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.
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.|Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Guodong
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Junhua
authors.identifier: http://orcid.org/0000-0001-8374-4352
authors.initials: J
authors.lastname: Mai
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Segura-Ibarra
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Suhong
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Haoran
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.|Division of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Eugene
authors.identifier: http://orcid.org/0000-0001-7675-3461
authors.initials: E
authors.lastname: Koay
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas-Houston Medical School, Houston, Texas, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Houston Methodist Cancer Center, Houston, Texas, USA.
authors.forename: Joe E
authors.initials: JE
authors.lastname: Ensor
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Elvin
authors.initials: E
authors.lastname: Blanco
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Xuewu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.|Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.|Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy*; D011099:Polyglutamic Acid; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011099:Polyglutamic Acid; D004317:Doxorubicin