基于“多模式镇痛”的双载药环境敏感型口服Janus纳米粒的构建及释药-吸收机制研究

Administrating single analgesic drug is being replaced by a combination of analgesic drugs with diverse modes as part of a multimodal approach to preventing pain, which is called “multimodal analgesia”. In this project, we will follow the concept of “multimodal analgesia” and the results of our preliminary experiments to design a new type of dual drug delivery systems, in order to realize synergistic analgesic by α-cobrotoxin (αCT) and resveratrol (Res). However, αCT as polypeptide will be encountered obstacles such as acid hydrolysis and low permeability of intestinal mucosa though oral administration, while Res as insoluble drug is limited in oral administration because of the low bioavailability. Thus, we plan to employe the modified multiple emulsion solvent evaporation method with environment-responsive carrier material of low molecular weight chitosan/sodium alginate, to prepare a new type of oral Janus nanoparticles, which have the advantage of unique cavity structure, controllable particle size, dual-drug codelivery, and are particularly attractive for the purpose of protect the drugs in the acidic stomach and burst instantaneously under neutral pH in the small intestine to release the loaded drugs, and improving the bioavailability of αCT and Res. In addition, we will use multi-site microdialysis, which simultaneously implant microdialysis probes in intestinal cavity, intestinal wall and mesenteric vein, to dynamic track the process of drug release and absorption combining with in vivo analysis technology. Associate with the mechanism of absorption from the results of co-culture model of gastrointestinal cells, we will further elucidate the mechanism of drug release-absorption, and expect to construct a appraisable system for research and evaluation of dual drug delivery systems. This project will provide brand new insights and research mode for oral administration and analgesic therapy of traditional chinese medicine and polypeptide loaded dual drug delivery system.

单一的镇痛药物难以达到完全的疼痛缓解，因此本项目遵循“多模式镇痛”理念并基于预试验结果，设计新型双药物传递系统（DDDSs）以实现神经毒素（αCT）和白藜芦醇（Res）经口服途径协同镇痛。针对多肽类镇痛药物αCT口服面临酸水解和肠黏膜低渗透性等障碍，以及难溶性镇痛药物Res口服生物利用度低的局限，以改良的复乳-溶剂蒸发法辅以环境敏感型载体材料低分子量壳聚糖/海藻酸钠，构建具有独特腔室结构、粒径可控、可协同递药的新型口服Janus纳米粒，以实现αCT和Res的独立包载和胃液中稳定、小肠中释药，并提高两者的生物利用度；同时，利用肠腔、肠壁、肠系膜静脉多位点组合微透析在体分析技术动态追踪释药和吸收过程，并结合胃肠道细胞共培养模型的吸收机制，深入阐释Janus纳米粒的“释药-吸收”机制，建立相对完善的研究评价体系，以期为中药/多肽双载药系统的口服递送及镇痛治疗提供全新的视野和研究模式。

单一的镇痛药物难以达到完全的疼痛缓解，因此本项目遵循“多模式镇痛”理念并基于预试验结果，设计新型双药物传递系统（DDDSs）以实现神经毒素（αCT）和白藜芦醇（Res）经口服途径协同镇痛。针对多肽类镇痛药物αCT口服面临酸水解和肠黏膜低渗透性等障碍，以及难溶性镇痛药物Res口服生物利用度低的局限，以改良的复乳-溶剂蒸发法辅以环境敏感型载体材料低分子量壳聚糖/海藻酸钠，构建具有独特腔室结构、粒径可控、可协同递药的新型口服Janus纳米粒，以实现αCT和Res的独立包载和胃液中稳定、小肠中释药，并提高两者的生物利用度；同时，利用在体分析技术动态追踪释药和吸收过程，并结合胃肠道细胞共培养模型的吸收机制，深入阐释Janus纳米粒的“释药-吸收”机制。课题所构建多肽类镇痛药物联合难溶性镇痛药物的新型双载药环境敏感型Janus纳米粒可见双室结构，外形均一，粒径约230nm，zeta电位23.6mV，神经毒素包封率为（77.61±3.59）%，载药量为（0.12±0.04）%；白藜芦醇包封率为（81.78±7.79）%，载药量为（19.13±6.31）%，体外释药结果显示其在胃液中几乎不释药，而在肠液中释药，已实现两种不同性质及分子量的药物的协同递送，且未见明显的细胞毒性；药效学评价结果显示该Janus纳米粒可实现αCT和Res经口服途径的协同镇痛。本研究为含有蛋白质多肽类药物的双载药递送系统的构建建立相对完善的研究评价体系，以期为中药/多肽双载药系统的口服递送及镇痛治疗提供全新的视野和研究模式。