CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, iChem (Collaborative Innovation Center of Chemistry for Energy Materials), Department of Polymer Science and Engineering, University of Science and Technology of China , Hefei, Anhui 230026, China.
Biomacromolecules. 2017 Aug 14;18(8):2571-2582. doi: 10.1021/acs.biomac.7b00693. Epub 2017 Jul 26.
The use of intracellular reductive microenvironment to control the release of therapeutic payloads has emerged as a popular approach to design and fabricate intelligent nanocarriers. However, these reduction-responsive nanocarriers are generally trapped within endolysosomes after internalization and are subjected to unwanted disintegration, remarkably compromising the therapeutic performance. Herein, amphiphilic polyprodrugs of poly(N,N-dimethylacrylamide-co-EoS)-b-PCPTM were synthesized via sequential reversible addition-fragmentation chain transfer (RAFT) polymerization, where EoS and CPTM are Eosin Y- and camptothecin (CPT)-based monomers, respectively. An oil-in-water (O/W) emulsion method was applied to self-assemble the amphiphilic polyprodrugs into hybrid vesicles in the presence of hydrophobic oleic acid (OA)-stabilized upconversion nanoparticles (UCNPs, NaYF:Yb/Er), rendering it possible to activate the EoS photosensitizer under a near-infrared (NIR) laser irradiation with the generation of singlet oxygen (O) through the energy transfer between UCNPs and EoS moieties. Notably, the in situ generated singlet oxygen (O) can not only exert its photodynamic therapy (PDT) effect but also disrupt the membranes of endolysosomes and thus facilitate the endosomal escape of internalized nanocarriers (i.e., photochemical internalization (PCI)). Cell experiments revealed that the hybrid vesicles could be facilely taken up by endocytosis. Although the internalized hybrid vesicles were initially trapped within endolysosomes, a remarkable endosomal escape into the cytoplasm was observed under 980 nm laser irradiation as a result of the PCI effect of O. The escaped hybrid vesicles subsequently underwent GSH-triggered CPT release in the cytosol, thereby activating the chemotherapy process. The integration of PDT module into the design of reduction-responsive nanocarriers provides a feasible approach to enhance the therapeutic performance.
利用细胞内还原性微环境来控制治疗有效载荷的释放，已成为设计和制造智能纳米载体的一种热门方法。然而，这些还原响应性纳米载体在被内化后通常会被困在内溶酶体中，并遭受不必要的崩解，从而显著影响治疗效果。在此，通过顺序可逆加成-断裂链转移（RAFT）聚合，合成了双亲性聚（N，N-二甲基丙烯酰胺-co-EoS）-b-PCPTM 聚前药，其中 EoS 和 CPTM 分别为曙红 Y 和喜树碱（CPT）基单体。应用油包水（O/W）乳液法，在前驱体存在的情况下，将双亲性聚前药自组装成混合囊泡，其中包含疏水性油酸（OA）稳定的上转换纳米粒子（UCNPs，NaYF:Yb/Er），使得可以在近红外（NIR）激光照射下激活 EoS 光敏剂，通过 UCNPs 和 EoS 部分之间的能量转移产生单线态氧（O）。值得注意的是，原位产生的单线态氧（O）不仅可以发挥其光动力治疗（PDT）作用，还可以破坏内溶酶体的膜，从而促进内化纳米载体的内体逃逸（即光化学内吞作用（PCI））。细胞实验表明，这些混合囊泡可以通过内吞作用轻易被摄取。尽管被内化的混合囊泡最初被捕获在内溶酶体中，但由于 O 的 PCI 作用，在 980nm 激光照射下，观察到明显的内体逃逸到细胞质中。逃逸的混合囊泡随后在细胞质中经历 GSH 触发的 CPT 释放，从而激活化学治疗过程。将 PDT 模块集成到还原响应性纳米载体的设计中，为提高治疗效果提供了一种可行的方法。
