Short-chain fatty acid-releasing nano-prodrugs for attenuating growth and metastasis of melanoma

Low-molecular-weight (LMW) short-chain fatty acids (SCFAs), such as propionic and butyric acids, have been reported to possess anti-neoplastic effects; however, rapid renal clearance and high dose-based side effects limit their clinical translation. Hence, in this study, we have designed a new self-assembling nano-prodrugs that can effectively supply SCFAs: endogenous enzyme-metabolizable block copolymer poly(ethylene glycol)block-poly(vinyl ester) possessing several units of SCFAs conjugated as side chains via ester linkages. These amphiphilic polymers spontaneously self-assemble into nanostructures under aqueous conditions to form orally administrable nano-prodrugs (butyric acid: NanoBA and propionic acid: NanoPA). Herein, we show the therapeutic efficacy of SCFA nanoparticles (NanoSCFA) in a mouse model of metastasis (melanoma). Ad libitum intake of our NanoSCFA markedly demonstrated a decrease in the metastatic tumor nodules in the lungs compared with the effect observed after LMW SCFA administration with no discernible toxicity to the GI tract. In contrast, LMW SCFAs, even at a lower concentration than that of the NanoSCFA, facilitated villus atrophy. Taken together, our work suggests that the use of NanoSCFA as a therapeutic intervention for metastatic cancer is preferable over typical LMW SCFAs. STATEMENT OF SIGNIFICANCE: Low-molecular-weight (LMW) short-chain fatty acids (SCFAs) have shown versatile therapeutic effects on various diseases, including anti-tumorigenesis effects. However, their clinical translation is limited due to their poor pharmacokinetic profile and adverse effects. To overcome these limitations, we have developed new amphiphilic block copolymer-based SCFA-prodrugs, which self-assemble into nanoparticles in aqueous media (NanoSCFA). SCFAs are covalently conjugated to the hydrophobic polymer segment via ester linkage, which can be enzymatically metabolized after oral administration. In the present study, we confirmed that ad libitum intake of NanoSCFAs retarded the growth and metastatic potential of B16-F10 tumors compared to the LMW SCFAs with negligible discernible toxicity, reflecting NanoSCFA as a preferable therapeutic intervention to LMW SCFA counterparts.