Wu
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Bendayan
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D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D016466:CHO Cells; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003911:Dextrans; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019450:Genes, MDR; D007700:Kinetics; D008863:Microspheres; D011134:Polysaccharides / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology; D014747:Vinblastine / Q000008:administration & dosage / Q000494:pharmacology
D000277:Adjuvants, Pharmaceutic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D003911:Dextrans; D011134:Polysaccharides; D014747:Vinblastine; D014700:Verapamil