Ultrasound-Enhanced Chemotherapy of Drug-Resistant Breast Cancer Tumors by Micellar-Encapsulated Paclitaxel

Abstract

Currently, delivery of the poorly water-soluble chemotherapeutic agent paclitaxel is associated with a substantial array of systemic toxicities and results in low-efficiency tumor treatment. A novel on-demand delivery system based on paclitaxel encapsulated in polymeric micelles in conjunction with triggered release of the drug by local ultrasonic irradiation of the tumor was evaluated in vitro and in vivo using a drug-resistant MCF7/ADmt breast cancer human cell line. The effects of local ultrasonic tumor irradiation on cellular proliferation and intracellular drug uptake were compared for a developmental micellar paclitaxel formulation (SYP-PM) and a currently available clinical intravenous formulation of paclitaxel. Without ultrasound, the uptake of paclitaxel from the micellar formulation was significantly lower than that from the clinical formulation, which is advantageous for preventing unwanted drug interactions with healthy tissues in vivo. When micellar encapsulation was combined with ultrasonically triggered release, drug uptake from micellar paclitaxel was increased more than 20-fold and cellular proliferation was inhibited by nearly 90%. Without ultrasound, the clinical formulation of paclitaxel and SYP-PM manifested low efficacy in vivo, whereas injections of SYP-PM combined with ultrasound resulted in complete tumor resolution. The ability of micellar-encapsulated paclitaxel to exert a significant cytotoxic effect only when subjected to ultrasound proves promising for the development of a tumor-targeted ultrasound-enhanced paclitaxel delivery system for clinical application. This treatment modality could be successfully used for the therapy of both drug-sensitive and drug-resistant tumors. The major advantages of a micellar formulation of paclitaxel combined with local tumor sonication are the aqueous base of the drug formulation, reduced systemic toxicity, potential for tumor targeting, and on-demand delivery of drug to tumor cells.