Hypoxic tumor microenvironment: Opportunities to develop targeted therapies

Abstract

In recent years, there has been great progress in the understanding of tumor biology and its surrounding microenvironment. Solid tumors create regions with low oxygen levels, generally termed as hypoxic regions. These hypoxic areas offer a tremendous opportunity to develop targeted therapies. Hypoxia is not a random by-product of the cellular milieu due to uncontrolled tumor growth; rather it is a constantly evolving participant in overall tumor growth and fate. This article reviews current trends and recent advances in drug therapies and delivery systems targeting hypoxia in the tumor microenvironment. In the first part, we give an account of important physicochemical changes and signaling pathways activated in the hypoxic microenvironment. This is then followed by various treatment strategies including hypoxia-sensitive signaling pathways and approaches to develop hypoxia-targeted drug delivery systems.

Keywords: HIF-1; Hypoxia; Physicochemical change; Solid tumor microenvironment; Targeted therapy; pH targeted.

Figure 1

A) Common mechanisms for oxygen-dependent activation of prodrugs; B) Bioreductive prodrugs and bioactive prodrugs; C) Concept of de-shielding and cell uptake (Top schematic); schematic illustration of the design and concept for achieving tumor specificity with layer-by-layer nanoparticles. This design takes advantage of a lower pH in hypoxic tissues to de-shield the terminal, polyethylene glycol) (PEG) layer, exposing the underlying positively charged poly-L-lysine (PLL) layer for cell targeting. L1: PLL modified with iminobiotin; L2: neutravidin; L3: biotin end-functionalized PEG (Bottom schematic); Reproduced from Poon et al (Poon, Chang, 2011); D) A graphical representation of the pH-responsive MSNP (Mesoporous silica nanoparticles) nanovalve. Schematic shows the working principle of nanovalves via protonation of the stalk and release of the β-cyclodextrin. (Top schematic); Measurement of lysosomal pH in THP-1 and KB-31 cells prior to and after NH₄Cl treatment (*p < 0.05). The dashed line indicates that a threshold pH (6.0) is required for nanovalve opening. Since NH₄Cl treatment elevates the pH to above this threshold, it eliminates the microenvironment that is required for cargo release. (Bottom graph); Reproduced from Meng et al (Meng, Xue, 2010).

Figure 2

Therapeutic targeting of tumor associated macrophages (TAMs). (A) During cancer progression, tumor-derived signals condition TAMs to directly promote tumor growth via neovascularization and the production of growth/survival factors. In addition, TAMs operate a range of immunosuppressive mechanisms that restrain the antitumor activity of infiltrating immune cells. (B) Therapies with anti-CSF-1R antibodies or (quasi-) specific inhibitors of CSF-1R tyrosine kinase activity effectively deplete TAMs, thus ablating their direct and indirect tumor-promoting actions. In turn, this results in tumor regression (or growth inhibition) via repression of cytotoxic immune responses. (C) Inhibition of tumor growth can also be achieved by functionally re-educating TAMs, rather than by killing them. This approach may be the most efficient because blockade of the tumor-promoting functions of TAMs may be coupled with enhancement of their immunostimulatory properties. Recent examples include IL-10 blockade, CSF-1R blockade in glioblastoma, or exogenous administration of pro-inflammatory cytokines. Abbreviations: NKs, natural killer cells; TAMs, tumor-associated macrophages. (Adopted in its original form from (Ostuni, Kratochvill, 2015))