Multiscale measurements distinguish cellular and interstitial hindrances to diffusion in vivo.
Molecular cancer therapy relies on interstitial diffusion for drug distribution in solid tumors. A mechanistic understanding of how tumor components affect diffusion is necessary to advance cancer drug development. Yet, because of limitations in current techniques, it is unclear how individual tissue components hinder diffusion. We developed multiscale fluorescence recovery after photobleaching (MS-FRAP) to address this deficiency. Diffusion measurements facilitated by MS-FRAP distinguish the diffusive hindrance of the interstitial versus cellular constituents in living tissue. Using multiscale diffusion measurements in vivo, we resolved the contributions of these two major tissue components toward impeding diffusive transport in solid tumors and subcutaneous tissue in mice. We further used MS-FRAP in interstitial matrix-mimetic gels and in vivo to show the influence of physical interactions between collagen and hyaluronan on diffusive hindrance through the interstitium. Through these studies, we show that interstitial hyaluronan paradoxically improves diffusion and that reducing cellularity enhances diffusive macromolecular transport in solid tumors.
Chauhan
Vikash P
VP
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Lanning
Ryan M
RM
Diop-Frimpong
Benjamin
B
Mok
Wilson
W
Brown
Edward B
EB
Padera
Timothy P
TP
Boucher
Yves
Y
Jain
Rakesh K
RK
D000465:Algorithms; D000818:Animals; D002468:Cell Physiological Phenomena; D002645:Chickens; D024042:Collagen Type I / Q000378:metabolism; D004058:Diffusion; D045604:Extracellular Fluid / Q000502:physiology*; D036681:Fluorescence Recovery After Photobleaching / Q000379:methods*; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000503:physiopathology; D051381:Rats; D040521:Subcutaneous Tissue / Q000502:physiology
D024042:Collagen Type I; D006820:Hyaluronic Acid