Injectable (−)-gossypol-loaded Pluronic P85 micelles for cancer chemoradiotherapy

Abstract

Purpose: The aim of tumor-specific chemoradiotherapy is to achieve synergistic anticancer effects with clinically acceptable toxicity. Our previous studies showed that Pluronic P85 augments radiation cancer cell killing of (±)-gossypol in vitro. In this study, the radiosensitizing effect of (−)-gossypol, more potent Bcl protein inhibitor, with Pluronic P85 was investigated.

Materials and methods: The inhibitory effect of (−)-gossypol solubilized Pluronic P85 with 0–8 Gy of radiation on clonogenic survival rate of A549 human lung adenocarcinoma cells was investigated in vitro. The anticancer effect of (−)-gossypol-solubilized Pluronic P85 with fractionated radiation of 15 Gy was assessed by A549 tumor-bearing mice.

Results: (-)-Gossypol-loaded Pluronic P85 was found to be a more potent radiosensitizer in vitro. Pluronic P85 increased the anti-proliferative activity of (−)-gossypol against A549 cells (82 ± 42 versus 190 ± 60 nM). In addition, the combination of P85 and (−)-gossypol effectively reduced clonogenic survival of A549 cells: (11 ± 5%) compared to (−)-gossypol and P85 alone (62 ± 27% and 93 ± 13%, respectively), and enhanced radiation cancer cell killing. In vivo, P85 (200 mg/kg/day) and (−)-gossypol (15 mg/kg/day) could be safely injected intravenously over 5 days and enhanced radiation-related tumor control in an A549 xenograft model.

Conclusion: Pluronic P85 and (−)-gossypol act as a novel dual agent radiosensitizer and holds promise as a chemoradiotherapeutic strategy.

Keywords:

• Chemoradiotherapy
• gossypol
• pluronic
• polymeric micelles
• radiosensitizer

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Additional information

Funding

National Institutes of Health, 10.13039/100000002 [R01AI101157].