Tumor Vascular Permeability, Accumulation, and Penetration of Macromolecular Drug Carriers

Abstract

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. 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. 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. 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.