Tumor Vascular Permeability, Accumulation, and Penetration of Macromolecular Drug Carriers Matthew R. Dreher, Wenge Liu, Charles R. Michelich, Mark W. Dewhirst, Fan Yuan, Ashutosh Chilkoti
The clinical treatment of solid tumors could be improved by controlling the pharmacologic properties of anticancer therapeutic agents to deliver a greater dose to the tumor; with conventional drugs, this dose is typically limited by toxic side effects in normal tissues (1–3). In 1906, Paul Ehrlich established the concept of drug delivery (4) by proposing a carrier that would “bring therapeutically active groups to the organ in question.” The goal of drug delivery is to increase the concentration of a therapeutic agent in the tumor while limiting systemic exposure. Numerous drug delivery technologies have been developed to accomplish this goal, including liposomes (5), micelles (6), antibody-directed enzyme-prodrug therapy (7), photodynamic therapy (8), affinity targeting (9), and macromolecular drug carriers (10,11). Many of these drug delivery approaches take advantage of the unique pathophysiology of tumor vasculature. As early as the 1920s, researchers using a transparent chamber and injectable dye techniques found that, in contrast to normal tissue, tumors Journal of the National Cancer Institute, Vol. 98, No. 5, March 1, 2006
contain a high density of abnormal blood vessels that are dilated and poorly differentiated, with chaotic architecture and aberrant branching (12–15). Subsequently, various functions of tumor vasculature were found to be impaired, such as a higher vascular permeability than normal vessels; these impaired functions contributed to the higher concentration of plasma proteins detected in tumor tissues than in normal tissues (16–25). This phenomenon was elucidated by Maeda and colleagues (26–28) [and reviewed by Seymour (29)], who described it as the enhanced permeability and retention effect, which results from a combination of the increased permeability of tumor blood vessels and the decreased rate of clearance caused by the lack of functional lymphatic vessels in the tumor, and results in the increased accumulation of macromolecules in tumors. These findings support the use of macromolecules in tumor diagnosis and in therapy as drug carriers because they passively accumulate in solid tumors after intravenous administration. A macromolecular drug carrier is typically composed of a macromolecule covalently linked to a therapeutic agent, and it targets solid tumors either passively (via its molecular weight and charge) or actively (via a specific affinity [e.g., an antibody] or stimulus) (11,30,31). In addition to the enhanced permeability and retention effect, macromolecular drug carriers have a longer plasma halflife, reduced toxicity in normal tissue, and higher activity against multiple drug-resistant cell lines than typical chemotherapeutic agents, and they have the ability to increase the solubility of poorly soluble drugs in plasma (10,11). Because of these characteristics, macromolecular drug carriers coupled to a low molecular weight drug often have higher anticancer efficacy than the low molecular weight drug alone (10,11). In general, the concentration of a macromolecule in tumors depends on two sets of parameters—one set that increases the accumulation of the macromolecule in tumors (such as perfusion, vascularity, vascular permeability, plasma half-life, and tumor-specific binding) and the other set that limits tumor localization (such as clearance through a vascular or lymphatic route) (1,32). For passively targeted macromolecules, only permeability, plasma half-life, and clearance are variable; these variables should depend on the molecular weight and charge of the drug carrier. In this study, we focused on the influence of the molecular weight of anionic macromolecules; the effect of charge has been well characterized elsewhere (33). The antitumor effect of a macromolecular drug carrier coupled to a drug depends on its accumulation in the tumor and its spatial
Affiliations of authors: Department of Biomedical Engineering (MRD, WL, CRM, FY, AC), Department of Radiation Oncology (MWD), Duke University, Durham, NC. Correspondence to: Ashutosh Chilkoti, PhD, Box 90281, Durham, NC 27708 (e-mail:
[email protected]). See “Notes” following “References.” DOI: 10.1093/jnci/djj070 © The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
[email protected].
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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 × 10−7 cm/s, 95% confidence interval [CI] = 134 to 174 × 10−7 cm/s, for 3.3-kDa dextran to 1.7 × 10−7 cm/s, 95% CI = 0.7 to 2.6 × 10−7 cm/s for 2-MDa dextran; P
