title: Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging.
abstract: The blood-brain barrier (BBB) is partially disrupted in brain tumors. Despite the gaps in the BBB, there is an inadequate amount of pharmacological agents delivered into the brain. Thus, the low delivery efficiency renders many of these agents ineffective in treating brain cancer. In this report, we proposed an "autocatalytic" approach for increasing the transport of nanoparticles into the brain. In this strategy, a small number of nanoparticles enter into the brain via transcytosis or through the BBB gaps. After penetrating the BBB, the nanoparticles release BBB modulators, which enables more nanoparticles to be transported, creating a positive feedback loop for increased delivery. Specifically, we demonstrated that these autocatalytic brain tumor-targeting poly(amine-co-ester) terpolymer nanoparticles (ABTT NPs) can readily cross the BBB and preferentially accumulate in brain tumors at a concentration of 4.3- and 94.0-fold greater than that in the liver and in brain regions without tumors, respectively. We further demonstrated that ABTT NPs were capable of mediating brain cancer gene therapy and chemotherapy. Our results suggest ABTT NPs can prime the brain to increase the systemic delivery of therapeutics for treating brain malignancies.
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Derek K
authors.initials: DK
authors.lastname: Kong
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Sasidhar
authors.initials: S
authors.lastname: Murikinati
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Yuan
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Liyuan
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Daofeng
authors.initials: D
authors.lastname: Tian
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Ye
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Holden
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: June-Hee
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Jean-Leon
authors.initials: JL
authors.lastname: Thomas
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Jaime
authors.initials: J
authors.lastname: Grutzendler
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Piepmeier
authors.affiliation: Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Jiangbing
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000628:therapy*; D045744:Cell Line, Tumor; D003652:Decanoic Acids / Q000737:chemistry; D016503:Drug Delivery Systems; D004983:Ethanolamines / Q000737:chemistry; D005260:Female; D015316:Genetic Therapy; D064593:Heterografts; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D061848:Optical Imaging; D017239:Paclitaxel / Q000008:administration & dosage; D010539:Permeability; D011108:Polymers / Q000737:chemistry; D011687:Purines / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry; D012604:Scorpion Venoms / Q000737:chemistry; D057900:Transcytosis; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D003652:Decanoic Acids; D004983:Ethanolamines; D011108:Polymers; D011687:Purines; D011720:Pyrazoles; D012604:Scorpion Venoms; C091539:Chlorotoxin; C430916:regadenoson; C008430:N-methyldiethanolamine; D020778:Matrix Metalloproteinase 2; C029410:ethyl sebacate; D017239:Paclitaxel
keywords: autocatalytic delivery; blood−brain barrier; brain cancer; nanoparticles