TASK ORDER TITLE: MICROBIAL METABOLITE MIMICRY, A NANO-DRUG FOR COLON CANCER PREVENTIONPREVENT PRECLINICAL DRUG DEVELOPMENT PROGRAM: PRECLINICAL EFF

大约75%的结直肠癌（CRC）病例是散发性的（发生在没有CRC遗传易感性的患者中），表明环境和生活方式的影响。由于饮食塑造了肠道微生物群，wd诱导的肠道生态失调和相关的致癌代谢物，如继发性胆汁酸脱氧胆酸（DCA），被认为在结直肠癌的发展中起关键作用。肠道菌群失调导致膳食营养代谢物合成减少，特别是短链脂肪酸（SCFAs）。事实上，将wd诱导的肠道生态失调与肥胖、炎症性肠病（IBD）和CRC风险增加联系起来的因素之一是SCFA合成水平的降低。以肠道生态失调为目标的化学预防策略可推动结直肠癌预防领域的发展。口服一种有效的药物可以减轻由WD引起的生态失调，从而预防肥胖人群的结直肠癌。

Approximately 75% of colorectal cancer (CRC) cases are sporadic (occurring in patients not genetically predisposed to CRC), suggesting environmental and lifestyle influences. Because diet shapes the gut microbiota, WD-induced gut dysbiosis and related carcinogenic metabolites, such as the secondary bile acid deoxycholic acid (DCA), have been suggested to play a critical role in the CRC development. Dysbiosis of the gut microbiome leads to reduced synthesis of dietary nutrient metabolites, in particular short-chain fatty acids (SCFAs). Indeed, one of the factors linking the WD-induced gut dysbiosis and increased risk of obesity, inflammatory bowel disease (IBD), and CRC is the reduced level of SCFA synthesis. Gut dysbiosis-targeted chemoprevention strategy could advance the field of CRC prevention. An effective drug would be orally delivered to mitigate the dysbiosis induced by a WD, thereby preventing CRC in obese populations. Bacterial fermentation of fiber results in the production of SCFAs, including butyrate (BU), propionate, and valerate. Extracellularly, SCFAs exert functions through G-protein coupled receptor (GPCR)-mediated signaling pathways in the immune cells, adipose tissue, and other organ sites. Intracellularly, BU and other SCFAs show histone deacetylase (HDAC) inhibitory properties, resulting in the activation of retinaldehyde dehydrogenase 1A (ALDH1A) and the enhanced conversion of retinaldehyde into all-trans retinoic acid (RA) in the gut, which regulates the gut homing of immune cells. It has been shown that WD-fed mice have a reduced concentration of BU as well as the copy number of the bcoA, which is a BU-producing gene found in the intestinal bacteria. It is possible that a combination of RA and HDAC inhibitor (HDACi), such as BU, may be anti-tumorigenic, as has been suggested by our previous studies, that showed a combination of a retinoid and a HDACi can induce apoptosis of colon cancer cells. In order to further test this approach in preclinical CRC models, a nanoparticle “RA-based HDACi” named BURA has been synthesized (US Patent Application No. 17/522,405; International Publication No. WO 2020/232399 A1). By itself, RA does not typically have an apoptotic cancer cell killing effect, however, an apoptotic effect on cultured cells was noted when RA was used in combination with a HDACi. The treatment strategy is to co-deliver BU and hydrophobic RA using hydrophilic polyvinyl alcohol (PVA), as an excipient. PVA is proven to improve stability, and bioavailability, as well as generate the sustained release of oral drugs to treat gastrointestinal diseases such as malaria and inflammatory bowel disease. The resulting nanodrug forms an amphiphilic polymer in which BU and RA are aggregated and encapsulated, and thereby protected in the center of a nanoparticle with hydrophilic moieties exposed to increase solubility. In this way, the free drugs BU and RA will be released together by encountering endogenous esterase that breaks the covalent bonds.