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Multiscale measurements distinguish cellular and interstitial hindrances to diffusion in vivo

Vikash P Chauhan1, Ryan M Lanning, Benjamin Diop-Frimpong

  • 1Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.

Biophysical Journal
|July 8, 2009
PubMed

Insights

Understanding how tumor components affect drug diffusion is key for cancer therapy. New methods show reducing tumor cell density improves drug transport, while interstitial hyaluronan surprisingly aids diffusion.

Area of Science:

  • Biomedical Engineering
  • Cancer Research
  • Drug Delivery

Background:

  • Molecular cancer therapy relies on interstitial diffusion for drug distribution within solid tumors.
  • A clear mechanistic understanding of how individual tumor components impede diffusion is lacking due to current technique limitations.
  • This knowledge gap hinders the advancement of effective cancer drug development and delivery strategies.

Purpose of the Study:

  • To develop and apply a novel technique to distinguish the diffusive hindrance of interstitial versus cellular components in living tissues.
  • To resolve the specific contributions of interstitial and cellular constituents to impeded diffusive transport in solid tumors.
  • To investigate the influence of physical interactions between collagen and hyaluronan on interstitial diffusion.

Main Methods:

  • Development of multiscale fluorescence recovery after photobleaching (MS-FRAP) to measure diffusion in living tissues.
  • Application of MS-FRAP for in vivo multiscale diffusion measurements in mouse solid tumors and subcutaneous tissue.
  • Utilizing MS-FRAP in interstitial matrix-mimetic gels and in vivo to analyze collagen-hyaluronan interactions.

Main Results:

  • MS-FRAP successfully distinguished the diffusive hindrance effects of interstitial and cellular components.
  • In vivo studies resolved the distinct contributions of these two major tissue types to impeding diffusive transport.
  • Interstitial hyaluronan was found to paradoxically improve diffusion, and reducing tumor cellularity enhanced macromolecular transport.

Conclusions:

  • Reducing tumor cellularity significantly enhances diffusive macromolecular transport in solid tumors.
  • Interstitial hyaluronan plays a beneficial role in improving diffusion, contrary to expectations.
  • The developed MS-FRAP technique provides unprecedented resolution for understanding diffusion barriers in complex biological tissues.

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