Preparation Of Capecitabine-loaded Prebiotics-based Nanoparticles For Colorectal Cancer Therapy

Colorectal cancer(CRC)has become the third most diagnosed cancer worldwide,and the incidence and mortality are on the rise.The occurrence and development of CRC are not only determined by epigenetic changes,but also influenced by the tumor microenvironment.Currently,chemotherapy is still the main treatment for CRC,but chemotherapeutic agents usually have side effects on normal cells.The first-line chemotherapeutic drug capecitabine(Cap),an oral prodrug of 5-fluorouracil(5-Fu),has tumor-specific toxicity and can improve the efficacy and tolerability of5-Fu-based chemotherapy.However,due to its short plasma half-life(0.5-1 h),twice-daily administration with a high dose is required,bringing consequent dose-related toxicity.The microbial community in the gastrointestinal tract(GIT)is closely related to the occurrence,the development and the therapeutic effect of CRC.In addition,gut microbiota homeostasis can also influence the efficacy and side effects of common cancer treatments such as chemotherapy.Therefore,modulating the gut microbiota is expected to improve the therapeutic effect of CRC.Prebiotics,a class of substances that can be utilized by beneficial bacteria to improve the gut micro-ecosystem,are potential tools for regulating gut microbiota.Natural products from plants,such as oligosaccharides,have been shown to have prebiotic effects.Its polymer structure is stable in the upper GIT and degradable by the microbiota in the intestines.With the development of nanotechnology,taking advantage of the good biocompatibility of oligosaccharides,they are applied in the design of nano-drug delivery systems,which can not only achieve controlled drug release in the GIT,but also enhance the effects of chemotherapy by modulating the gut microbiota.Therefore,in order to prolong the plasma half-life of Cap and enhance its antitumor effect by modulating the gut microbiota,we designed and constructed a Cap-loaded prebiotic nanoparticle,SCXN,in which Cap was conjugated with stearic acid to increase its hydrophobicity,and the conjugate was encapsulated by the amphiphilic derivative of the prebiotic xylan.SCXN prolonged the drug absorption and transport in the intestines,slowed the drug clearance in blood,and increased the intra-tumoral Cap concentration in the CRC mice model after oral administration.Meanwhile,SCXN facilitated the probiotics proliferation and short chain fatty acid production.Through gut microbiota modulation,SCXN stimulated the anti-tumor immune responses,especially promoting the CD8~+T cells infiltration in tumors,and enhanced the tumor-suppressing effect of Cap.SCXN exhibited good biocompatibility after multi-dose treatments and prolonged the CRC-bearing-mice’s lifespan.Prebiotics-based nano drug delivery systems combine gut microbiota modulation and chemotherapy,and are expected to become a safe and effective new strategy for CRC treatment.