Effective drug delivery is restricted by pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, poorly-permeable blood vessels limit the intratumoral permeation and penetration of chemo or nanotherapeutic drugs. New and clinically viable strategies are urgently sought to breach the neoplastic barriers that prevent effective drug delivery. Here, we present an original idea to boost drug delivery by selectively knocking down the tumor vascular barrier in a human pancreatic cancer model. Clinical radiation activates the tumor endothelial-targeted gold nanoparticles to induce a physical vascular damage due to the high photoelectric interactions. Active modulation of these tumor neovessels lead to distinct changes in tumor vascular permeability. Noninvasive MRI and fluorescence studies, using a short-circulating nanocarrier with MR-sensitive gadolinium and a long-circulating nanocarrier with fluorescence-sensitive nearinfrared dye, demonstrate more than two-fold increase in nanodrug delivery, post tumor vascular modulation. Functional changes in altered tumor blood vessels and its downstream parameters, particularly, changes in Ktrans (permeability), Kep (flux rate), and Ve (extracellular interstitial volume), reflect changes that relate to augmented drug delivery. The proposed dual-targeted therapy effectively invades the tumor vascular barrier and improve nanodrug delivery in a human pancreatic tumor model and it may also be applied to other nonresectable, intransigent tumors that barely respond to standard drug therapies.

Department of Radiation Oncology Brigham and Women's Hospital Dana Farber Cancer Institute and Harvard Medical School Boston MA United States

Division of Medical Physics and Engineering University of Texas Southwestern Medical Center Texas United States

Experimental Molecular Imaging University Hospital and Helmholtz Institute for Biomedical Engineering RWTH Aachen University Aachen Germany

Institut Lumière Matière UMR 5306 Université Claude Bernard Lyon 1 CNRS Villeurbanne France

Institute for Advanced Biosciences UGA INSERM U1209 CNRS UMR 5309 Joint Research Center Grenoble France

Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic Heyrovsky Square 2 16206 Prague 6 Czech Republic

LA ICP MS and ICP ES Laboratories Department of Earth and Environmental Sciences Boston University Boston MA United States

Lurie Family Imaging Center Department of Radiology Dana Farber Cancer Institute and Harvard Medical School Boston MA United States

Nanomedicine Science and Technology Center and Department of Physics Northeastern University Boston MA United States

Sci Rep. 2020 Sep 15;10(1):15344. doi: 10.1038/s41598-020-72253-7. PubMed

Sci Rep. 2022 Aug 2;12(1):13216. doi: 10.1038/s41598-022-17483-7. PubMed

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