Tumor Microenvironment-Mediated Construction and Deconstruction of Extracellular Drug-Delivery Depots

Protein therapy has been considered the most direct and safe approach to treat cancer. Targeting delivery of extracellularly active protein without internalization barriers, such as membrane permeation and endosome escape, is efficient and holds vast promise for anticancer treatment. Herein, we desc...

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Bibliographic Details
Published in:Nano letters 2016-02, Vol.16 (2), p.1118-1126
Main Authors: Hu, Quanyin, Sun, Wujin, Lu, Yue, Bomba, Hunter N, Ye, Yanqi, Jiang, Tianyue, Isaacson, Ari J, Gu, Zhen
Format: Article
Language:English
Subjects:
Angiogenesis Inhibitors - administration & dosage
Angiogenesis Inhibitors - chemistry
Animals
Antineoplastic Combined Chemotherapy Protocols - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - chemistry
Apoptosis
Apoptosis - drug effects
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Cancer
Cell Line, Tumor
Cell Membrane Permeability - drug effects
Cellular
Drug Delivery Systems
Endosomes - drug effects
Enzymes
Gene Transfer Techniques
Humans
Hyaluronoglucosaminidase - biosynthesis
Hyaluronoglucosaminidase - chemistry
Membranes
Mice
Nanostructure
Proteins
Snake Venoms - administration & dosage
Snake Venoms - chemistry
TNF-Related Apoptosis-Inducing Ligand - administration & dosage
Tumor Microenvironment - drug effects
Tumors
Xenograft Model Antitumor Assays
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Summary:Protein therapy has been considered the most direct and safe approach to treat cancer. Targeting delivery of extracellularly active protein without internalization barriers, such as membrane permeation and endosome escape, is efficient and holds vast promise for anticancer treatment. Herein, we describe a “transformable” core–shell based nanocarrier (designated CS-NG), which can enzymatically assemble into microsized extracellular depots at the tumor site with assistance of hyaluronidase (HAase), an overexpressed enzyme at the tumor microenvironment. Equipped with an acid-degradable modality, the resulting CS-NG can substantially release combinational anticancer drugstumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) and antiangiogenic cilengitide toward the membrane of cancer cells and endothelial cells at the acidic tumor microenvironment, respectively. Enhanced cytotoxicity on MDA-MB-231 cells and improved antitumor efficacy were observed using CS-NG, which was attributed to the inhibition of cellular internalization and prolonged retention time in vivo.
ISSN:1530-6984
1530-6992
DOI:10.1021/acs.nanolett.5b04343