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Microfluidic Device for Recreating a Tumor Microenvironment in Vitro
Published on: November 20, 2011
Measurement of macromolecular diffusion coefficients in human tumors
Edward B Brown1, Yves Boucher, Selim Nasser
1Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Boston, MA 02114, USA. edbrown@steele.mgh.harvard.edu
Abstract:
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.
Insights
This study measured macromolecule diffusion in human tumors, finding higher diffusion coefficients for bovine serum albumin (BSA) and immunoglobulin M (IgM) in human colon adenocarcinomas than in xenografts.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Pharmacokinetics
Background:
- Macromolecule diffusion in tumors impacts therapeutic delivery.
- Previous diffusion measurements were limited to animal models.
- Understanding in vivo diffusion is crucial for drug development.
Purpose of the Study:
- To quantify macromolecule diffusion coefficients in human tumors.
- To establish a method for calculating in vivo diffusion from ex vivo measurements.
- To compare diffusion in human tumors versus animal models.
Main Methods:
- Measured diffusion coefficients of bovine serum albumin (BSA) and immunoglobulin M (IgM) in human tumor biopsies using fluorescence recovery after photobleaching.
- Quantified effects of excision and cooling on diffusion in human tumor xenografts.
- Calculated in vivo human tumor diffusion coefficients from ex vivo xenograft data.
Main Results:
- Obtained the first quantitative in vivo diffusion coefficients for BSA and IgM in human tumors.
- Found higher diffusion coefficients for BSA and IgM in human colon adenocarcinomas compared to xenografts.
- Observed that lower collagen content in human tumors likely contributes to increased diffusion.
Conclusions:
- Established a novel approach to determine macromolecule diffusion in human tumors.
- Human tumor diffusion characteristics differ from those in xenografts, influenced by tumor microenvironment.
- Measurements enable quantitative prediction of macromolecular therapeutic transport and efficacy in human tumors.
