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Enhanced Tumor Retention Effect by Click Chemistry for Improved Cancer Immunochemotherapy

Mei, Ling, Liu, Yayuan, Rao, Jingdong, Tang, Xian, Li, Man, Zhang, Zhirong, He, Qin
ACS applied materials & interfaces 2018 v.10 no.21 pp. 17582-17593
T-lymphocytes, adjuvants, agonists, antigen presentation, cell death, copper, dendritic cells, doxorubicin, lipid A, metastasis, mice, micelles, nanoparticles, permeability, reticuloendothelial system, therapeutics
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.