Developing poly(ethylene glycol)- <i>b</i> -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 <i>in vivo</i> 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^BHB). Here, methoxy-poly(ethylene glycol) was employed as the hydrophilic segment of the block copolymer to stabilize the nanoparticles in aqueous environments, thus enabling Nano^BHBs to be administrable both orally and through injection. Experimental results showed that Nano^BHB has low toxicity and releases free BHB for an extended period <i>in vitro</i> and <i>in vivo</i>. Moreover, Nano^BHB 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^BHB as a sustainable release formulation to supply BHB for medicinal applications.