Cyclodextrin-derived Nano-medicine Suppresses the Progression of Colorectal Cancer. Cyclodextrin-derived Nano-medicine Suppresses the Progression of Colorectal Cancer

The malignancy of colorectal cancer is connected with inflammation, which poses great therapeutic challenges. To integratetherapeutic targets with anti-inflammation strategy, wedeveloped a biocompatible, non-covalent channel-type nanoparticles that was fabricated through host-guest complexation and multiple assemble of mannose-modified ?-cyclodextrin (M-?-CD) with Regorafenib (RG), denoted as RG@M-?-CD. For in vivo application, the channel-type formulation optimized the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer (CAC) and CT26 models, RG@M-?-CD was proven to be a targeted, safe and effective anti-tumor nanomedicine that suppressed tumor cells proliferation, lesioned neovascularization, and attanuated inflammation. To investigate the therapeutic mechanism of RG@M-?-CD nanomedicine, small pieces of colon tissue with tumors from control group and treatment group were used to perform the microarray for gene expression anaylsis. The RGnanomedicine is constructed through the host-guest assemble between mannose-modified ?-cyclodextrin (M-?-CD) and TKI Regorafenib (RG). With multiple assemble, the host-guest system is transformed into nanoparticle, denoted as RG@M-?-CD (or RG nanomedicine). Overall design: Colitis-associated colon cancer model is established using AOM-DSS in C57 mice. The CAC mice are then treated with Rgnanomedicine or PBS. After treatment, the tumor loading colon tissues are selected to perform the mRNA expression evaluation.

结直肠癌的恶性进展与炎症反应密切相关，这为临床治疗带来了巨大挑战。为将治疗靶点与抗炎策略相结合，我们开发了一种生物相容性优异的非共价通道型纳米粒：该纳米粒通过主客体络合反应，由甘露糖修饰β-环糊精（mannose-modified β-cyclodextrin，M-β-CD）与瑞戈非尼（Regorafenib，RG）多级组装制备得到，命名为RG@M-β-CD。针对体内应用场景，该通道型制剂优化了瑞戈非尼的药代动力学特性与组织分布情况。在结肠炎相关结直肠癌（colitis-associated cancer，CAC）模型与CT26肿瘤模型中，RG@M-β-CD被证实为一款靶向性良好、安全高效的抗肿瘤纳米药物，可抑制肿瘤细胞增殖、破坏肿瘤新生血管并减轻炎症反应。为探究RG@M-β-CD纳米药物的治疗机制，我们从对照组与给药组小鼠的带瘤结肠组织中截取小块样本，开展基因表达微阵列分析。该RG纳米药物通过甘露糖修饰β-环糊精（M-β-CD）与酪氨酸激酶抑制剂（Tyrosine Kinase Inhibitor，TKI）瑞戈非尼（RG）的主客体组装构建而成。经多级组装后，该主客体体系形成纳米粒，即RG@M-β-CD（亦可简称为RG纳米药物）。整体实验设计：我们采用氧化偶氮甲烷-葡聚糖硫酸钠（azoxymethane-dextran sulfate sodium，AOM-DSS）法在C57小鼠体内构建结肠炎相关结直肠癌模型，随后将造模成功的CAC小鼠分为两组，分别给予RG纳米药物或磷酸盐缓冲液（Phosphate Buffered Saline，PBS）处理。给药结束后，选取各组的带瘤结肠组织进行mRNA表达水平检测。