Self-assembling butyric acid prodrug acts as a sensitizer for cancer radiotherapy

Abstract

Butyric acid, is reported to radiosensitize cancer cell lines in vitro. Their short systemic half-lives may explain their lack of in vivo efficacy. To manage the unsuitable pharmacokinetics of low-molecular-weight (LMW) butyric acid, we have designed a new polymeric prodrug comprising amphiphilic block copolymers, [poly(ethylene glycol)-b-poly(vinyl butyrate)s] (PEG-b-PV(BA)), with tens of butyric acid units conjugated through enzymatically metabolizable ester linkages as side chains in the hydrophobic segment. PEG-b-PV(BA) spontaneously forms self-assembling nanoparticles (NanoBA) with diameters of tens of nanometers. Pharmacological studies of intraperitoneal administration revealed that the retention of NanoBA in the plasma and tumors was extended up to 48–72 h compared to its LMW counterparts, as evidenced using in vivo imaging, immunoblotting of the PEG segment of the block copolymers, and radioisotope techniques. These results corroborated the LC-MS/MS-based study, validating the prominent in vivo liberation of butyric acid for a prolonged period (24 h) in NanoBA administered group compared to the LMW butyric acid, which cleared within approximately 0.5 h post-administration. Furthermore, radiation treatment after 24 h of intraperitoneal NanoBA administration toward tumor (B16-F10)-bearing mice exhibited significantly slower tumor growth in comparison with control irradiated tumors and LMW butyric acid-treated group, which was attributable to attenuated radioresistance Cox-2 and NF-κβ survival pathways. Current findings demonstrate that our self-assembling nanoparticle NanoBA prodrug substantially enhances the radiosensitizing effect of butyric acid in solid tumors in vivo, supporting the use of NanoBA for future clinical ramifications.