A Novel Nanodrug for Metabolic Disease Treatment - PROJECT ABSTRACT Metabolic health issues such as metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus (T2DM) are risks for hepatocellular carcinoma (HCC) and colorectal cancer (CRC). Emerging evidence has revealed that diet-induced dysbiosis contributes to metabolic disease development, including digestive tract cancer. Thus, gut dysbiosis-targeted drug discovery should be explored, which is anticipated to advance the field of metabolic disease prevention and treatment. This project aims to develop and characterize an orally delivered nanodrug designed and synthesized to compensate for the shortage of microbial metabolite- regulated signaling within the gut-liver axis, i.e., commonly found in patients with liver and colon cancer. Our data show that human CRC and HCC exhibit elevated protein deacetylases and reduced signaling for short-chain fatty acids (SCFAs), which have histone deacetylase (HDAC) inhibitory properties. HDAC inhibitors enhance intestinal retinoic acid (RA) signaling, which is consistently reduced in human HCC and CRC. We have validated the interactive benefits of HDAC inhibitors and RA in cancer cells and animal models. We, therefore, have designed and synthesized “RA-based HDAC inhibitors” using polymers. One of the synthesized drugs, PRORA, was produced by covalently linking propionic acid (PRO), an HDAC inhibitor, and all-trans retinoic acid (RA) to polyvinyl alcohol (PVA), which self-assembled into nanomicelles. This nano-conjugation enables the simultaneous co-delivery of two active ingredients. PRORA can be absorbed by intestinal epithelial cells. We have validated that nano-formulated PRORA has systemic metabolic benefits in two human-relevant preclinical models, i.e., diet-induced obese mice and bile acid receptor FXR knockout (KO) mice. In both models, oral therapy with PRORA improves insulin sensitivity, treats MASH, and reduces hyperlipidemia, splenomegaly, and body fat, with no noticeable toxicity. Based on this exciting success, we propose two Aims to further characterize PRORA. Aim 1 optimizes PRORA formulation using different molecular weights of PVA, followed by physicochemical characterization, including particle size, morphology, structure, and stability. The optimized formulation will be evaluated for intestinal absorption, safety through toxicology testing, pharmacokinetics, and therapeutic efficacy. Aim 2 utilizes optimized formulation and dosage to investigate the mechanisms in obese mice and FXR KO mice, which spontaneously develop MASH and HCC. Supported by the unbiased omic data, we will study the effects of PRORA on intestinal GLP-1 signaling, the interaction between immunity and metabolism, and transcriptional networks. Optimizing and elucidating the mechanisms of orally delivered PRORA will support its clinical translation for the treatment and prevention of metabolic diseases.
