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. 2024 Aug 13;25(1):2382084.
doi: 10.1080/14686996.2024.2382084. eCollection 2024.

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

Duc Tri Bui  1 , Yukio Nagasaki  2   3   4   5   6
Affiliations

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

Duc Tri Bui et al. Sci Technol Adv Mater. .

Abstract

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 in vivo 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 NanoBHB). Here, methoxy-poly(ethylene glycol) was employed as the hydrophilic segment of the block copolymer to stabilize the nanoparticles in aqueous environments, thus enabling NanoBHBs to be administrable both orally and through injection. Experimental results showed that NanoBHB has low toxicity and releases free BHB for an extended period in vitro and in vivo. Moreover, NanoBHB exhibits superior nephroprotective effects in cisplatin-induced acute kidney injury mouse models compared to low-molecular-weight (LMW) sodium BHB, suggesting the potential of NanoBHB as a sustainable release formulation to supply BHB for medicinal applications.

Keywords: Acute kidney injury; ketone bodies; nanoparticles; poly(ethylene glycol)-b-poly(β-hydroxybutyrate); β-hydroxybutyrate.

Plain language summary

We engineered self-assembling poly(ethylene glycol)-b-poly(D,L-β-hydroxybutyrate) nanoparticles as a prodrug for continuous release of β-hydroxybutyrate, inducing bioactivity as a ketone body and providing nephroprotective properties against acute kidney injuries.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Design of poly(β-hydroxybutyrate)-based nanoparticles and strategy to protect kidneys.
Figure 2.
Figure 2.
Synthesis and characterization of mPEG-b-poly(BHB).
Figure 3.
Figure 3.
Preparation of nanoparticles and optimization of the design.
Figure 4.
Figure 4.
Characterization of NanoBHB.
Figure 5.
Figure 5.
Biodegradability of NanoBHB.
Figure 6.
Figure 6.
Safety of NanoBHB.
Figure 7.
Figure 7.
Nephroprotective effects of NanoBHB in cisplatin-induced AKI models.
Figure 8.
Figure 8.
Bioavailability of BHB after NanoBHB injection and proposed mechanism.
See this image and copyright information in PMC

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