长循环、智能靶向p32的pH敏感纳米粒子@血红细胞膜纳米载药体系用于乳腺癌的靶向治疗

The accumulation of nano-delivery systems can be achieved by enhancing the circulating time of nanoparticles in vivo or by tumor-homing peptide modification. Long circulation can maximumly enhanced the nanoparticle accumulation in tumor site via EPR effect. Active tumor targeting is the basic property of nano-delivery systems in cancer therapy. However, the circulation behaviors and tumor targeting efficiencies of most of the nanosystems are still needed to be improved. From our previous study, we found that the intelligent nanogel systems exhibited great potential in the designation and construction of novel nano drug delivery systems. Based on the excellent pH responsive properties of nanogel systems, we intent to design and prepare a hybrid nanosystem for long circulation drug delivery and intelligent targeting to p32-a receptor protein which are over expressed in breast cancer tissue. The hybrid nanosystem composed with a pH sensitive nanoaprticle as the core and the red blood cell membrane as the shell. Furthermore, the pH sensitive nanoparticle core was also a novel core-shell pH sensitive nanoparticle system formed by self assembling of PCL-PHMAMA, PCL was used as the hydrophobic core while PHMAMA as the pH sensitive shell. After the modification of Lyp-1 and TAT, the cellular uptake of the PCL-PHMAMA nanoparticles was greatly enhanced in MCF-7 breast cancer cells culturing. The introduction of red blood cell membrane greatly enhanced the circulation time of ligand modified PCL-PHMAMA nanoparticles in vivo. And the PHMAMA layer took place structure expansion in weak acidic environment, which means that the red blood cell membrane coating can be damaged by the structure expansion in acidic environment. The microenvironment of solid tumor exhibited weak acidic. Therefore, while the hybrid nanosystems pass through the tumor tissue, the ultra pH sensitive of PHMAMA layer enlarged, damaged the RBCs membrane, the ligand exposure. The ligand take action in tumor site. Moreover, the shrinkage structure of the PHMAMA layer in pH=7.4 can also reduce the undesired drug release from the nanosystems in body circulation. The research of this project provides a novel way in the construction of smart nanosystems with long circulating and efficient tumor targeting properties.

纳米体系在肿瘤部位的富集可通过提高循环时间和肿瘤靶向性配体修饰获得。长循环特性可延长纳米体系的循环时间，提高纳米体系在肿瘤部位的富集，增强抑瘤效果。肿瘤靶向性是纳米体系在肿瘤治疗过程中的必需功能。已有纳米体系的长循环能力及肿瘤靶向性仍不够理想，需开发新型纳米体系。通过前期研究表明，智能纳米水凝胶在构建新型纳米体系中具有极大的潜力。在本项目中，申请人在原有对智能纳米水凝胶的研究基础上，采用壳层pH敏感的纳米粒作为内核，再采用血红细胞膜对其进行包覆，开发pH敏感的复合纳米体系，通过该体系的长循环特性及智能肿瘤靶向性，提高纳米体系在体内的药物递送效率及抗肿瘤效果。在中性条件下，内核的壳层处于收缩状态，药物突释得到控制、修饰的配体被血红细胞膜所保护、具有血红细胞的长循环特性，在复合体系流经肿瘤组织时，壳层发生体积膨胀，血红细胞膜破裂，使细胞膜包覆的肿瘤靶向性配体暴露，在肿瘤部位直接产生靶向作用。

纳米体系在肿瘤部位的富集可通过提高循环时间和肿瘤靶向性配体修饰获得。长循环特性可延长纳米体系的循环时间，提高纳米体系在肿瘤部位的富集，增强抑瘤效果。肿瘤靶向性是纳米体系在肿瘤治疗过程中的必需功能。已有纳米体系的长循环能力及肿瘤靶向性仍不够理想，需开发新型纳米体系。通过前期研究表明，智能纳米水凝胶在构建新型纳米体系中具有极大的潜力。而血红细胞由于其表面蛋白的存在，使其具有长循环特性。因此，在本项目中，申请人在原有对智能纳米水凝胶的研究基础上，进一步开发新型纳米生物材料体系，并在保留其长循环特性的前提下分离提取血红细胞膜，采用血红细胞膜对新型纳米体系进行包覆，研究考察了复合纳米体系在提高肿瘤富集、增强抗肿瘤效果的应用。研究结果表明，血红细胞膜已成功被提取分离，并与纳米体系成功复合，复合后的纳米体系体内循环时间延长，抗肿瘤效果相应得到提高。同时，采用配体修饰的纳米体系不仅提高了药物递送效率，而且可作为良好的载体用于药物的共传输，实现对肿瘤的联合治疗。此外，研究结果亦表明采用联合治疗能够有效提高抗肿瘤效果，并能够在抑制原发肿瘤的同时，对肿瘤的转移及远端肿瘤的生长均有缓解作用。在本项目的资助下发表SCI论文6篇，其中以第一作者或通讯作者发表在ACS Applied Materials & Interfaces期刊发表论文3篇，在Advanced Science期刊发表1篇，在Biomaterials Science期刊发表论文一篇；申请专利一项（已公开）。本项目已基本完成项目计划内容，研究成果已基本达到项目的预期目标。