Injectable Supramolecular Hydrogels as Delivery Agents of Bcl-2 Conversion Gene for the Effective Shrinkage of Therapeutic Resistance Tumors
Injectable Supramolecular Hydrogels as Delivery Agents of Bcl-2 Conversion Gene for the Effective Shrinkage of Therapeutic Resistance Tumors
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DOI：
10.1002/adhm.201700159
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发表时间：
2017-06-07
影响因子：
10
通讯作者：
Wu, Yun-Long
中科院分区：
文献类型：
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作者：
Liu, Xuan;Chen, Xiaohong;Wu, Yun-Long
可注射水凝胶以微创的方式传递治疗性基因，并在肿瘤部位实现长期缓释，将副作用降至最低，这在癌症治疗和精确医学中具有吸引力，但其合理设计仍然是一个挑战。本文基于α-环糊精(α-CD)与阳离子甲氧基-聚乙二醇聚(e-己内酯)-b-聚乙二亚胺(mpeg-PCL-PEI)共聚物之间的聚环糊精形成聚合物，设计了一种可注射的超分子水凝胶体系，能够与阴离子质粒DNA形成聚合物，以实现有效的持续基因传递。值得一提的是，与非病毒基因转染金标准PEI(25 KDa)相比，由于形成了胶束和更稳定的多聚体，mPG-PCL-PEI共聚物具有类似的PDNA结合能力、更高的基因转染率、更低的细胞毒性。更重要的是，这种mpeg-PCL-PEI/α-CD/PDNA超分子水凝胶显示了PDNA以多聚体的形式持续释放长达7d。利用这些优点，这种超分子水凝胶系统被用作持续释放Bcl2转化基因的注射载体，在高表达抗细胞凋亡的Bcl2蛋白的啮齿动物模型中得到了应用。这项工作首次表明可注射的mpeg-PCL-PEI/α-CD超分子水凝胶能够以多聚体的形式有效地抑制体内肿瘤的生长，具有良好的可控释放Bcl2转化基因的效果，这一“朋友之敌”策略将有利于各种应用，包括按需基因传递和个性化药物治疗。
Injectable hydrogels to deliver therapeutic genes in a minimally invasive manner and to achieve long term sustained release at tumor sites to minimize side effects are attractive for cancer therapy and precision medicine, but its rational design remains a challenge. In this report, an injectable supramolecular hydrogel system is designed based on the polypesudorotaxane formation between a-cyclodextrin (alpha-CD) and cationic methoxy-poly(ethylene glycol)b-poly(e-caprolactone)-b-poly(ethylene imine) (MPEG-PCL-PEI) copolymer, with the ability to form polyplexes with anionic plasmid DNA for effective sustained gene delivery. To be mentioned, the MPEG-PCL-PEI copolymers show similar pDNA binding ability, better gene transfection efficiency, lower cytotoxicity than nonviral gene transfection gold standard PEI (25 kDa), due to the formation of micelles and more stable polyplexes. More importantly, this MPEG-PCL-PEI/alpha-CD/pDNA supramolecular hydrogel shows a sustained release of pDNA in form of polyplex for up to 7 d. By taking these advantages, this supramolecular hydrogel system is applied as an injectable carrier for sustained Bcl-2 conversion gene release, in an in vivo rodent model of therapeutic resistant hepatocarcinoma with high expression of antiapoptotic Bcl-2 protein. This work represents the first time that injectable MPEG-PCL-PEI/alpha-CD supramolecular hydrogels possess good controllable release effect of Bcl-2 conversion genes in the form of polyplex to effectively inhibit in vivo tumor growth and this "enemy to friend" strategy will benefit various applications, including on-demand gene delivery and personalized medicine.