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Nano Lett. 2016 Feb 10;16(2):1118-26. doi: 10.1021/acs.nanolett.5b04343. Epub 2016 Jan 19.

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

Hu Q1,2, Sun W1,2, Lu Y1,2, Bomba HN1,2, Ye Y1,2, Jiang T3, Isaacson AJ4, Gu Z1,2,5.

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Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University , Raleigh, North Carolina 27695, United States.
Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
School of Pharmaceutical Sciences, Nanjing Tech University , Nanjing 210000, Jiangsu China.
Department of Radiology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27514, United States.
Department of Medicine, University of North Carolina School of Medicine , Chapel Hill, North Carolina 27599, United States.


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.


Drug delivery; antiangiogenesis; apoptosis; stimuli-responsive; tumor microenvironment

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