The tumor microenvironment and strategies to improve drug distribution

Abstract

The microenvironment within tumors is composed of a heterogeneous mixture of cells with varying levels of nutrients and oxygen. Differences in oxygen content result in survival or compensatory mechanisms within tumors that may favor a more malignant or lethal phenotype. Cells that are rapidly proliferating are richly nourished and preferentially located close to blood vessels. Chemotherapy can target and kill cells that are adjacent to the vasculature, while cells that reside farther away are often not exposed to adequate amounts of drug and may survive and repopulate following treatment. The characteristics of the tumor microenvironment can be manipulated in order to design more effective therapies. In this review, we describe important features of the tumor microenvironment and discuss strategies whereby drug distribution and activity may be improved.

Keywords: drug distribution; drug penetration; hypoxia-activated pro-drugs; pharmacodynamic markers; solid tumor; tumor microenvironment.

Figure 1

(A) Strategies to overcome limited drug distribution in solid tumors. Solid tumors are featured by irregular and poorly organized vasculature. This makes blood-borne oxygen and nutrients difficult to reach tumors cells distant from vessels and eventually leads to formation of regions with low oxygen (hypoxia) and nutrient concentrations. In these areas, tumor cells are usually highly resistant to chemotherapy and radiation therapy. Drug distribution in solid tumors is influenced by many factors, such as physicochemical properties of drugs, consumption of drugs by cells proximal to blood vessels, and the volume and organization of the extracellular matrix (ECM). Strategies to enhance drug distribution in tumors (indicated by yellow background and dashed lines) include increase of tumor blood flow, decrease of high interstitial fluid pressure (IFP), and modification of ECM. Combination treatment using “conventional” therapeutics together with drugs (e.g., hypoxia-activated pro-drugs and agents targeting autophagy) that are able to specifically target cells distant from vasculature also have potential to improve therapeutic efficacy. (B) Schematic representation of multilayered cell cultures (MCCs) to quantify drug penetration. A drug is first added into the small compartment above the MCC. After its passage from the semi-liquid media through the MCC, drug is sampled from the receiving compartment below the MCC and measured.

Figure 2

Prostate cancer PC-3 xenografts (A) untreated control or (B) treated with docetaxel (15 mg/kg). (A,B) Show changes in γH2aX (in cyan), a biomarker of drug effect, in relation to tumor blood vessels (in red) at 10 min after injection. (C) Represents quantitative analysis of the distribution of γH2aX-positive cells in relation to the nearest blood vessel in tumors treated with docetaxel for 10 min (green line) and untreated controls (blue line). Points indicate average of six mice per group; bars, SE. ♢: control; ∘: docetaxel.