Gemcitabine and rapamycin-loaded mixed polymeric thermogel for metastatic pancreatic cancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death and has a poor 5-year overall survival. The superior therapeutic benefits of combination or co-administration of drugs as intraperitoneal chemotherapy have increased interest in developing strategies to deliver chemotherapeutic agents to patients safely. In this study, we prepared a gel comprising the thermosensitive poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) polymer and gemcitabine (GEM), which is currently used as the primary chemotherapy for PDAC and rapamycin (RAPA), a mammalian TOR (mTOR) inhibitor, to deliver the drug through intraperitoneal injection. We performed in vitro cytotoxicity experiments to verify the synergistic effects of the two drugs at different molar ratios and characterized the physicochemical properties of the GEM, RAPA, and GEM/RAPA-loaded thermosensitive PLGA-PEG-PLGA gels, hereafter referred to as (g(G), g(R), and g(GR)), respectively. The g(GR) comprising PLGA-PEG-PLGA polymer (25% w/v) and GEM and RAPA at a molar ratio of 11:1 showed synergism and was optimized. An in vitro cytotoxicity assay was performed by treating Panc-1-luc2 tumor spheroids with g(G), g(R), or g(GR). The g(GR) treatment group showed a 2.75-fold higher inhibition rate than the non-treated (NT) and vehicle-treated groups. Furthermore, in vivo drug release assay in mice by intraperitoneal injection of g(G), g(R), or g(GR) showed a more rapid release rate of GEM than RAPA, similar to the in vitro release pattern. The drugs in the gel were released faster in vivo than in vitro and degraded in 48 h. In addition, g(GR) showed the highest anti-tumor efficacy with no toxicity to mice. These results provide evidence for the safety and efficacy of g(GR) for intraperitoneal drug delivery. This study will assist in developing and clinically administering topical anti-cancer formulations.

Anticancer Evaluation of Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles Encapsulating Fenbendazole and Rapamycin in Ovarian Cancer.

Purpose: We aimed to inhibit ovarian cancer (OC) development by interfering with microtubule polymerization and inhibiting mTOR signaling. To achieve this, previously developed micelles containing fenbendazole and rapamycin were applied. Methods: Herein, we prepared micelles for drug delivery using fenbendazole and rapamycin at a 1:2 molar ratio and methoxy poly(ethylene glycol)-b-poly(caprolactone)(mPEG-b-PCL) via freeze-drying. We revealed their long-term storage capacity of up to 120 days. Furthermore, a cytotoxicity test was performed on the OC cell line HeyA8, and an orthotopic model was established for evaluating in vivo antitumor efficacy. Results: Fenbendazole/rapamycin-loaded mPEG-b-PCL micelle (M-FR) had an average particle size of 37.2 ± 1.10 nm, a zeta potential of -0.07 ± 0.09 mV, and a polydispersity index of 0.20 ± 0.02. Additionally, the average encapsulation efficiency of fenbendazole was 75.7 ± 4.61% and that of rapamycin was 98.0 ± 1.97%. In the clonogenic assay, M-FR was 6.9 times more effective than that free fenbendazole/rapamycin. The in vitro drug release profile showed slower release in the combination formulation than in the single formulation. Conclusion: There was no toxicity, and tumor growth was suppressed substantially by our formulation compared with that seen with the control. The findings of our study lay a foundation for using fenbendazole and rapamycin for OC treatment.