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Ultrasmall Core-Shell Silica Nanoparticles for Precision Drug Delivery in a High-Grade Malignant Brain Tumor Model.
Juthani, Rupa; Madajewski, Brian; Yoo, Barney; Zhang, Li; Chen, Pei-Ming; Chen, Feng; Turker, Melik Z; Ma, Kai; Overholtzer, Michael; Longo, Valerie A; Carlin, Sean; Aragon-Sanabria, Virginia; Huse, Jason; Gonen, Mithat; Zanzonico, Pat; Rudin, Charles M; Wiesner, Ulrich; Bradbury, Michelle S; Brennan, Cameron W.
Afiliação
  • Juthani R; Department of Neurosurgery, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Madajewski B; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Yoo B; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York. brennanc@mskcc.org bradburm@mskcc.org by104@hunter.cuny.edu ubw1@cornell.edu.
  • Zhang L; Department of Chemistry, Hunter College, The City University of New York, New York, New York.
  • Chen PM; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Chen F; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Turker MZ; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Ma K; Department of Materials Science & Engineering, Cornell University, Ithaca, New York.
  • Overholtzer M; Department of Materials Science & Engineering, Cornell University, Ithaca, New York.
  • Longo VA; Cell Biology Program, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Carlin S; BCMB Allied Program, Weill Cornell Medical College, New York, New York.
  • Aragon-Sanabria V; Small-Animal Imaging Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Huse J; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Gonen M; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Zanzonico P; Human Oncology & Pathogenesis Program, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Rudin CM; Department of Epidemiology and Biostatistics, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Wiesner U; Department of Medical Physics, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Bradbury MS; Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Brennan CW; Department of Materials Science & Engineering, Cornell University, Ithaca, New York. brennanc@mskcc.org bradburm@mskcc.org by104@hunter.cuny.edu ubw1@cornell.edu.
Clin Cancer Res ; 26(1): 147-158, 2020 01 01.
Article em En | MEDLINE | ID: mdl-31515460
PURPOSE: Small-molecule inhibitors have revolutionized treatment of certain genomically defined solid cancers. Despite breakthroughs in treating systemic disease, central nervous system (CNS) metastatic progression is common, and advancements in treating CNS malignancies remain sparse. By improving drug penetration across a variably permeable blood-brain barrier and diffusion across intratumoral compartments, more uniform delivery and distribution can be achieved to enhance efficacy. EXPERIMENTAL DESIGN: Ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), were functionalized with αv integrin-binding (cRGD), or nontargeting (cRAD) peptides, and PET labels (124I, 89Zr) to investigate the utility of dual-modality cRGD-C' dots for enhancing accumulation, distribution, and retention (ADR) in a genetically engineered mouse model of glioblastoma (mGBM). mGBMs were systemically treated with 124I-cRGD- or 124I-cRAD-C' dots and sacrificed at 3 and 96 hours, with concurrent intravital injections of FITC-dextran for mapping blood-brain barrier breakdown and the nuclear stain Hoechst. We further assessed target inhibition and ADR following attachment of dasatinib, creating nanoparticle-drug conjugates (Das-NDCs). Imaging findings were confirmed with ex vivo autoradiography, fluorescence microscopy, and p-S6RP IHC. RESULTS: Improvements in brain tumor delivery and penetration, as well as enhancement in the ADR, were observed following administration of integrin-targeted C' dots, as compared with a nontargeted control. Furthermore, attachment of the small-molecule inhibitor, dasatinib, led to its successful drug delivery throughout mGBM, demonstrated by downstream pathway inhibition. CONCLUSIONS: These results demonstrate that highly engineered C' dots are promising drug delivery vehicles capable of navigating the complex physiologic barriers observed in a clinically relevant brain tumor model.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Sistemas de Liberação de Medicamentos / Glioblastoma / Dióxido de Silício / Inibidores de Proteínas Quinases / Nanopartículas / Dasatinibe Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Clin Cancer Res Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Sistemas de Liberação de Medicamentos / Glioblastoma / Dióxido de Silício / Inibidores de Proteínas Quinases / Nanopartículas / Dasatinibe Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Clin Cancer Res Ano de publicação: 2020 Tipo de documento: Article