Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
Theranostics. 2019 Jan 1;9(2):337-354. doi: 10.7150/thno.29026. eCollection 2019.
High-efficiency treatment for tumor is not easy to achieve owing to the existence of metastasis, which remains the arch-criminal of most tumor deaths. Conventional chemotherapy exhibits insufficient inhibitory efficiency on tumor metastasis and more powerful strategies to conquer metastatic tumors are urgently needed. In this study, a rational chemoimmunotherapy strategy was adopted to treat highly aggressive melanoma based on a newly developed multifunctional nanoplatform. Firstly, immunoadjuvant cytosine-phosphate-guanine oligonucleotides (CpG ODNs) were used to boost the doxorubicin (DOX)-elicited immune responses, which synergistically suppressed tumor growth and metastasis. And the anti-metastatic low molecular weight heparin (LMWH) was also integrated, thus multiple anti-metastatic effects to against tumor metastasis were achieved. G4 PAMAM was serving as the main support to conjugate DOX by pH-sensitive hydrazone bond (PPD) and the synthesized conjugates were confirmed by H-NMR spectra, IR spectra and HRMS. Immunoadjuvant CpG ODNs were loaded by electrostatic adsorption to formulate PPD/CpG. After the coating of anti-metastatic LMWH, the designed LMWH/PPD/CpG was fabricated and characterized. The platelets-related and platelets-unrelated anti-metastatic mechanisms were investigated on B16F10 the immune activation effects, anti-tumor and anti-metastatic efficacy of LMWH/PPD/CpG were evaluated on a B16F10 melanoma xenograft model. DOX elicited tumor-specific immune responses by ICD, and the immunological effects could be further promoted by CpG ODNs, exhibiting enhanced maturation of dendritic cells (DCs) and increased level of cytolytic T lymphocytes (CTLs) . Owing to the coating of LMWH, the platelets-induced epithelial-mesenchymal-like transition of tumor cells was hindered and the actin cytoskeletal arrangement of tumor cells was affected, thus the migration ability of tumor cells was further inhibited. This multifunctional nanoplatform showed enhanced treatment efficiency on melanoma primary tumor and pulmonary metastasis. The immune activation and multiple anti-metastatic effects of LMWH/PPD/CpG establish a novel therapeutic strategy for melanoma. This anti-metastatic nanoplatform could be broadly applied for the co-delivery of other nucleic acids and chemotherapeutic drugs to treat highly aggressive tumors.
高效治疗肿瘤并不容易，因为转移的存在，这仍然是大多数肿瘤死亡的罪魁祸首。传统的化疗对肿瘤转移的抑制效率不足，迫切需要更强大的策略来攻克转移性肿瘤。在这项研究中，基于新开发的多功能纳米平台，采用合理的化学生物免疫治疗策略来治疗高度侵袭性黑色素瘤。首先，使用免疫佐剂胞嘧啶-磷酸-鸟嘌呤寡核苷酸（CpG ODNs）来增强阿霉素（DOX）引起的免疫反应，从而协同抑制肿瘤生长和转移。并且还整合了抗转移低分子量肝素（LMWH），从而实现了多种抗转移作用来对抗肿瘤转移。G4 PAMAM 作为通过 pH 敏感腙键（PPD）连接 DOX 的主要支撑物，通过 H-NMR 光谱、IR 光谱和 HRMS 来确认合成的缀合物。通过静电吸附装载免疫佐剂 CpG ODNs 以形成 PPD/CpG。在涂覆抗转移 LMWH 后，制备并表征了设计的 LMWH/PPD/CpG。在 B16F10 黑色素瘤异种移植模型上评估了 LMWH/PPD/CpG 的血小板相关和血小板无关的抗转移机制、免疫激活作用、抗肿瘤和抗转移疗效。DOX 通过 ICD 引起肿瘤特异性免疫反应，CpG ODNs 可进一步促进免疫反应，表现为树突状细胞（DCs）成熟增强，细胞毒性 T 淋巴细胞（CTLs）水平升高。由于 LMWH 的涂层，血小板诱导的肿瘤细胞上皮-间充质样转化受到阻碍，肿瘤细胞的肌动蛋白细胞骨架排列受到影响，从而进一步抑制了肿瘤细胞的迁移能力。这种多功能纳米平台对黑色素瘤原发肿瘤和肺转移显示出增强的治疗效果。LMWH/PPD/CpG 的免疫激活和多种抗转移作用为黑色素瘤建立了一种新的治疗策略。这种抗转移纳米平台可广泛应用于其他核酸和化疗药物的共递送，以治疗高度侵袭性肿瘤。
