Biochemical hallmarks-targeting antineoplastic nanotherapeutics

Abstract

Tumor microenvironments (TMEs) have received increasing attention in recent years as they play pivotal roles in tumorigenesis, progression, metastases, and resistance to the traditional modalities of cancer therapy like chemotherapy. With the rapid development of nanotechnology, effective antineoplastic nanotherapeutics targeting the aberrant hallmarks of TMEs have been proposed. The appropriate design and fabrication endow nanomedicines with the abilities for active targeting, TMEs-responsiveness, and optimization of physicochemical properties of tumors, thereby overcoming transport barriers and significantly improving antineoplastic therapeutic benefits. This review begins with the origins and characteristics of TMEs and discusses the latest strategies for modulating the TMEs by focusing on the regulation of biochemical microenvironments, such as tumor acidosis, hypoxia, and dysregulated metabolism. Finally, this review summarizes the challenges in the development of smart anti-cancer nanotherapeutics for TME modulation and examines the promising strategies for combination therapies with traditional treatments for further clinical translation.

Keywords: Biochemical hallmark; Cancer therapy; Controlled drug delivery; Nanoparticle; Tumor microenvironment.

Graphical abstract

Scheme 1

Nanotherapeutics regulate the biochemical hallmarks of TMEs, including acidosis, hypoxia, and dysregulated metabolism.

Fig. 1

LDH NPs regulated acidic TMEs and inhibited tumor growth. (a) LDH NPs regulated the acidic TMEs by generating hydroxide ions and disrupting cancer cell lysosomes, and induced the body to develop adaptive immunity and inhibit tumor growth. (b) pH of deionized water containing LDH NPs (10−500 μg/mL) or NaHCO₃ (7.4−370 μg/mL). (c) Effect of LDH NPs on pH of B16F10 cancer cell culture medium (2 × 10⁵ cells per well). (d) Calculated pH value of tumors (n = 3) collected from different groups. Data are means ± SEM. (e) Different cancer cells were treated with LDH NPs, and cell viability at the indicated concentrations. Data are means ± SEM. (f) Mean tumor volume of mice with colon tumors under different treatments (n = 8). (g) Mean tumor volume of melanoma mice under different treatments (n = 7 for saline and NaHCO₃ groups; n = 8 for LDH group). For f and g, statistical significance was calculated by two-way ANOVA with Tukey's post-hoc test. Reproduced with permission [56]. Copyright 2022, American Chemical Society.

Fig. 2

Photothermal control of O₂ generation by PSPP-Au₉₈₀-D and triggering of multi-mechanism combined therapy. (a) Synthesis of PSPP-Au₉₈₀-D or PSPP-Au₇₃₀. (b) O₂ concentration measured with probe of a portable dissolved O₂ meter. (c) Final O₂ concentration of PSPP-Au₉₈₀-D, PSPP-D, and SPP-Au₉₈₀-D (n = 3). (d) Changes of O₂ concentration in different groups upon 980 nm laser irradiation. (e) Experimental design in vivo. (f, g) Tumor growth (f) and weight (g) curves of different groups (n = 4; **P < 0.01, ***P < 0.001). (h) Semi-quantitative analysis of differently treated hypoxic fluorescence areas in histological images (n = 10; **P < 0.01, ***P < 0.001). Reproduced with permission [151]. Copyright 2022, Wiley-VCH.

Fig. 3

Hypoxia-responsive nanoparticle (HRNP) targeting hypoxia-correlated protumorigenic gene (CDC20) improved the effectiveness of treatment for breast cancer. (a) Significant elevation of CDC20 mRNA in breast cancer tissues in contrast to normal and paratumor tissues. (b) GSEA analysis of association between CDC20 and hypoxia in TMEs. (c) Preparation of HRNP/siRNA and mechanism of disassembly in a hypoxic reductive microenvironment. (d) HRNP/siCDC20 delivery into cancer cell cytoplasm to induce G2/M arrest and cell apoptosis for effective cancer therapy. (e) CDC20 expression in MCF-7 cells administered HRNP/siCDC20 under different O₂ levels. (f) Comparison of normoxic and hypoxic MCF-7 cell proliferation after treatment with free siCDC20 or HRNP/siCDC20. As a control group, cells were cultured in growth media devoid of HRNP and free siRNA. Data are shown as mean ± SD (n = 3; ***P < 0.001). (g) CDC20 expression in Ctrl and HRNP/siCDC20 group. (h) Average tumor growth curves across treatment groups. (i, j) Tumor inhibition rate and tumor weight in MCF-7 tumor-bearing mice administrated with Ctrl, siCDC20, HRNP/siCtrl, or HRNP/siCDC20. Reproduced with permission [233]. Copyright 2020, Copyright 2017, American Chemical Society.

