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Nanogel-Incorporated Physical and Chemical Hybrid Gels for Highly Effective Chemo-Protein Combination Therapy

机译：纳米凝胶结合的物理和化学混合凝胶，用于高效的化学-蛋白质组合治疗

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摘要

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-gamma). 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-gamma, 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.
机译：基于化学和蛋白质的治疗方法是两种治疗指数，毒性和其他药理特性截然不同的恶性肿瘤的主要治疗方法。对于预期的体内应用，它们还具有明显不同的配方挑战，需要分别解决。在这项研究中，我们试图克服基于化学和蛋白质的治疗方法的配方障碍，并报告可注射纳米凝胶的发展，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介素2（IL-2）和重组人干扰素-γ（IFN-γ）。 nPCG是通过4臂聚（乙二醇）-b-聚（L-谷氨酸）（PPLG）和羟丙基壳聚糖/ 4臂聚（乙二醇）-b-poly的离子交联引起的快速凝胶化而设计的（L-赖氨酸）（HPCS / PPLL），然后通过氧化的，含胆固醇的葡聚糖（OCDEX）纳米凝胶与HPCS / PPLL的席夫碱反应形成共价键，从而导致水凝胶模量（G'约13.8 kPa）和更高的稳定性。该nPCG包含DOX，IL-2和IFN-γ，通过调节Janus激酶/信号转导子中的凋亡相关基因和异种移植物中的转录激活子（JAK / STAT）和线粒体途径，显示出协同的抗癌功效。荷瘤小鼠。

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  • 来源
    《Advanced Functional Materials》 |2015年第43期|6744-6755|共12页
  • 作者

    Wu Xilong; He Chaoliang; Wu Yundi; Chen Xuesi; Cheng Jianjun;

  • 作者单位

    Chinese Acad Sci, Changchun Inst Appl Chem, Key Lab Polymer Ecomat, Changchun 130022, Peoples R China|Univ Chinese Acad Sci, Beijing 100049, Peoples R China;

    Chinese Acad Sci, Changchun Inst Appl Chem, Key Lab Polymer Ecomat, Changchun 130022, Peoples R China;

    Chinese Acad Sci, Changchun Inst Appl Chem, Key Lab Polymer Ecomat, Changchun 130022, Peoples R China;

    Chinese Acad Sci, Changchun Inst Appl Chem, Key Lab Polymer Ecomat, Changchun 130022, Peoples R China;

    Univ Illinois, Dept Mat Sci & Engn, Urbana, IL 61801 USA;

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