title: Multimodal in vivo imaging exposes the voyage of nanoparticles in tumor microcirculation.
abstract: Tumors present numerous biobarriers to the successful delivery of nanoparticles. Decreased blood flow and high interstitial pressure in tumors dictate the degree of resistance to extravasation of nanoparticles. To understand how a nanoparticle can overcome these biobarriers, we developed a multimodal in vivo imaging methodology, which enabled the noninvasive measurement of microvascular parameters and deposition of nanoparticles at the microscopic scale. To monitor the spatiotemporal progression of tumor vasculature and its vascular permeability to nanoparticles at the microcapillary level, we developed a quantitative in vivo imaging method using an iodinated liposomal contrast agent and a micro-CT. Following perfusion CT for quantitative assessment of blood flow, small animal fluorescence molecular tomography was used to image the in vivo fate of cocktails containing liposomes of different sizes labeled with different NIR fluorophores. The animal studies showed that the deposition of liposomes depended on local blood flow. Considering tumor regions of different blood flow, the deposition of liposomes followed a size-dependent pattern. In general, the larger liposomes effectively extravasated in fast flow regions, while smaller liposomes performed better in slow flow regions. We also evaluated whether the tumor retention of nanoparticles is dictated by targeting them to a receptor overexpressed by the cancer cells. Targeting of 100 nm liposomes showed no benefits at any flow rate. However, active targeting of 30 nm liposomes substantially increased their deposition in slow flow tumor regions (∼12-fold increase), which suggested that targeting prevented the washout of the smaller nanoparticles from the tumor interstitium back to blood circulation.
authors: Department of Biomedical Engineering, Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Randall
authors: R
authors: Toy
authors: Elliott
authors: E
authors: Hayden
authors: Andrew
authors: A
authors: Camann
authors: Zachary
authors: Z
authors: Berman
authors: Peter
authors: P
authors: Vicente
authors: Emily
authors: E
authors: Tran
authors: Joseph
authors: J
authors: Meyers
authors: Jenna
authors: J
authors: Pansky
authors: Pubudu M
authors: PM
authors: Peiris
authors: Hanping
authors: H
authors: Wu
authors: Agata
authors: A
authors: Exner
authors: David
authors: D
authors: Wilson
authors: Ketan B
authors: KB
authors: Ghaghada
authors: Efstathios
authors: E
authors: Karathanasis
mesh_terms: D000818:Animals; D003287:Contrast Media; D008833:Microcirculation; D008856:Microscopy, Fluorescence / Q000379:methods; D055806:Microvessels / Q000737:chemistry* / Q000000981:diagnostic imaging / Q000473:pathology; D057054:Molecular Imaging / Q000379:methods*; D009038:Motion; D053769:Nanocapsules / Q000032:analysis* / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000737:chemistry* / Q000000981:diagnostic imaging / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000473:pathology; D051381:Rats; D013382:Subtraction Technique; D014057:Tomography, X-Ray Computed / Q000379:methods*
chemical_list: D003287:Contrast Media; D053769:Nanocapsules