Targeting Tumor Hypoxia with Nanoparticle-Based Therapies: Challenges, Opportunities, and Clinical Implications

Abstract

Hypoxia is a crucial factor in tumor biology, affecting various solid tumors to different extents. Its influence spans both early and advanced stages of cancer, altering cellular functions and promoting resistance to therapy. Hypoxia reduces the effectiveness of radiotherapy, chemotherapy, and immunotherapy, making it a target for improving therapeutic outcomes. Despite extensive research, gaps persist, necessitating the exploration of new chemical and pharmacological interventions to modulate hypoxia-related pathways. This review discusses the complex pathways involved in hypoxia and the associated pharmacotherapies, highlighting the limitations of current treatments. It emphasizes the potential of nanoparticle-based platforms for delivering anti-hypoxic agents, particularly oxygen (O₂), to the tumor microenvironment. Combining anti-hypoxic drugs with conventional cancer therapies shows promise in enhancing remission rates. The intricate relationship between hypoxia and tumor progression necessitates novel therapeutic strategies. Nanoparticle-based delivery systems can significantly improve cancer treatment efficacy by targeting hypoxia-associated pathways. The synergistic effects of combined therapies underscore the importance of multimodal approaches in overcoming hypoxia-mediated resistance. Continued research and innovation in this area hold great potential for advancing cancer therapy and improving patient outcomes.

Keywords: cancer therapy; hypoxia; nanoparticle delivery; therapy resistance; tumor biology.

Figure 1

Hypoxia-inducing factor-mediated signaling pathways. HIF-1α, HIF-2α, and HIF-1β are the most prominent factors that cause hypoxia. Several genes are overexpressed in hypoxia, resulting in different proteins, growth factors, and enzyme malfunction. These changes trigger heterogeneity, such as nutritional deficiency, angiogenesis, metabolic changes, acidosis, and immunosuppression. VEGF—vascular endothelial growth factor; PDGF—platelet-derived growth factor; Ang4—angiogenin-4; SDF-1—stromal cell-derived factor; CXCR4—CXC chemokine receptor type 4; HK—hexokinase; LDH—lactate dehydrogenase; PDHK—pyruvate dehydrogenase kinase; CA-IX—carbonic anhydrase-IX; ADRP Glut-1—adipose differentiation-related protein glucose transporter-1; Oct4—octamer-binding transcription factor 4; EPO—erythropoietin.

Figure 2

Pharmacological inactivation of HIF signaling. (A) PT2399 and PT2385 are potent and selective HIF-2α antagonists that directly bind to HIF-2α and inhibit it. E2N2968 inhibits HIF-1α via direct binding. PHD is prolyl hydroxylase domain enzyme. (B) Indirect inhibition is through various pathways by inhibiting transcription, translation, HIFα mRNA expression, HIFα protein synthesis, protein stabilization, accumulation, etc.

Figure 3

Recombinant anaerobic bacteria: 1. Autophagy: Salmonella typhimurium, Listeria monocytogenes, and Clostridium difficile toxins. 2. When dendritic cells are exposed to tumor antigens and interact with bacterial components, they produce high amounts of IL-1, a proinflammatory cytokine that activates CD8+ T cells. 3. By activating TLR5 on activated CD8+ T cells, bacterial flagellin augments active CD8+ T cells’ antitumor response. Perforin and granzyme proteins that are secreted by activated CD8+ T lymphocytes efficiently kill tumor cells in primary and metastatic cancers. 4. Additionally, both flagellin and TLR5 signaling decrease the amount of CD4+CD25+ regulatory T (Treg) cells, boosting the antitumor response of activated CD8+ T cells. 5. The flagellin produced by S. typhimurium stimulates the production of interferon- (IFN-), a crucial cytokine in innate and adaptive immunity. 6. MDSCs infected with Listeria have an immune-stimulatory phenotype characterized by increased IL-12 production, augmenting CD8+ T and NK cell responses. 7. Both S. typhimurium and Clostridium infections have the potential to cause a significant rise in neutrophils 8. When macrophages contact bacterial components (LPS and flagellin) or cancer cells infected with Salmonella, the macrophage inflammasome is activated, boosting the release of IL-1 and TNF into the tumor microenvironment. 9. Increased neutrophil production of TNF and TNF-related apoptosis-inducing ligand (TRAIL) enhances the immune response and induces apoptosis in tumor cells.

Figure 4

Combinatorial models of targeting tumor hypoxia.