Evaluation of Anticancer Efficacy of D-α-Tocopheryl Polyethylene-Glycol Succinate and Soluplus® Mixed Micelles Loaded with Olaparib and Rapamycin Against Ovarian Cancer

Int J Nanomedicine. 2024 Aug 2:19:7871-7893. doi: 10.2147/IJN.S468935. eCollection 2024.

Abstract

Purpose: Ovarian cancer has the highest mortality rate and lowest survival rate among female reproductive system malignancies. There are treatment options of surgery and chemotherapy, but both are limited. In this study, we developed and evaluated micelles composed of D-α-tocopheryl polyethylene-glycol (PEG) 1000 succinate (TPGS) and Soluplus® (SOL) loaded with olaparib (OLA), a poly(ADP-ribose)polymerase (PARP) inhibitor, and rapamycin (RAPA), a mammalian target of rapamycin (mTOR) inhibitor in ovarian cancer.

Methods: We prepared micelles containing different molar ratios of OLA and RAPA embedded in different weight ratios of TPGS and SOL (OLA/RAPA-TPGS/SOL) were prepared and physicochemical characterized. Furthermore, we performed in vitro cytotoxicity experiments of OLA, RAPA, and OLA/RAPA-TPGS/SOL. In vivo toxicity and antitumor efficacy assays were also performed to assess the efficacy of the mixed micellar system.

Results: OLA/RAPA-TPGS/SOL containing a 4:1 TPGS:SOL weight ratio and a 2:3 OLA:RAPA molar ratio showed synergistic effects and were optimized. The drug encapsulation efficiency of this formulation was >65%, and the physicochemical properties were sustained for 180 days. Moreover, the formulation had a high cell uptake rate and significantly inhibited cell migration (**p < 0.01). In the in vivo toxicity test, no toxicity was observed, with the exception of the high dose group. Furthermore, OLA/RAPA-TPGS/SOL markedly inhibited tumor spheroid and tumor growth in vivo.

Conclusion: Compared to the control, OLA/RAPA-TPGS/SOL showed significant tumor inhibition. These findings lay a foundation for the use of TPGS/SOL mixed micelles loaded with OLA and RAPA in the treatment of ovarian cancer.

Keywords: IV formula; antitumor efficacy; combination therapy; mixed micelle; nanoformulation.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Carriers / chemistry
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Micelles*
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / pathology
  • Phthalazines* / administration & dosage
  • Phthalazines* / chemistry
  • Phthalazines* / pharmacokinetics
  • Phthalazines* / pharmacology
  • Piperazines* / chemistry
  • Piperazines* / pharmacology
  • Polyethylene Glycols* / chemistry
  • Polyvinyls* / chemistry
  • Polyvinyls* / pharmacology
  • Sirolimus* / administration & dosage
  • Sirolimus* / chemistry
  • Sirolimus* / pharmacokinetics
  • Sirolimus* / pharmacology
  • Vitamin E* / chemistry
  • Vitamin E* / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Micelles
  • Piperazines
  • Polyethylene Glycols
  • tocophersolan
  • Vitamin E
  • olaparib
  • polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer
  • Sirolimus
  • Phthalazines
  • Polyvinyls
  • Antineoplastic Agents
  • Drug Carriers

Grants and funding

This research was supported by “Regional Innovation Strategy (RIS)” through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE) (2021RIS-001). This research was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, grant number NRF-2022R1C1C1007107. This work was supported by the the Ministry of Science and ICT, (2024-22030007-30) and Commercialization Promotion Agency for R&D Outcomes(COMPA); and under the framework of international cooperation program managed by the National Research Foundation of Korea (2022K2A9A2A0800016412). This study was supported by SMC-SKKU Future Convergence Research Program Grant (SMO1231041).