Developing poly(ethylene glycol)--poly(β-hydroxybutyrate)-based self-assembling prodrug for the management of cisplatin-induced acute kidney injury.

Although β-hydroxybutyrate (BHB), one of the endogenous body ketones, possesses high bioactivities, it is rapidly consumed, metabolized, and eliminated from the body. In this study, we designed new self-assembling nanoparticles that sustainably released BHB to improve bioavailability and evaluated their efficacy in experiments using rodent animal models. Since poly(β-hydroxybutyrate) [poly(BHB)] is regarded as a polymeric prodrug that is hydrolyzed by endogenous enzymes and releases BHB in a sustained manner, our idea was to engineer hydrophobic poly(BHB) in one of the segments in the amphiphilic block copolymer, of which self-assembles in water to form nanoparticles of tens of nanometers in size (abbreviated as Nano). Here, methoxy-poly(ethylene glycol) was employed as the hydrophilic segment of the block copolymer to stabilize the nanoparticles in aqueous environments, thus enabling Nanos to be administrable both orally and through injection. Experimental results showed that Nano has low toxicity and releases free BHB for an extended period and . Moreover, Nano exhibits superior nephroprotective effects in cisplatin-induced acute kidney injury mouse models compared to low-molecular-weight (LMW) sodium BHB, suggesting the potential of Nano as a sustainable release formulation to supply BHB for medicinal applications.