Examination of Gossypol-Pluronic Micelles as Potential Radiosensitizers

Abstract

Abstract. Chemoradiotherapy, the combination of chemotherapy and radiotherapy to treat cancer, has the potential to enhance local therapeutic effects and simultaneously treat systemic disease. However, chemoradiotherapy may also enhance normal tissue effects leading to both acute and late toxicities. Furthermore, subtherapeutic chemoradiotherapy may result in aggressive tumor repopulation. Tumorspecific radiosensitizing chemotherapy may yield a synergistic therapeutic effect and avoid augmentation of normal tissue toxicity. In this study, the radiosensitizing effects of gossypol were investigated. Also, Pluronics were studied for gossypol solubilization and co-radiosensitization effects. Gossypol inhibits Bcl-2 and Bcl-X L , antiapoptotic proteins that are overexpressed in various cancer cells. Pluronic micelles (P85, F88, L35, and P123) effectively encapsulated gossypol, raising its water solubility by more than 1000-fold. Cytotoxic, anticlonogenic, and radiosensitizing effects were evaluated to characterize gossypol and Pluronic combinations. Gossypol and P85 had the strongest antiproliferative effect on A549 human lung adenocarcinoma cells in a cell viability assay. The IC 50 value was seven times lower than gossypol only treatment (330±70 nM vs 2400±400 nM, (mean±SE)). Gossypol and P85 showed significant inhibition of clonogenic survival, approximately 30% inhibition, compared to treatment with gossypol alone. An experimental sequencing study demonstrated greater inhibition of clonogenic survival when drug treatment followed radiation compared to a sequence of drug treatment followed by radiation. These results suggest that Pluronic micelles readily solubilize gossypol and that the combination of gossypol and P85 may augment the therapeutic effects of ionizing radiation.

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

“…13 times lower than the value for (±)-gossypol (2400±430 nM) (Tomoda et al 2015). Moreover, Pluronic P85 acting as a unimeric species at 1700 nM (i.e.…”

“…The effect of (−)-gossypol on A549 clonogenic survival was dose-dependent and resulted in a complete loss of clonogenic survival of A549 cells at 2.0 μM. The effect of (−)-gossypol on clonogenic survival of A549 cells was much stronger than that of (±)-gossypol: 0.99±0.04 at 2 μM (Tomoda et al 2015). P85 did not significantly inhibit A549 clonogenic survival (0.93±0.08), whereas (−)-gossypol at 1.0 μM reduced A549 clonogenic survival to 0.7±0.1.…”

“…The experimental procedure was similar to previously described methods (Tomoda et al 2015). Briefly, a feeder layer of A549 cells was prepared by radiation at 30 Gy using a 137 Cs irradiator (JL Shepherd Model 109 Irradiator, JL Shepherd & Associates, CA).…”

“…More recently, Pluronics have been shown to be very effective in solubilizing gossypol in water, reaching ca. 10 mg/mL, and Pluronic P85 has demonstrated enhancement of the radisensitization achieved with (±)-gossypol (Tomoda et al 2015). Given that (−)-gossypol is more potent than (±)-gossypol due to a higher affinity for Bcl-2 and Bcl-XL proteins (Benz et al 1990, Wang et al 2009), (−)-gossypol is a better candidate for drug development.…”

Rethinking Alkylating(-Like) Agents for Solid Tumor Management

“…Paradoxically, radioresistance can also occur from disruption of blood supply to the altered tissue after surgery and chemotherapy, leading to hypoxic foci. Tumor radiosensitivity can then be modulated by chemical radiosensitizers that simultaneously enhance the therapeutic benefit of RT locally and exert their own cytotoxic effect [31,32]…”