Dual pH-responsive multifunctional nanoparticles for targeted treatment of breast cancer by combining immunotherapy and chemotherapy
Dual pH-responsive multifunctional nanoparticles for targeted treatment of breast cancer by combining immunotherapy and chemotherapy
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双pH响应多功能纳米粒子联合免疫疗法和化疗靶向治疗乳腺癌
DOI：
10.1016/j.actbio.2017.11.010
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发表时间：
2018-01-15
影响因子：
9.7
通讯作者：
Wang, Yinsong
中科院分区：
文献类型：
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作者：
Liu, Yuanyuan;Qiao, Linan;Wang, Yinsong
在本研究中，设计了一种双重pH响应的多功能纳米颗粒系统，用于结合免疫治疗和化疗，通过靶向免疫细胞和癌细胞来治疗乳腺癌。将一种经证实的抗肿瘤免疫调节剂R848与聚（L-组氨酸）（PHIS）包封以形成PHIS/R848纳米核。多柔比星（DOX）通过酸可裂解的腙键连接与透明质酸（HA）缀合以合成聚合物前药HA-DOX，其随后被包覆在PHIS/R848纳米核的外部以形成HA-DOX/PHIS/R848纳米颗粒。PHIS在pH 6.5（接近肿瘤微环境的pH值）附近的电离将该材料的性质从疏水性转变为亲水性，从而触发R848的释放以发挥免疫调节作用。HA-DOX中的腙键在约pH 5.5（内/溶酶体的pH）下的断裂加速DOX的释放以发挥细胞毒性作用。在免疫细胞中，PHIS/R848纳米核表现出与游离R848诱导的免疫调节活性类似的强免疫调节活性。在过表达CD 44的乳腺癌细胞中，HA-DOX通过CD 44介导的内吞作用被特异性内化，并显著抑制细胞生长。在4 T1荷瘤小鼠体内，HA-DOX/PHIS/R848纳米粒表现出良好的肿瘤靶向性，通过调节肿瘤免疫和杀伤肿瘤细胞，显著抑制肿瘤生长。综上所述，该多功能纳米粒子系统可以将R848和DOX分别递送到肿瘤微环境和乳腺癌细胞中，实现免疫治疗和化疗对乳腺癌的协同效应。主要的挑战是同时特异性地靶向癌症和免疫细胞。本研究设计了一种基于聚L-组氨酸和透明质酸的双重pH响应性多功能纳米粒体系，通过不同的包封方式实现了免疫调节剂R848和化疗药物阿霉素的共载。通过响应肿瘤微环境和细胞内细胞器的酸性pH值，这种多功能纳米颗粒系统可以在细胞外释放R848并将DOX靶向递送到乳腺癌细胞，从而实现针对乳腺癌的免疫治疗和化疗的协同效应。(C)2017 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
In the present study, a dual pH-responsive multifunctional nanoparticle system was designed for combining immunotherapy and chemotherapy to treat breast cancer through targeting immune cells and cancer cells. A proven anti-tumor immune regulator, R848, was encapsulated with poly(L-histidine) (PHIS) to form PHIS/R848 nanocores. Doxorubicin (DOX) was conjugated to hyaluronic acid (HA) through an acid-cleavable hydrazone bond linkage to synthesize polymeric prodrug HA-DOX, which was subsequently coated outside PHIS/R848 nanocores to form HA-DOX/PHIS/R848 nanoparticles. Ionization of PHIS around pH 6.5 (a pH value close to that of tumor microenvironment) switched the nature of this material from hydrophobic to hydrophilic, and thus triggered the release of R848 to exert immunoregulatory action. The rupture of hydrazone bond in HA-DOX at about pH 5.5 (pH of endo/lysosomes) accelerated the release of DOX to exert cytotoxic effects. In immune cells, PHIS/R848 nanocores exhibited strong immunoregulatory activities similar to those induced by free R848. In breast cancer cells overexpressing CD44, HA-DOX was specially internalized by CD44-mediated endocytosis and significantly inhibited the cell growth. In 4T1 tumor-bearing mice, HA-DOX/PHIS/R848 nanoparticles showed excellent tumor-targeting ability and remarkably inhibited the tumor growth by regulating tumor immunity and killing tumor cells. In summary, this multifunctional nanoparticle system could deliver R848 and DOX respectively to tumor microenvironment and breast cancer cells to achieve synergistic effects of immunotherapy and chemotherapy against breast cancer.Statement of SignificanceCombination of immunotherapy and chemotherapy is becoming a promising new treatment for cancer. The major challenge is to target cancer and immune cells simultaneously and specifically. In this study, a dual pH-responsive multifunctional nanoparticle system based on poly(L-histidine) and hyaluronic acid was designed for co-loading R848 (immune-regulator) and doxorubicin (chemotherapeutic drug) through different encapsulation modes. By responding to the acidic pHs of tumor microenvironment and intracellular organelles, this multifunctional nanoparticle system could release R848 extracellularly and deliver DOX targetedly to breast cancer cells, thus achieving synergistic effects of immunotherapy and chemotherapy against breast cancer. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.