Optimization and Pharmacokinetic Evaluation of Synergistic Fenbendazole and Rapamycin Co-Encapsulated in Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles

Abstract

We aimed to develop a nanocarrier formulation incorporating fenbendazole (FEN) and rapamycin (RAPA) with strong efficacy against A549 cancer cells. As FEN and RAPA are poorly soluble in water, it is difficult to apply them clinically in vivo. Therefore, we attempted to resolve this problem by encapsulating these drugs in polymeric micelles. Methods: We evaluated drug synergy using the combination index (CI) values of various molar ratios of FEN and RAPA. We formed and tested micelles composed of different polymers. Moreover, we conducted cytotoxicity, stability, release, pharmacokinetic, and biodistribution studies to investigate the antitumor effects of FEN/RAPA-loaded mPEG-b-PCL micelles. Results: We selected mPEG-b-PCL-containing FEN and RAPA at a molar ratio of 1:2 because these particles were consistent in size and had high encapsulation efficiency (EE, %) and drug loading (DL, %) capacity. The in vitro cytotoxicity was assessed for various FEN, RAPA, and combined FEN/RAPA formulations. After long-term exposures, both the solutions and the micelles had similar efficacy against A549 cancer cells. The in vivo pharmacokinetic study revealed that FEN/RAPA-loaded mPEG-b-PCL micelles had a relatively higher area under the plasma concentration-time curve from 0 to 2 h (AUC 0-2 h ) and 0 to 8 h (AUC 0-8 h ) and plasma concentration at time zero (C o ) than that of the FEN/RAPA solution. The in vivo biodistribution assay revealed that the IV injection of FEN/RAPA-loaded mPEGb-PCL micelles resulted in lower pulmonary FEN concentration than the IV injection of the FEN/RAPA solution. Conclusion: When FEN and RAPA had a 1:2 molar ratio, they showed synergism. Additionally, using data from in vitro cytotoxicity, synergism between a 1:2 molar ratio of FEN and RAPA was observed in the micelle formulation. The FEN/RAPA-loaded mPEGb-PCL micelle had enhanced bioavailability than the FEN/RAPA solution.

Safety Profile of Rapamycin Perfluorocarbon Nanoparticles for Preventing Cisplatin-Induced Kidney Injury

“…The comparison of one- and two-compartment kinetic models indicated that the two-compartment model with first-order elimination from the central compartment described rapamycin blood concentration time profiles better than the one-compartment model. The observed kinetic behavior of rapamycin is consistent with that documented in preclinical and clinical pharmacokinetic studies [ 44 , 45 , 46 ]. The results of the disposition kinetics characterization following a single IV dose of 0.1 mg/kg unformulated free rapamycin or rapamycin nanoparticles in C57BL/6 mice demonstrated that the blood concentration time profile of rapamycin follows a biexponential time course typical of two-compartment disposition.…”

Synergistic Encapsulation of Paclitaxel and Sorafenib by Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles for Ovarian Cancer Therapy

“…Although surgical and chemotherapy strategies for treating OC are evolving [63], the 5-year overall survival rate for OC remains low at 40%. The development of novel treatments for OC is, therefore, needed; micelles, used in combination therapy, may be an alternative [64,65]. The advantage of combination therapy is that anticancer drugs with different mechanisms can be applied to OC treatment.…”

“…For micelles, it can be hypothesized that the PTX/SRF from micelles was released at a slower rate than the free drug. This is because it was absorbed into cancer cells, increasing the CI value [65,71]. In the in vitro cytotoxicity evaluation, the free drug had a lower IC 50 value than did the micelle formulation as it is applied directly to cancer cells.…”

Evaluation of pH-Sensitive Polymeric Micelles Using Citraconic Amide Bonds for the Co-Delivery of Paclitaxel, Etoposide, and Rapamycin

“…Drug combination therapy using several different mechanisms has emerged as a way to improve the limitations of multidrug resistance and side effects associated with high doses of single dosage forms [ 8 , 9 ]. Such combination therapy has been regarded as a promising therapeutic strategy as it reduces anticancer drug resistance, overcomes tumor heterogeneity, and provides synergistic anticancer effects [ 10 , 11 ].…”