An injectable nanoparticle generator enhances delivery of cancer therapeutics

Rong Xu; Guodong Zhang; Junhua Mai; Xiaoyong Deng; Victor Segura-Ibarra; Suhong Wu; Jianliang Shen; Haoran Liu; Zhenhua Hu; Lingxiao Chen; Yi Huang; Eugene Koay; Yu Huang; Jun Liu; Joe E. Ensor; Elvin Blanco; Xuewu Liu; Mauro Ferrari; Haifa Shen

doi:10.1038/nbt.3506

An injectable nanoparticle generator enhances delivery of cancer therapeutics

Rong Xu, Guodong Zhang, Junhua Mai, Xiaoyong Deng, Victor Segura-Ibarra, Suhong Wu, Jianliang Shen, Haoran Liu, Zhenhua Hu, Lingxiao Chen, Yi Huang, Eugene Koay, Yu Huang, Jun Liu, Joe E. Ensor, Elvin Blanco, Xuewu Liu, Mauro Ferrari, Haifa Shen

Research output: Contribution to journal › Article › peer-review

239 Scopus citations

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.

Original language	English (US)
Pages (from-to)	414-418
Number of pages	5
Journal	Nature biotechnology
Volume	34
Issue number	4
DOIs	https://doi.org/10.1038/nbt.3506
State	Published - Apr 1 2016

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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10.1038/nbt.3506

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title = "An injectable nanoparticle generator enhances delivery of cancer therapeutics",

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.",

author = "Rong Xu and Guodong Zhang and Junhua Mai and Xiaoyong Deng and Victor Segura-Ibarra and Suhong Wu and Jianliang Shen and Haoran Liu and Zhenhua Hu and Lingxiao Chen and Yi Huang and Eugene Koay and Yu Huang and Jun Liu and Ensor, {Joe E.} and Elvin Blanco and Xuewu Liu and Mauro Ferrari and Haifa Shen",

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AU - Xu, Rong

AU - Zhang, Guodong

AU - Mai, Junhua

AU - Deng, Xiaoyong

AU - Segura-Ibarra, Victor

AU - Wu, Suhong

AU - Shen, Jianliang

AU - Liu, Haoran

AU - Hu, Zhenhua

AU - Chen, Lingxiao

AU - Huang, Yi

AU - Koay, Eugene

AU - Huang, Yu

AU - Liu, Jun

AU - Ensor, Joe E.

AU - Blanco, Elvin

AU - Liu, Xuewu

AU - Ferrari, Mauro

AU - Shen, Haifa

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N2 - 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.

AB - 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.

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An injectable nanoparticle generator enhances delivery of cancer therapeutics

Abstract

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