Combining two strategies to improve perfusion and drug delivery in solid tumors

Abstract

Blood perfusion in tumors can be significantly lower than that in the surrounding normal tissue owing to the leakiness and/or compression of tumor blood vessels. Impaired perfusion reduces oxygen supply and results in a hypoxic microenvironment. Hypoxia promotes tumor progression and immunosuppression, and enhances the invasive and metastatic potential of cancer cells. Furthermore, poor perfusion lowers the delivery of systemically administered drugs. Therapeutic strategies to improve perfusion include reduction in vascular permeability by vascular normalization and vascular decompression by alleviating physical forces (solid stress) inside tumors. Both strategies have shown promise, but guidelines on how to use these strategies optimally are lacking. To this end, we developed a mathematical model to guide the optimal use of these strategies. The model accounts for vascular, transvascular, and interstitial fluid and drug transport as well as the diameter and permeability of tumor vessels. Model simulations reveal an optimal perfusion region when vessels are uncompressed, but not very leaky. Within this region, intratumoral distribution of drugs is optimized, particularly for drugs 10 nm in diameter or smaller and of low binding affinity. Therefore, treatments should modify vessel diameter and/or permeability such that perfusion is optimal. Vascular normalization is more effective for hyperpermeable but largely uncompressed vessels (e.g., glioblastomas), whereas solid stress alleviation is more beneficial for compressed but less-permeable vessels (e.g., pancreatic ductal adenocarcinomas). In the case of tumors with hyperpermeable and compressed vessels (e.g., subset of mammary carcinomas), the two strategies need to be combined for improved treatment outcomes.

Keywords: mathematical modeling; mechanical forces; tumor microenvironment; vessel decompression; vessel permeability.

Fig. 1.

Schematic of therapeutic strategies to improve tumor perfusion. (A) Abnormalities in interendothelial junctions, pericyte coverage, and/or basement membrane lead to hyperpermeability of tumor blood vessels and excessive fluid leakage that slows down blood flow. (B) Vascular normalization fortifies the vessel wall, resulting in smaller interendothelial gaps (“pores”) and improved perfusion. (C) Structural components of the tumor microenvironment exert forces on blood vessels, resulting in vessel compression and reduced blood flow. (D) Alleviation of these forces by selective depletion of tumor constituents (e.g., cells or extracellular matrix) can decompress the vessels and improve vessel perfusion. BM, basement membrane; CC, cancer and/or stromal cell; EC, endothelial cell; ECM, extracellular matrix; PC, pericyte.

Fig. 2.

Results for the fraction of perfused vessels as a function of the vessel diameter and the vessel wall pore size, a determinant of vascular permeability. Two values of the hydraulic conductivity of the interstitial space were used: (A) 1 × 10⁻⁷ cm²/mmHg-s and (B) 1 × 10⁻⁶ cm²/mmHg-s. The compressed central region occupies 80% of the tumor. The colors represent the values of the fraction of perfused vessels and the dashed line depicts the region within which vessel decompression is beneficial. The fraction of the well-perfused vessels becomes optimal for uncompressed (larger diameter) and low-permeable (smaller vessel wall pore size) vessels. The fraction of perfused vessels decreases if the tumor vessels are compressed or hyperpermeable. Vessel decompression is beneficial for compressed and low-permeable vessels.

Fig. 3.

Results for (A) fraction of perfused vessels and (B) effective vascular density as a function of vessel diameter and vessel wall pore size. The dashed line depicts the region within which vascular normalization is beneficial (referred to as optimal perfusion region), the circle shows the initial values, and the solid lines show potential paths of the treatment. The fraction of the well-perfused vessels and the effective vascular density become optimal for uncompressed (larger diameter) and low-permeable (smaller vessel wall pore size) vessels. The fraction of perfused vessels decreases if the tumor vessels are compressed or hyperpermeable. Vascular normalization is beneficial for compressed and hyperpermeable vessels.

Fig. 4.

Normalization window as a function of dose and time. Higher doses of antiangiogenic treatment over time increase vessel pruning, which in turn decreases the effective vascular density and impairs vascular efficiency. As a result the fraction of perfused vessels and the region of optimal perfusion decrease. These dose- and time-dependent effects create a normalization window within which drug delivery is optimized. (Inset) Schematic presents the effects of dose and time on the normalization window (adapted from ref. 2).

Fig. 5.

Schematic of the proposed therapeutic strategies to improve perfusion and drug delivery. Tumors with hyperpermeable and uncompressed vessels benefit from vascular normalization strategy (red arrow). Tumors with compressed and low or moderately permeable vessels benefit from vessel decompression/stress-alleviation strategy (green arrow). Tumors with compressed and hyperpermeable vessels benefit from the application of stress-alleviation treatment to decompress vessels along with vascular normalization treatment to decrease permeability (two-color arrows).

Fig. 6.

Intratumoral distribution of therapeutic agents as a function of perfused vessel fraction for drugs with (A) low binding affinity and (B) high binding affinity (details in Supporting Information). Three curves in each panel show the intratumoral distribution of drugs of three sizes (1, 10, and 60 nm) versus the fraction of perfused vessels. The curves demonstrate that the intratumoral distribution of drugs of all three sizes increases with the fraction of perfused vessels, but in a nonlinear manner. The increase is more substantial for smaller drugs than for larger drugs. Intratumoral distribution is defined as the fraction of the tumor extravascular space that the drug is bound to cancer cells in amounts higher than 1% of the concentration at the inlet of the vascular network.