Nanogel-Incorporated Physical and Chemical Hybrid Gels for Highly Effective Chemo-Protein Combination Therapy
Nanogel-Incorporated Physical and Chemical Hybrid Gels for Highly Effective Chemo-Protein Combination Therapy
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用于高效化学-蛋白质联合疗法的纳米凝胶物理和化学混合凝胶
DOI：
10.1002/adfm.201502742
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发表时间：
2015
影响因子：
19
通讯作者：
Cheng Jianjun
中科院分区：
文献类型：
--
作者：
Wu Xilong;He Chaoliang;Wu Yundi;Chen Xuesi;Cheng Jianjun
基于化学和蛋白质的疗法是治疗恶性肿瘤的两种主要方式，具有截然不同的治疗指数，毒性和其他药理学特性。对于预期的体内应用，它们也具有明显不同的制剂挑战，需要单独解决。在这项研究中，我们试图克服基于化学和蛋白质的治疗剂的制剂障碍，并报告了可注射纳米凝胶的开发，这是一类交联的物理和化学复合凝胶（nPCG），用于联合递送阿霉素（DOX），蛋白质细胞因子重组人白细胞介素-2（IL-2）和重组人干扰素-γ（IFN-γ）。nPCG通过4臂聚乙烯的离子交联诱导快速凝胶化而设计（乙二醇）-B-聚（l-谷氨酸）（PPLG）和羟丙基壳聚糖/4臂聚（乙二醇）-B-聚（l-赖氨酸）（HPCS/PPLL），然后通过氧化的、带有胆固醇的葡聚糖（OCDEX）纳米凝胶与HPCS/PPLL的席夫碱反应形成共价键，这导致增加的水凝胶模量（G'约13.8kPa）和改善的稳定性。这种含有DOX、IL-2和IFN-γ的nPCG通过调节Janus激酶/信号转导和转录激活因子（JAK/STAT）途径和异种移植荷瘤小鼠线粒体途径中的细胞凋亡相关基因显示出协同抗癌功效。
Chemo‐ and protein‐based therapeutics are two major modalities for the treatment of malignant tumors with drastically different therapeutic indices, toxicity, and other pharmacological properties. For intended in vivo applications, they also have distinctly different formulation challenges to be addressed separately. In this study, we attempt to overcome the formulation barriers of chemo‐ and protein‐based therapeutics, and report the development of injectable nanogels, a class of crosslinked physical and chemical composite gels (nPCGs), for the joint delivery of doxorubicin (DOX), protein cytokines recombinant human interleukin‐2 (IL‐2), and recombinant human interferon‐gamma (IFN‐γ). The nPCGs are designed through a quick gelation induced by ionic crosslinking of 4‐arm poly(ethylene glycol)‐b‐poly(l‐glutamic acid) (PPLG) and hydroxypropyl chitosan/4‐arm poly(ethylene glycol)‐b‐poly(l‐lysine) (HPCS/PPLL), followed by the formation of covalent bonds via a Schiff‐base reaction of the oxidized, cholesterol‐bearing dextran (OCDEX) nanogels with HPCS/PPLL, which results in increased hydrogel moduli (G' around 13.8 kPa) and improved stability. This nPCG, which contains DOX, IL‐2, and IFN‐γ, shows a synergistic anticancer efficacy through the regulation of apoptosis‐related genes in Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways and mitochondrial pathways in xenograft tumor‐bearing mice.