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Nanoparticle formulation improves doxorubicin efficacy by enhancing host antitumor immunity
Journal of Controlled Release ( IF 10.8 ) Pub Date : 2017-11-13 , DOI: 10.1016/j.jconrel.2017.11.021
Eric M. Mastria , Leon Y. Cai , Matthew J. Kan , Xinghai Li , Jeffrey L. Schaal , Steven Fiering , Michael D. Gunn , Mark W. Dewhirst , Smita K. Nair , Ashutosh Chilkoti

Strategies that enhance the host antitumor immune response promise to revolutionize cancer therapy. Optimally mobilizing the immune system will likely require a multi-pronged approach to overcome the resistance developed by tumors to therapy. Recently, it has become recognized that doxorubicin can contribute to re-establishing host antitumor immunity through the generation of immunogenic cell death. However, the potential for delivery strategies to further enhance the immunological effects of doxorubicin has not been adequately examined. We report herein that Chimeric Polypeptide Doxorubicin (CP-Dox), a nanoparticle formulation of doxorubicin, enhances antitumor immunity. Compared to free doxorubicin, a single intravenous (IV) administration of CP-Dox at the maximum tolerated dose increases the infiltration of leukocytes into the tumor, slowing tumor growth and preventing metastasis in poorly immunogenic 4T1 mammary carcinoma. We demonstrate that the full efficacy of CP-Dox is dependent on CD8 + T cells and IFN-γ. CP-dox treatment also repolarized intratumoral myeloid cells towards an antitumor phenotype. These findings demonstrate that a nanoparticle drug is distinct from the free drug in its ability to productively stimulate antitumor immunity. Our study strongly argues for the use of antitumor immunotherapies combined with nanoparticle-packaged chemotherapy.



中文翻译:

纳米颗粒制剂可通过增强宿主抗肿瘤免疫力来提高阿霉素的功效

增强宿主抗肿瘤免疫反应的策略有望彻底改变癌症治疗。最佳地调动免疫系统可能需要采取多管齐下的方法来克服肿瘤对治疗产生的耐药性。最近,已经认识到阿霉素可以通过产生免疫原性细胞死亡而有助于重建宿主抗肿瘤免疫力。但是,尚未充分研究可能进一步增强阿霉素免疫学作用的递送策略。我们在这里报告说,嵌合多肽阿霉素(CP-Dox),阿霉素的纳米颗粒制剂,增强了抗肿瘤免疫力。与游离阿霉素相比,以最大耐受剂量单次静脉内(IV)施用CP-Dox可增加白细胞向肿瘤的浸润,降低免疫原性差的4T1乳腺癌的肿瘤生长并预防转移。我们证明,CP-Dox的全部功效取决于CD8 + T细胞和IFN-γ。CP-dox治疗还使肿瘤内的髓样细胞极化为抗肿瘤表型。这些发现证明,纳米颗粒药物与游离药物的区别在于其有效地刺激抗肿瘤免疫的能力。我们的研究强烈主张将抗肿瘤免疫疗法与纳米颗粒包装的化学疗法结合使用。这些发现证明,纳米颗粒药物与游离药物的区别在于其有效地刺激抗肿瘤免疫的能力。我们的研究强烈主张将抗肿瘤免疫疗法与纳米颗粒包装的化学疗法结合使用。这些发现表明,纳米颗粒药物与游离药物的区别在于其有效地刺激抗肿瘤免疫的能力。我们的研究强烈主张将抗肿瘤免疫疗法与纳米颗粒包装的化学疗法结合使用。

更新日期:2017-11-13
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