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

任务单标题：微生物代谢物拟态，一种预防结肠癌的纳米药物预防临床前药物开发计划：临床前 EFF

• 批准号: 10706658
• 负责人: MARGIE CLAPPER
• 金额: $ 70.25万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10706658
• 关键词: Adipose tissue; Apoptosis; Apoptotic; Bacteria; Bile Acids; Biological Availability; Butyrates; Cancer Model; Cells; Chemoprevention; Chemopreventive Agent; Colon Carcinoma; Colorectal Cancer; Cultured Cells; Deoxycholic Acid; Development; Diet; Early Intervention; Encapsulated; Excipients; Exposure to; Fermentation; Fiber; G-Protein-Coupled Receptors; Gastrointestinal Diseases; Genes; Histone Deacetylase; Histone Deacetylase Inhibitor; Homing; Hydrophobicity; Immune; Inflammatory Bowel Diseases; International; Intervention; Intestines; Legal patent; Life Style; Link; Malaria; Methods; Mus; Names; Nutrient; Oral; Organ; Patients; Pharmaceutical Preparations; Play; Polymers; Polyvinyl Alcohol; Preclinical Drug Development; Prevention Protocols; Production; Program Development; Property; Propionates; Publications; Research; Retinaldehyde; Retinoids; Role; Sample Size; Shapes; Signal Pathway; Site; Solubility; Testing; Travel; Tretinoin; Valerates; Volatile Fatty Acids; amphiphilicity; base; cancer cell; carcinogenicity; cell killing; colorectal cancer prevention; covalent bond; dietary; dysbiosis; esterase; experimental study; extracellular; gut dysbiosis; gut microbiome; gut microbiota; hydrophilicity; improved; microbial; mimicry; mouse model; nanodrug; nanoparticle; obese person; obesity risk; pre-clinical; receptor-mediated signaling; retinaldehyde dehydrogenase; sex; treatment strategy; tumorigenic

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.

大约75％的结直肠癌（CRC）病例是零星的（发生在不易偏爱CRC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菌群，因此已建议饮食诱导的肠道营养不良和相关的致癌代谢产物，例如二胆酸脱氧胆酸（DCA），在CRC发育中起着至关重要的作用。肠道微生物组的营养不良导致饮食中营养代谢产物的合成降低，特别是短链脂肪酸（SCFA）。实际上，将WD诱导的肠道营养不良和肥胖，炎症性肠病（IBD）和CRC的风险增加的因素之一是SCFA合成水平降低。肠道营养不良的化学预防策略可以推动预防CRC的领域。有效的药物将被口服用于减轻WD引起的营养不良，从而防止肥胖种群中的CRC。 纤维的细菌发酵导致SCFA的产生，包括丁酸酯（BU），丙酸和瓣膜。细胞外，SCFA通过G蛋白耦合受体（GPCR）介导的信号通路发挥功能，在免疫细胞，脂肪组织和其他器官部位发挥作用。细胞内的BU和其他SCFA显示出组蛋白脱乙酰基酶（HDAC）抑制特性，从而激活视网膜甲醛脱氢酶1a（ALDH1A），并增强了视黄醛的转化为全球酸（RA）在gut中的全球酸（RA），从而调节了g的细胞，从而使细胞受到不受控制的细胞。已经表明，WD喂养的小鼠的BU浓度降低，BCOA的拷贝数降低，BCOA的拷贝数是在肠道细菌中发现的BU生产基因。 正如我们先前的研究表明，RA和HDAC抑制剂（HDACI）（例如BU）的组合可能是抗肿瘤的，这表明类维生素类动物和HDACI的组合可以诱导结肠癌细胞的凋亡。为了在临床前CRC模型中进一步测试这种方法，已合成了一个名为Bura的纳米颗粒“基于RA的HDACI”（美国专利申请号17/522,405；国际出版物号WO 2020/232399 A1）。 就其本身而言，RA通常不会具有凋亡的癌细胞杀伤作用，但是，当将RA与HDACI结合使用时，会发现对培养细胞的凋亡作用。治疗策略是使用亲水性聚乙烯醇（PVA）作为赋形剂共递送BU和疏水性RA。事实证明，PVA可以提高稳定性和生物利用度，并产生持续释放口服药物来治疗胃肠道疾病，例如疟疾和炎症性肠病。所得的纳米果会形成一种两亲的聚合物，其中Bu和Ra聚集并封装，从而在纳米颗粒的中心受到保护，并在纳米颗粒的中心进行了亲水性部分，暴露于增加溶解度。这样，将通过遇到破坏共价键的内源性酯酶一起释放自由药物BU和RA。