Bone marrow vessels are hyperpermeable to macromolecules and nanoscale medicine in a size-dependent manner

Bone marrow (BM) has roles in health and disease, so systemically administered nanocarriers (NCs) targeting or avoiding BM are desirable. While the hydrodynamic diameter of NCs can be tuned to target or avoid various organs, the size dependence of extravasation from BM vessels is unknown. To clarify the size dependence of passive transvascular transport in the BM, we performed vessel permeability measurements in murine calvaria using confocal fluorescent microscopy with fluorescently labeled dextrans, albumin, and polymeric micelles as model probes. Unexpectedly, we found the permeability of BM vessels to macromolecules decreases with increasing hydrodynamic diameter between 4 nm and 32 nm. We modeled this permeability data with mathematical models to predict an effective pore size for sinusoids of 47 nm and non-sinusoids of 37 nm, with estimated maximum pore sizes of 61 nm and 53 nm, respectively. Finally, we tested these model predictions by demonstrating that the extravasation of 70 nm polymeric micelles, which are larger than the estimated maximum pore size, is hindered relative to 30 nm polymeric micelles. These results establish design criteria for controlling NC hydrodynamic diameter towards modulating delivery to BM.