title: Investigation and intervention of autophagy to guide cancer treatment with nanogels.
abstract: Cancer cells use autophagy to resist poor survival environmental conditions such as low PH, poor nutrients as well as chemical therapy. Nanogels have been used as efficient chemical drug carriers for cancer treatment. However, the effect of nanogels on autophagy is still unknown. Here, we used Rab proteins as the marker of multiple trafficking vesicles in endocytosis and LC3 as the marker of autophagy to investigate the intracellular trafficking network of Rhodamine B (Rho)-labeled nanogels. The nanogels were internalized by the cells through multiple protein dependent endocytosis and micropinocytosis. After inception by the cells, the nanogels were transported into multiple Rab positive vesicles including early endosomes (EEs), late endosomes (LEs), recycling endosomes (REs) and lipid droplets. Finally, these Rab positive vesicles were transported to lysosome. In addition, GLUT4 exocytosis vesicles could transport the nanogels out of the cells. Moreover, nanogels could induce autophagy and be sequestered in autophagosomes. The crosstalk between autophagosomes and Rab positive vesicles were investigated, we found that autophagosomes may receive nanogels through multiple Rab positive vesicles. Co-delivery of autophagy inhibitors such as chloroquine (CQ) and the chemotherapeutic drug doxorubicin (DOX) by nanogels blocked the autophagy induced by DOX greatly decreasing both of the volume and weight of the tumors in mice tumor models. Investigation and intervention of the autophagy pathway could provide a new method to improve the therapeutic effect of anticancer nanogels.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Liang
authors.forename: Jianjun
authors.initials: J
authors.lastname: Gu
authors.forename: Danfeng
authors.initials: D
authors.lastname: Chang
authors.forename: Jinxie
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Chen
authors.forename: Yanqi
authors.initials: Y
authors.lastname: Ye
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Tao
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zeng
authors.forename: Gan
authors.initials: G
authors.lastname: Liu
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000818:Animals; D001343:Autophagy; D002738:Chloroquine / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D004705:Endocytosis; D011992:Endosomes; D005089:Exocytosis; D005260:Female; D005782:Gels; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D053758:Nanoparticles; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D012235:Rhodamines; D023041:Xenograft Model Antitumor Assays; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D005782:Gels; D012235:Rhodamines; D004317:Doxorubicin; D002738:Chloroquine; D020691:rab GTP-Binding Proteins; C029773:rhodamine B