Difunctional Pluronic copolymer micelles for paclitaxel delivery: synergistic effect of folate-mediated targeting and Pluronic-mediated overcoming multidrug resistance in tumor cell lines.
A significant obstacle for successful chemotherapy with paclitaxel (PTX) is multidrug resistance (MDR) in tumor cells. Micelles and mixed micelles were prepared from Pluronic block copolymer P105 or L101 as PTX delivery systems for overcoming MDR. Both micelle systems were covalently modified with the targeting agent folic acid to recognize and bind a variety of tumor cells via their surface-overexpressed folate receptor. There was an increased level of uptake of folate-conjugated micellar PTX (i.e. FOL-P105/PTX, FOL-PL/PTX) compared to plain micellar PTX (i.e. P105/PTX, PL/PTX) in human breast cancer MDR cell sublines, MCF-7/ADR, and the uptake of folate-conjugated micellar PTX could be inhibited by free folic acid, which suggested that the level of uptake could be mediated by the folate receptor. The cytotoxicity of folate-conjugated micellar PTX in the MDR cell culture model was much higher compared with plain micellar PTX or free PTX, and the plain micellar PTX also has higher cytotoxicity than free PTX. Overall, the MDR cells are more susceptible to the cytotoxic effects of Pluronic micellar PTX than their parental cells. The introduction of folic acid into P105 or PL mixed micelles enhanced the cell-killing effect by active internalization. Increased internalization explained the improved cytotoxicity of the FOL-micellar PTX to tumor cells. We suggest that the combined mechanisms of folate-mediated active internalization and Pluronic-mediated overcoming MDR be beneficial in treatment of MDR solid tumors by targeting delivery of micellar PTX into the tumor cells where folate receptor is frequently overexpressed, reducing accumulation of micellar PTX in other tissues or organs and further reducing side effects and toxicities of the drug.
Wang
Yongzhong
Y
Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 200032, PR China.
Yu
Li
L
Han
Limei
L
Sha
Xianyi
X
Fang
Xiaoling
X
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004339:Drug Compounding; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008823:Micelles; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020442:Poloxamer / Q000737:chemistry*; D011956:Receptors, Cell Surface / Q000378:metabolism; D012995:Solubility; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D004337:Drug Carriers; D058973:Folate Receptors, GPI-Anchored; D008823:Micelles; D011956:Receptors, Cell Surface; D020442:Poloxamer; D005492:Folic Acid; C519610:pluronic P105; D017239:Paclitaxel