Poloxamer 407/TPGS mixed micelles for delivery of gambogic acid to breast and multidrug-resistant cancer

Abstract

Background: Delivery of a high concentration of anticancer drugs specifically to cancer cells remains the biggest challenge for the treatment of multidrug-resistant cancer. Poloxamers and D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) are known inhibitors of P-glycoprotein (P-gp). Mixed micelles prepared from Poloxamer 407 and TPGS may increase the therapeutic efficacy of the drug by delivering high concentrations inside the cells and inhibiting P-gp. Gambogic acid (GA) is a naturally derived novel anticancer agent, but poor solubility and toxic side effects limit its use. In this study, we have developed Poloxamer 407 and TPGS mixed micelle-encapsulating GA for the treatment of breast and multidrug-resistant cancer. Methods: GA-loaded Poloxamer 407/TPGS mixed micelles were prepared using a thin film hydration method, and their physicochemical properties were characterized. Cellular accumulation and cytotoxicity of the GA-loaded Poloxamer 407/TPGS mixed micelles were studied in breast cancer cells, MCF-7 cells, and multidrug-resistant NCI/ADR-RES cells. Results:The diameter of GA-loaded Poloxamer 407/TPGS mixed micelles was about 17.4 ± 0.5 nm and the zeta potential -13.57 mV. The entrapment efficiency of GA was 93.1% ± 0.5% and drug loading was about 9.38% ± 0.29%. Differential scanning calorimetry and X-ray powder diffraction studies confirmed that GA is encapsulated by the polymers. The in vitro release studies showed that mixed micelles sustained the release of GA for more than 4 days. Results from cellular uptake studies indicated that GA-loaded Poloxamer 407/TPGS mixed micelles had increased cellular uptake of GA in NCI/ADR-RES cells. Cytotoxicity of GA-loaded Poloxamer 407/TPGS mixed micelles was found to be 2.9 times higher in multidrug-resistant NCI/ADR-RES cells, and 1.6 times higher in MCF-7 cells, as compared with unencapsulated GA. Conclusion: This study suggests that Poloxamer 407/TPGS mixed micelles can be used as a delivery system for GA to treat breast and multidrug-resistant cancer.

Tumor neovasculature-targeted cationic PEGylated liposomes of gambogic acid for the treatment of triple-negative breast cancer

“…Hence, difference in the cytotoxicity between free GA and GAL was found to be negligible in vitro . In similar observations with our study, Saxena and Hussain, (2012) demonstrated that GA encapsulated in poloxamer 407/TPGS showed comparable in vitro cytotoxicity than free GA in breast cancer MCF-7 cells (Saxena and Hussain, 2012). …”

Adding Vitamin E-TPGS to the Formulation of Genexol-PM: Specially Mixed Micelles Improve Drug-Loading Ability and Cytotoxicity against Multidrug-Resistant Tumors Significantly

“…Because it is a small hydrophobic molecule, iodine was incorporated into the hydrophobic cores of the micelles. This caused a conversion of I 3 − to I 2 , which maintained the saturated concentration of I 2 solution [ 29 ]. The CMC value of each group was determined by plotting the absorption intensity against the logarithm of the polymer mass concentration ( Fig.…”

“…The critical micelle concentrations (CMC) of PEG-PLA, VE-TPGS, and their mixture (VE-TPGS/PEG-PLA = 13/87, w/w) were determined using iodine UV spectroscopy as described previously [ 29 ]. A set of polymer solutions at various concentrations (1 ml, 0.0001% to 0.1%, w/v) was prepared with 5 μl of KI/I 2 standard solution added.…”

Polymeric drugs: Advances in the development of pharmacologically active polymers

“…Zhu et al also reported the dual functionality of TPGS in poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a pore-forming agent and stabilizer that resulted in small particle size, high encapsulation efficiency and fast release of docetaxel and P-gp inhibition to overcome MDR in vivo [34] (Scheme 4A). Increasing number of similar formulations have incorporated TPGS to deliver anti-cancer drugs in multidrug resistant cancers [35–41]. Similar concept of pharmacologically active polymer surfactant using embelin, a known inhibitor of X-linked inhibitor of apoptosis protein, was recently advanced by the Li lab [42,43].…”