Modulation of the Tumor Stroma and Associated Novel Nanoparticle Strategies to Enhance Tumor Targeting

Growth of malignant cells in solid tumors induces changes to the tumor microenvironment (TME). These changes result in promotion of tumor growth, invasion, and metastasis, but also in tumor resistance to drugs and radiotherapy. The enhanced permeability and retention (EPR) effect in neo-angiogenic tumor tissue enables the transport of therapeutic molecules from the circulation into the tumor, but studies show that further diffusion of these agents is often not sufficient for efficient tumor eradication. Despite the hyperpermeable vasculature facilitating the delivery of drugs and tracers, the high density of stromal cells and matrix proteins, in combination with the elevated interstitial fluid pressure in the microenvironment of solid tumors, presents a barrier which limits the delivery of compounds to the core of the tumor. Reversing the cancer-cell-induced changes to the microenvironment as well as novel nanoparticle strategies to circumvent tumor-induced stromal changes have therefore been suggested as potential methods to improve the delivery of therapeutic molecules and drug efficacy. Strategies to modulate the TME, i.e., normalization of tumor vasculature and depletion of excessive stromal proteins and cells, show promising results in enhancing delivery of therapeutic compounds. Modulation of the TME may therefore enhance the efficacy of current cancer treatments and facilitate the development of novel treatment methods as an alternative for invasive resection procedures.