Delivery of Molecular and Nanoscale Medicine to Tumors: Transport Barriers and Strategies

Abstract

Tumors are similar to organs, with unique physiology giving rise to an unusual set of transport barriers to drug delivery. Cancer therapy is limited by nonuniform drug delivery via blood vessels, inhomogeneous drug transport into tumor interstitium from the vascular compartment, and hindered transport through tumor interstitium to the target cells. Four major abnormal physical and physiological properties contribute to these transport barriers. Accumulated solid stress compresses blood vessels to diminish the drug supply to many tumor regions. Immature vasculature with high viscous and geometric resistances and reduced pressure gradients leads to sluggish and heterogeneous blood flow in tumors to further limit drug supply. Nonfunctional lymphatics coupled with highly permeable blood vessels result in elevated hydrostatic pressure in tumors to abrogate convective drug transport from blood vessels into and throughout most of the tumor tissue. Finally, a dense structure of interstitial matrix and cells serves as a tortuous, viscous, and steric barrier to diffusion of therapeutic agents. In this review, we discuss the origins and implications of these barriers. We then highlight strategies for overcoming these barriers by modulating either drug properties or the tumor microenvironment itself to enhance the delivery and effectiveness of drugs in tumors.

Targeting Inflammation to Improve Tumor Drug Delivery

“…At the same time hypo-perfusion and hypoxia compromise normal immune response, thus rendering the tumor impervious to the immune system [11,12] with an invasive and metastatic phenotype [13]. As expected, reduced blood supply also interferes with effective drug delivery to the tumor [9].Additionally, tumor vessel hyper-permeability drives IFP elevation to values comparable to microvascular pressure, thus, diminishing pressure gradients across the tumor vessel wall and hindering convective transport of drugs [4][5][6]. …”

“…Chemotherapeutic drugs are, without a doubt, potent cytotoxic agents. However, they often fail to cure cancer due to the fact that they are unable to reach cancer cells within the tumor in sufficient amounts [5,6]. Hence, the discovery of more efficient approaches to enhance tumor drug delivery is imperative.…”

“…This, in turn, further enhances the uniform elevation of the interstitial fluid pressure (IFP) and renders diffusion the dominant transport mechanism in the tumor interior. Therefore, when therapeutics extravasate from the hyper-permeable tumor vessels, they are not able to effectively penetrate deep into the tumor [5].…”

“…Additionally, tumor vessel hyper-permeability drives IFP elevation to values comparable to microvascular pressure, thus, diminishing pressure gradients across the tumor vessel wall and hindering convective transport of drugs [4][5][6]. …”

“…This, in turn, further enhances the uniform elevation of the interstitial fluid pressure (IFP) and renders diffusion the dominant transport mechanism in the tumor interior. Therefore, when therapeutics extravasate from the hyper-permeable tumor vessels, they are not able to effectively penetrate deep into the tumor [5].A second cause of inefficient drug delivery is the presence of hyper-permeable (leaky) blood vessels occurring due to upregulation of pro-angiogenic factors that subsequently leads to formation of immature vessels with structural abnormalities such as wide junctions between the endothelial cells, and large numbers of fenestrae and intercellular openings, resulting in the formation of tumor vessels whose pores can be up to two orders of magnitude larger than normal [7,8]. Consequently, the blood supply reaching the tumor is decreased due to excessive fluid loss from the vascular to the extravascular space of the tumor, as well as due to the state of dysfunction in which tumor blood vessels are in, being characterized by lack of hierarchy, formation of vascular shunts and partially collapsed lumen [9,10].…”