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



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.



(-)-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.



Pluronic P85 and (-)-gossypol act as a novel dual agent radiosensitizer and holds promise as a chemoradiotherapeutic strategy.
a Pharmaceutical Sciences Division, School of Pharmacy , University of Wisconsin , Madison , USA.
Keishiro
K
Tomoda
a Pharmaceutical Sciences Division, School of Pharmacy , University of Wisconsin , Madison , USA.
Hsin C
HC
Chiang
b Mercy Regional Cancer Center Radiation Oncology , Janesville , Wisconsin , USA.
Kevin R
KR
Kozak
a Pharmaceutical Sciences Division, School of Pharmacy , University of Wisconsin , Madison , USA.|c Faculty of Pharmacy , King Abdulaziz , Jeddah , Saudi Arabia.
Glen S
GS
Kwon
D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006072:Gossypol / Q000008:administration & dosage*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000473:pathology* / Q000628:therapy*; D011060:Poloxalene / Q000008:administration & dosage*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; C422648:pluronic block copolymer p85; D011060:Poloxalene; D006072:Gossypol
Chemoradiotherapy; gossypol; pluronic; polymeric micelles; radiosensitizer