UCST型载药胶束/纳米纤维复合膜对癌细胞沿腹膜扩散的抑制机制研究

Sevaral residual cancer cells prefer to proliferate along peritoneum after cancer resection, how to restrain such proliferation has become one of the key point to prevent recurrence of cancers. Drug carriers by electrospinning has been widely used in the field of controlled drug release. However, relevant literatures haven’t reported yet about how to immobilize the carriers in the postoperative wound site and keep them switchable release. Herein, the proposal focuses to prepare nanofiber composite membranes via coaxial electrospinning with water-soluble polymer (UCST-Type micelles and silver nanoparticles loaded ) as the core and hydrophobic polymer as shell. Immobilized UCST-Type micelle in the composite membranes show switchable drug release due to increased temperature, which induced by periodic near-infrared light irradiation on composite membrane containing silver nanparticles implanted inside peritoneum after cancer resection. Thus the immobilized composite membrane in postoperative wound site can inhibit the proliferation of residual cancer cells along the peritoneum and realized long-term of drug release. The effects of the morphology and structure of the coaxial fibrous composite membranes on the drug release performance will be investigated systematically. The sensitivity of fiber composite membrane response to near infrared light and the inhibition efficiency on cancer cells proliferation will be investigated. The achievements of this proposal will provide a new insight into effectively restrain proliferation along peritoneum after cancer resection.

研究显示多种癌症术后残留癌细胞较易沿腹膜扩散，如何抑制此类扩散成为预防癌症复发的关键之一。静电纺丝法制备的药物载体已被广泛应用于抗癌药物缓控释领域，但如何实现药物载体在术后创口部位长时间锚定且开关式释放的研究尚无相关报道。本项目旨在利用同轴静电纺丝法制备以水溶性聚合物（负载UCST型温敏载药胶束和银纳米粒子）为芯层，以疏水型聚合物为壳层的纳米纤维复合膜。通过近红外光周期性辐照术后植入腹腔内的复合膜，周期性辐照银纳米粒子导致的升温能诱导锚定在复合膜内UCST型胶束开关式释放所载药物，锚定在术后创口部位的复合膜和超长的药物释放周期能抑制癌细胞沿腹膜的扩散。系统研究同轴纤维复合膜的形貌和结构等对药物开关式释放性能的影响规律，重点考察纤维复合膜对近红外光响应的灵敏性及对术后残留癌细胞沿腹膜扩散的抑制效果。本项目的研究成果可为术后残留癌细胞沿腹膜扩散的有效抑制提供新的思路。

针对负载UCST温敏胶束电纺纤维复合膜在抗肿瘤方面的拓展应用，本项目执行期间发展了基于静电纺丝与微流控技术的微纳米材料构筑方法，研究了不同制备工艺参数对于微纳米材料理化性能的影响以及抗肿瘤效果。通过自由基聚合合成了一系列具有UCST温敏响应性的聚（丙烯腈-co-丙烯酰胺）聚合物胶束。通过调节单体的配比实现了对于胶束临界转化温度的控制，研究了制备工艺对微纳结构纤维膜的理化性质的影响。在制备了UCST温敏胶束的基础上，发展了多种其他刺激响应机制。探究了金属氧化物四氧化三铁纳米颗粒在不同溶剂中的自聚集现象和纳米颗粒在聚合物载体内的运动分布机制。构建了具有光响应性的负载四氧化三铁纳米颗粒聚乳酸薄膜；负载四氧化三铁纳米颗粒聚己内酯电纺纤维；具有刺激响应药物释放性能的吲哚菁绿/纤维素纳米晶复合药物载体和能够实现胰岛素释放的人工细胞。实验结果证明，低能量（小于2J/cm2）和短脉冲（小于3ns）激光激发复合膜产生的微纳气泡足以杀死术后残留的肿瘤细胞。这种“轻柔式杀伤”的方法在癌细胞扩散抑制和胞内递送领域均展现出广阔的应用前景。为通过简单的方法构建生物相容性和生物可降解性好的微纳结构材料提供了新的思路。自2018年以来，以通讯作者共发表和本项目相关的SCI收录论文10篇，包括1篇Nature Nanotechnology和2篇Advanced Materials，申请国内发明专利5件，其中授权2件。

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