title: Remodeling Tumor Vasculature to Enhance Delivery of Intermediate-Sized Nanoparticles.
abstract: Restoration of dysfunctional tumor vasculature can reestablish the pressure gradient between intravascular and interstitial space that is essential for transporting nanomedicines into solid tumors. Morphologic and functional normalization of tumor vessels improves tissue perfusion to facilitate intratumoral nanoparticle delivery. However, this remodeling process also reduces tumor vessel permeability, which can impair nanoparticle transport. Although nanoparticles sized below 10 nm maximally benefited from tumor vessel normalization therapy for enhanced nanomedicine delivery, the small particle size severely limits its applicability. Here, we show that intermediate-sized nanoparticles (20-40 nm) can also benefit from tumor vasculature remodeling. We demonstrate that a window of opportunity exists for a two-stage transport strategy of different nanoparticle sizes. Overall, tumor vessel remodeling enhances the transvascular delivery of intermediate-size nanoparticles of up to 40 nm. Once within the tumor matrix, however, smaller nanoparticles experience a significantly lesser degree of diffusional hindrance, resulting in a more homogeneous distribution within the tumor interstitium. These findings suggest that antiangiogenic therapy and nanoparticle design can be combined in a multistage fashion, with two sets of size-inclusion criteria, to achieve optimal nanomedicine delivery into solid tumors.
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center , Houston, Texas, United States.
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.affiliation: The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the Collaborative Innovation Center of Hematology, Soochow University , China.|Department of Neurosurgery, Mayo Clinic College of Medicine , Jacksonville, Florida, United States.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Radiation Oncology, Yale-New Haven Hospital , New Haven, Connecticut, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: An
authors.affiliation: Department of Neurosurgery, Mayo Clinic College of Medicine , Jacksonville, Florida, United States.
authors.forename: Betty Y S
authors.initials: BY
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D016503:Drug Delivery Systems; D006801:Humans; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010316:Particle Size
chemical_list: D020533:Angiogenesis Inhibitors
keywords: antiangiogenic therapy; nanomedicine; tumor delivery; tumor targeting