基于FRET技术的两级响应基因干预/检测一体化载体的构建及其在肿瘤治疗中的作用

目前，影像介导的、肿瘤特异性的纳米载体用于肿瘤的诊疗一体化是肿瘤精准医疗的一个新发展方向。然而经静脉递送的诊疗制剂往往要经过血液，组织和细胞三级生理屏障才能达到靶部位。因此如何利用肿瘤微环境来设计具有生物响应性的遮蔽结构来减少非特异作用并同步实现肿瘤特异性的医学成像是一个挑战。本项目拟制备一种具有酶响应的超支化聚缩水甘油醚遮蔽外壳与具有胞内谷胱甘肽响应降解的超支化聚酰胺-胺内核，通过主客体作用而组装成的两级响应基因治疗/成像一体化载体。其遮蔽外壳具有电荷遮蔽和荧光淬灭的双重作用，其聚阳离子内核同时负载治疗基因和近红外探针。该核壳组装体经血液递送时抗非特异性吸附并使内核荧光淬灭，在肿瘤微环境的酶解下脱去外壳并恢复基因转染和成像活性。这一微环境驱动“光开关”载体兼顾血液递送安全性、肿瘤微环境响应的靶向性和成像能力、基因胞浆递送高效性。因此，该两级响应智能载体为诊疗一体化载体的分子设计提供思路。

Currently, Imaging-guided site-specific delivery systems based on nanomaterials for cancer theranostics have been recognized as promising alternatives to traditional therapies in clinic. However, the theranostic nanomedicines must go through a cascade of three-stage biological barriers (blood-tissue-cell) to achieve targeted site. Therefore How to fabricate a nanomedicine with bio-responsive shielding structure for synchronizing non-specific interaction resistance and tumor-specific imaging is still a challenge. In our project, a two-stage responsive nanomedicine is prepared by glutathione-responsive hyperbranched poly(amidoamine)s as the core and enzyme-responsive hyperbranched polyglycerol as shielding shell through supramolecular host-guest interaction for synchronous gene therapy and near-infrared imaging. The shielding shell is endowed both charge shielding and fluorescence quenching abilities, while the polycation core is loaded with therapeutic gene and NIR probe. Such a core/shell assembly exhibits non-specific adsorption resistance with probe in quenched state in blood, and then displays enzyme-triggered shell detachment from the core in tumor microenvironments, leading gene transfection and imaging capacity recovery. Therefore this nanomedicine with “photoswitch” integrates blood compatibility, tumor microenvironment triggered targeting and imaging abilities and gene delivery efficiency. It will direct the design and synthesis of novel theranostic nanomedicines for clinical application.