Tumor Niche Influences the Activity and Delivery of Anticancer Drugs: Pharmacology Meets Chemistry

Abstract

Cellular and molecular characteristics of the tumor microenvironment are fundamental for the formation of niches. These structures include both cellular and matrix components and have been shown to protect and promote cancer formation and progression. The peculiarities of tumor niches have been suggested by many authors as targets with high therapeutic potential. This narrative review analyzes the chemical characteristics of the tumor microenvironment and describes experimental and clinical approaches to influence its contribution to cancer promotion and the spread of metastases. In particular, the possible chemical differences, like pH, oxygen levels, and cell composition, to be used for the design of drugs or the delivery of antiproliferative moieties for a more precise oncology approach, will be discussed. The literature proposes a vast number of molecules, but this review focuses on hypoxia-activated molecules, pH-sensitive nanocarriers, metal-based drugs, and gasotransmitters targeting selectively the tumor microenvironment as possible negative modulators of the contribution of niches to tumor promotion. The chemical peculiarities of the tumor niche are discussed for possible pharmacological developments.

Keywords: hypoxia; metal-based drugs; nanoparticles; pH-sensitive nanocarriers; precise oncology; tumor microenvironment chemistry; tumor niche.

Figure 1

Schematic representation of the bidirectional interactions between the different components of the TME (in bold). TME = tumor microenvironment; CSCs = cancer stem cells; CAFs = cancer-associated fibroblasts; ECM = extracellular matrix; M2 = tumor-associated macrophages (TAMs); MMPs = metalloproteinases.

Figure 2

Schematic representation of the evolution of TME with niche formation. Cancer evolution and progression to metastases are sustained by TME modification and cells of different origin composition. TME chemical and biochemical properties (e.g., hypoxia and acidification) can promote the selective activation or release, like functionalized and pH-sensitive nanoparticles. TME = tumor microenvironment; CSCs = cancer stem cells; CAFs = cancer-associated fibroblasts; ITHs = intratumoral heterogeneous cancer cells; M1 = pro-inflammatory macrophages; M2 = tumor-associated macrophages (TAMs); MMP = metalloproteinase; siRNA = small interfering RNA; NPs = nanoparticles.

Figure 3

Structural representations of a few selected metal complexes cited in the paper: Co(III) complex with a nitrogen mustard [Co(Meacac)₂(dce)]Cl (Meacac = methyl acetylacetonate, dce = N,N-bis(2-chloroethyl)ethylenediamine); sodium nitroprusside (SNP); tricarbonyldichlororuthenium(II) dimer (CORM-2); [2-acetoxy-(2-propynyl)benzoate]hexacarbonyldicobalt (Co-ASS).

Figure 4

Schematic and simplified behavior of [Co(Meacac)₂(dce)]Cl (Meacac = methyl acetylacetonate, dce = N,N-bis(2-chloroethyl)ethylenediamine) in hypoxic vs. normoxic environments (the two environments are highlighted in red and blue, respectively). In hypoxic cells, the Co(III) reduction prevails over the Co(II) reoxidation. Cellular reductants that could help the reduction process are DT diaphorase, xanthine dehydrogenase, nitroreductase, and cytochrome P450 reductase. After reduction, the Co(II) intermediate leads to aquation, forming the Co(II) species that may start a Fenton-like reaction, producing DNA-damaging reactive oxygen species (ROS) and, hence, bringing cells to death. The released nitrogen mustard is able to alkylate DNA bases (N7 position of guanines to form interstrand cross-links), which results in the impairment of DNA replication and transcription, leading to cell death.

Figure 5

Octahedral Pt(IV) complexes exploited for antiproliferative strategies.

Figure 6

Simplified scheme of the 2e⁻ reduction of a cisplatin-based dicarboxylato Pt(IV) complex (activation by reduction) followed by the formation of DNA adducts between Pt(II) species and DNA, leading to cell death, mainly by apoptosis.