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Enhanced Tumor Retention Effect by Click Chemistry for Improved Cancer Immunochemotherapy

Author:
Mei, Ling, Liu, Yayuan, Rao, Jingdong, Tang, Xian, Li, Man, Zhang, Zhirong, He, Qin
Source:
ACS applied materials & interfaces 2018 v.10 no.21 pp. 17582-17593
ISSN:
1944-8252
Subject:
T-lymphocytes, adjuvants, agonists, antigen presentation, cell death, copper, dendritic cells, doxorubicin, lipid A, metastasis, mice, micelles, nanoparticles, permeability, reticuloendothelial system, therapeutics
Abstract:
Because of the limited drug concentration in tumor tissues and inappropriate treatment strategies, tumor recurrence and metastasis are critical challenges for effectively treating malignancies. A key challenge for effective delivery of nanoparticles is to reduce uptake by reticuloendothelial system and to enhance the permeability and retention effect. Herein, we demonstrated Cu(I)-catalyzed click chemistry triggered the aggregation of azide/alkyne-modified micelles, enhancing micelles accumulation in tumor tissues. In addition, combined doxorubicin with the adjuvant monophosphoryl lipid A, an agonist of toll-like receptor4, generated immunogenic cell death, which further promoted maturity of dendritic cells, antigen presentation and induced strong effector T cells in vivo. Following combined with anti-PD-L1 therapy, substantial antitumor and metastasis inhibitory effects were achieved because of the reduced PD-L1 expression and regulatory T cells. In addition, effective long-term immunity from memory T cell responses protected mice from tumor recurrence.
Agid:
5961185