title: Image-Guided Radiotherapy Targets Macromolecules through Altering the Tumor Microenvironment.
abstract: Current strategies to target tumors with nanomedicines rely on passive delivery via the enhanced permeability and retention effect, leveraging the disorganized tumor microvasculature to promote macromolecule extravasation and the reduced lymphatic and venous drainage that favor retention. Nonetheless, FDA approvals and clinical use of nanomedicines have lagged, reflecting failure to display superiority over conventional formulations. Here, we have exploited image-guided X-irradiation to augment nanoparticle accumulation in tumors. A single 5 Gy dose of radiation, below that required to significantly delay tumor growth, can markedly enhance delivery of macromolecules and nanoparticles. The radiation effect was independent of endothelial cell integrity, suggesting a primary role for damage to microvascular pericytes and/or interstitial extracellular matrix. Significantly, radiation-guided delivery potentiated the therapeutic effects of PEGylated liposomal doxorubicin on experimental tumors. Applied to patients, these results suggest repurposing image-guided radiotherapy as a tool to guide cancer nanomedicine delivery, enhancing local control for primary tumors and metastatic disease while limiting systemic toxicity.
authors: Ludwig Center for Metastasis Research, The University of Chicago , 5758 South Maryland Avenue, MC 9006, Chicago, Illinois 60637, United States.|Department of Molecular Genetics and Cellular Biology, The University of Chicago , 929 East 57th Street, GCIS W519, Chicago, Illinois 60637, United States.
authors: Oliver K
authors: OK
authors: Appelbe
authors: Ludwig Center for Metastasis Research, The University of Chicago , 5758 South Maryland Avenue, MC 9006, Chicago, Illinois 60637, United States.|Department of Molecular Genetics and Cellular Biology, The University of Chicago , 929 East 57th Street, GCIS W519, Chicago, Illinois 60637, United States.
authors: Qingbei
authors: Q
authors: Zhang
authors: Department of Radiation and Cellular Oncology, The University of Chicago , 5758 South Maryland Avenue, MC 9006, Chicago, Illinois 60637, United States.
authors: Charles A
authors: CA
authors: Pelizzari
authors: Ludwig Center for Metastasis Research, The University of Chicago , 5758 South Maryland Avenue, MC 9006, Chicago, Illinois 60637, United States.|Department of Radiation and Cellular Oncology, The University of Chicago , 5758 South Maryland Avenue, MC 9006, Chicago, Illinois 60637, United States.
authors: Ralph R
authors: RR
authors: Weichselbaum
authors: Ludwig Center for Metastasis Research, The University of Chicago , 5758 South Maryland Avenue, MC 9006, Chicago, Illinois 60637, United States.|Department of Molecular Genetics and Cellular Biology, The University of Chicago , 929 East 57th Street, GCIS W519, Chicago, Illinois 60637, United States.
authors: Stephen J
authors: SJ
authors: Kron
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry; D011839:Radiation, Ionizing; D061089:Radiotherapy, Image-Guided / Q000379:methods*; D059016:Tumor Microenvironment / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
keywords: enhanced permeability and retention; ionizing radiation; nanoparticle delivery; tumor microenvironment