Vascular Bursts Act as a Versatile Tumor Vessel Permeation Route for Blood-Borne Particles and Cells

Dynamic bursting in tumor vasculature has recently sparked interest as a novel particle transportation route for drug delivery. These bursts facilitate the transport of sub-100 nm nanoparticles into tumors, though their contribution on the access of other blood-borne particles remains unknown. To evaluate the versatility of this phenomenon, the in vivo kinetics of a variety of intravenously injected particles and their penetration in tumor xenografts and allografts are compared. Dextran, polymeric micelles, liposomes, and polymeric vesicles with diameters ranging from 32 to 302 nm are found to colocalize in virtually all vascular bursts. By mathematical modeling, the burst vent size is estimated to be 625 nm or larger, indicating the dynamic and stochastic formation of large permeation routes in tumor vasculature. Furthermore, some burst vents are found to be µm-sized, allowing the transport of 1 µm microspheres. Moreover, antibody drugs and platelets are capable of utilizing vascular burst transportation, demonstrating the application of this phenomenon to other types of therapeutics and cellular components. These findings indicate the vast potential of vascular bursts, extending the biological and therapeutic significance of this phenomenon to a wide range of blood-borne particles and cells.