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Nat Biotechnol. 2016 Apr;34(4):414-8. doi: 10.1038/nbt.3506. Epub 2016 Mar 14.

An injectable nanoparticle generator enhances delivery of cancer therapeutics.

Author information

1
Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
2
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3
Division of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
4
Department of Pathology and Laboratory Medicine, The University of Texas-Houston Medical School, Houston, Texas, USA.
5
Houston Methodist Cancer Center, Houston, Texas, USA.
6
Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
7
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, USA.

Abstract

The efficacy of cancer drugs is often limited because only a small fraction of the administered dose accumulates in tumors. Here we report an injectable nanoparticle generator (iNPG) that overcomes multiple biological barriers to cancer drug delivery. The iNPG is a discoidal micrometer-sized particle that can be loaded with chemotherapeutics. We conjugate doxorubicin to poly(L-glutamic acid) by means of a pH-sensitive cleavable linker, and load the polymeric drug (pDox) into iNPG to assemble iNPG-pDox. Once released from iNPG, pDox spontaneously forms nanometer-sized particles in aqueous solution. Intravenously injected iNPG-pDox accumulates at tumors due to natural tropism and enhanced vascular dynamics and releases pDox nanoparticles that are internalized by tumor cells. Intracellularly, pDox nanoparticles are transported to the perinuclear region and cleaved into Dox, thereby avoiding excretion by drug efflux pumps. Compared to its individual components or current therapeutic formulations, iNPG-pDox shows enhanced efficacy in MDA-MB-231 and 4T1 mouse models of metastatic breast cancer, including functional cures in 40-50% of treated mice.

PMID:
26974511
PMCID:
PMC5070674
DOI:
10.1038/nbt.3506
[Indexed for MEDLINE]
Free PMC Article

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