Measurement of macromolecular diffusion coefficients in human tumors.
The diffusive transport of macromolecules in tumors is an important determinant of the delivery of many anticancer therapeutics. However, measurements of diffusive transport to date have only been performed in animal models. In this work, diffusion coefficients of BSA and IgM were measured in human tumor biopsies (cooled to 4-7 degrees C to prevent degradation) using fluorescence recovery after photobleaching. To quantify the effects of excision and cooling, the diffusion coefficient of BSA and IgM was measured in human tumor xenografts in situ and after cooling and excision. The change in diffusion coefficients before and after excision of xenografts was used to calculate in vivo diffusion coefficients in human tumors from ex vivo measurements. Using this approach, we obtained the first quantitative determinations of macromolecular diffusion coefficients in human tumors and find that the diffusion coefficients of BSA and IgM in human colon were adenocarcinomas higher than those in xenografts. This difference is consistent with lower collagen content in the accessible regions of these human tumors. These measurements allow the quantitative prediction of the diffusive transport of like-sized macromolecular therapeutics in human tumors. These measurements should help in modeling the transport of novel large MW therapeutics, and hence in estimating their distribution and efficacy in tumors.
Brown
Edward B
EB
Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Boston, MA 02114, USA. edbrown@steele.mgh.harvard.edu
Boucher
Yves
Y
Nasser
Selim
S
Jain
Rakesh K
RK
D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D003094:Collagen / Q000032:analysis / Q000737:chemistry; D004058:Diffusion; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D036681:Fluorescence Recovery After Photobleaching; D005583:Fourier Analysis; D006801:Humans; D007075:Immunoglobulin M / Q000737:chemistry / Q000378:metabolism; D046911:Macromolecular Substances / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D036641:Microscopy, Fluorescence, Multiphoton; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism; D013696:Temperature; D014183:Transplantation, Heterologous
D007075:Immunoglobulin M; D046911:Macromolecular Substances; C039217:fluorescein isothiocyanate bovine serum albumin; D012710:Serum Albumin, Bovine; D003094:Collagen; D016650:Fluorescein-5-isothiocyanate