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Updated: Aug 11, 2026
Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice
Published on: January 19, 2018
Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers
Matthew R Dreher1, Wenge Liu, Charles R Michelich
1Department of Biomedical Engineering, Duke University, Durham, NC, USA.
Background:
Delivery of anticancer therapeutic agents to solid tumors is problematic. Macromolecular drug carriers are an attractive alternative drug delivery method because they appear to target tumors and have limited toxicity in normal tissues. We investigated how molecular weight influences the accumulation of a model macromolecular drug carrier, dextran covalently linked to a fluorophore, in tumors.
Methods:
We used dextrans with molecular weights from 3.3 kDa to 2 MDa. Vascular permeability, accumulation, and three-dimensional penetration of these dextrans were simultaneously measured in solid tumors via a dorsal skin fold window chamber, intravital laser-scanning confocal microscopy, and custom image analysis.
Results:
Increasing the molecular weight of dextran statistically significantly reduced its vascular permeability by approximately two orders of magnitude (i.e., from 154 x 10(-7) cm/s, 95% confidence interval [CI] = 134 to 174 x 10(-7) cm/s, for 3.3-kDa dextran to 1.7 x 10(-7) cm/s, 95% CI = 0.7 to 2.6 x 10(-7) cm/s for 2-MDa dextran; P < .001, two-sided Kruskal-Wallis test) but increased its plasma half-life, which provided ample time for extravasation (i.e., to enter tumor tissue from the vasculature). Tumor accumulation was maximal for dextrans with molecular weights between 40 and 70 kDa. Dextrans of 3.3 and 10 kDa penetrated deeply (greater than 35 microm) and homogeneously into tumor tissue from the vessel wall. After a 30-minute period, a high concentration was observed only approximately 15 microm from the vessel wall for 40- to 70-kDa dextrans and only 5 microm for 2-MDa dextrans.
Conclusions:
Increasing the molecular weight of dextran statistically significantly reduced its tumor vascular permeability. Dextrans of 40 and 70 kDa had the highest accumulation in solid tumors but were largely concentrated near the vascular surface.
Insights
Molecular weight significantly impacts dextran drug carrier delivery to solid tumors. Optimal accumulation occurred with 40-70 kDa dextrans, though they concentrated near tumor vasculature.
Area of Science:
- Biomedical Engineering
- Drug Delivery Systems
- Tumor Microenvironment Research
Background:
- Solid tumor drug delivery faces challenges.
- Macromolecular carriers offer targeted delivery with reduced toxicity.
- Investigating dextran molecular weight's role in tumor accumulation.
Purpose of the Study:
- To determine how dextran molecular weight influences its accumulation in solid tumors.
- To evaluate the impact of molecular weight on vascular permeability and tissue penetration.
Main Methods:
- Utilized dextrans ranging from 3.3 kDa to 2 MDa.
- Employed intravital microscopy and window chambers for real-time measurements.
- Analyzed vascular permeability, tumor accumulation, and 3D penetration.
Main Results:
- Higher molecular weight dextrans showed significantly reduced vascular permeability.
- Tumor accumulation peaked for 40-70 kDa dextrans.
- Smaller dextrans (3.3-10 kDa) penetrated deeper, while larger ones (40-70 kDa) accumulated most but remained near vessels.
Conclusions:
- Dextran molecular weight critically affects tumor vascular permeability and accumulation.
- 40-70 kDa dextrans demonstrated highest tumor accumulation but limited deep penetration.
- Drug carrier design must balance accumulation and penetration for effective solid tumor therapy.
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