Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China; Nano Sci-Tech Institute, University of Science and Technology of China, Suzhou 215123, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China; Shanghai University College of Sciences, Shanghai 200444, China.
Biomaterials. 2018 Mar;158:56-73. doi: 10.1016/j.biomaterials.2017.12.018. Epub 2017 Dec 22.
Chemoresistance remains a formidable hurdle against cancer therapy. Seeking for novel therapy strategies is an urgent need for those who no longer benefit from chemotherapy. Chemoresistance is usually associated with the dysfunction of intrinsic apoptosis. Targeting extrinsic apoptosis via TRAIL signaling and the death receptors could be a potential solution to treat chemoresistant cancer. A highly biocompatible nano system for codelivery of the TRAIL DNA and the death receptor sensitizer monensin was developed, in which low-molecular-weight PEI (LMW-PEI) was crosslinked by the sulfhydryl cyclodextrin via disulfide bonds, and then bound with DNA, thus forming the bioreducible polyplex cores. In addition, the cyclodextrin also functioned as a carrier for the hydrophobic monensin via host-guest inclusion. Poly-γ-glutamic acid (γ-PGA) was used to modify the polyplex core via charge interaction. The γ-PGA corona can specifically bind with the tumor-associated gamma-glutamyl transpeptidase (GGT) overexpressed on the tumor cells, and achieve tumor-targeting delivery. Moreover, the tumor-homing peptide RGD-modified γ-PGA was also prepared as the surface coating materials for further improving gene delivery efficiency. This gene delivery system was characterized by the dual ligand-targeting, dual stimuli-responsive features. The ligands of RGD and γ-PGA can target the tumor-associated receptors (i.e., integrin and GGT). The conformation of γ-PGA is pH-sensitive, and the tumor acidic micro environments could trigger the detachment of surface-coating γ-PGA. The disulfide crosslinking LMW-PEI is redox-sensitive, and its fast disassembling in the tumor cells could favor the efficient gene delivery. The anti-tumor efficacy was demonstrated both in vitro and in vivo. Moreover, MYC-mediated synthetic lethality could be an important mechanism for overcoming the drug resistance. An important finding of our studies is the demonstration of the in vivo treatment efficacy of TRAIL/monensin, thus providing a potential novel therapeutic strategy for overcoming drug-resistant cancer.
化学耐药性仍然是癌症治疗的一个巨大障碍。对于那些不再受益于化疗的人来说，寻找新的治疗策略是当务之急。化学耐药性通常与内在凋亡的功能障碍有关。通过 TRAIL 信号和死亡受体靶向细胞外凋亡可能是治疗耐药性癌症的一种潜在解决方案。开发了一种用于 TRAIL DNA 和死亡受体敏化剂莫能菌素共递送的高生物相容性纳米系统，其中低分子量聚乙烯亚胺（LMW-PEI）通过二硫键交联巯基环糊精，然后与 DNA 结合，从而形成可还原的多聚物核。此外，环糊精还通过主客体包合作用作为疏水性莫能菌素的载体。聚γ-谷氨酸（γ-PGA）通过电荷相互作用用于修饰多聚物核。γ-PGA 冠可以特异性结合肿瘤相关的谷氨酰转肽酶（GGT），该酶在肿瘤细胞上过表达，并实现肿瘤靶向递药。此外，还制备了肿瘤归巢肽 RGD 修饰的 γ-PGA 作为表面涂层材料，以进一步提高基因递送效率。该基因递送系统具有双重配体靶向、双重刺激响应的特点。RGD 和 γ-PGA 的配体可以靶向肿瘤相关受体（即整合素和 GGT）。γ-PGA 的构象对 pH 敏感，肿瘤酸性微环境可以触发表面涂层 γ-PGA 的脱落。LMW-PEI 的二硫交联是氧化还原敏感的，其在肿瘤细胞中的快速解体有利于有效的基因递送。在体外和体内都证明了该基因递送系统的抗肿瘤功效。此外，MYC 介导的合成致死可能是克服耐药性的一个重要机制。我们研究的一个重要发现是证明了 TRAIL/莫能菌素的体内治疗效果，从而为克服耐药性癌症提供了一种潜在的新治疗策略。