Fig. 4

RGFM simultaneously disrupted multiple metabolic pathways and their feedback regulations. (a) Synthesis of RGFM. (b) Cytotoxicity of RGFM for 4T1 cells (n = 4). (c) Heatmap of genes altered by RGFM treatment. Red squares indicated the increased transcription of relevant genes. (d) Apoptosis profile of 4T1 cells after RGFM treatment. (e) 4T1 tumor growth curves after different treatments ([Rap] = 1.0 mg (kg BW)⁻¹). Treatments were performed on day 1 and 6. Data were shown as mean ± SEM (n = 6). (f) 4T1 tumor weight collected on day 14. (g, h) Quantification of fluorescence intensity of HIF-1α and Pearson's colocalization coefficients of HIF-1α and cell nuclear (n = 4). (i) Quantification of fluorescence intensity of SIRT-4 (n = 4). Reproduced with permission [268]. Copyright 2024, American Chemical Society.

Fig. 5

BPTES-NP inhibited glutaminase and tumor growth. (a) Mouse tumor metabolomics analysis after BPTES-NP treatment. *P < 0.05. (b) Comparison of tumors from mice exposed to blank-NP (blue bars) and BPTES-NP (red bars) for lactate to glucose ratio. Data are shown as mean ± SEM (n = 5; **P < 0.01). (c) Relative tumor volume of mouse models exposed to BPTES-NP and blank-NP once every three days. Data are shown as mean ± SEM (n = 8; **P < 0.01). (d) Relative tumor volume of mouse models exposed to 12.5 mg (kg BW)⁻¹ BPTES (n = 12) or vehicle control (n = 11). Data are shown as mean ± SEM. NS, no significant difference. (e) Relative tumor volume of patient-derived orthotopic pancreatic tumors was collected on day 0 and 16 (200 mg (kg BW)⁻¹ CB-839, twice per day by oral gavage). Data are shown as mean ± SEM (n = 8; **P < 0.01). (f, g) Liver response to therapy with BPTES-NP and CB-839. Blood levels of alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) are calculated. Data are shown as mean ± SEM (n = 8, *P < 0.05). Reproduced with permission [288]. Copyright 2016, National Academy of Sciences.

Fig. 6

High concentrations of intracellular phosphate triggered RPMANB NP to release IDO inhibitor and chemotherapeutic agent for combination therapy. (a) Preparation of hybrid nanomedicine RPMANB NP with the ability to co-deliver a CLB and an NLG919. (b) Anti-cancer immune response and chemo-immunotherapy by RPMANB NP. (c) Release of NLG919 from MOF NP@NLG919 or RPMANB NP in saline and PBS containing different phosphate concentrations. (d, e) Growth curves of primary tumors (d) and distant tumors (e) of 4T1-tumor-bearing mice after different treatments (n = 5; **P < 0.01, ***P < 0.001). I: PBS; II: NLG919; III: RPMAB NP; IV: chlorambucil; V: RPMAB NP+L (785 nm, 50 mW cm⁻², 30 min); VI: RPMANB NP; VII: RPMANB NP+L (785 nm, 50 mW cm⁻², 30 min). Reproduced with permission [304]. Copyright 2021, Wiley-VCH.

Fig. 7

Man-OVA(RSV) NP inhibited DC cholesterol metabolism and increased tumor antigen presentation, thereby enhancing the body's anti-cancer immunity. (a) Preparation process of Gel@NPs. (b) Man-OVA(RSV)-mediated antigen degradation and antigen presentation via interfering with the metabolic MVA pathway. (c) GGPP level in BMDCs with different treatments. (d, e) Changes of primary (d) and distant (e) tumor volume in C57BL/6 (n = 5). Reproduced with permission [316]. Copyright 2022, Elsevier.

Fig. 8

LFU20 accumulated in tumors and released cytotoxic fluorouridine phosphate to inhibit cancer cell proliferation. (a) Solid-phase synthesis, self-assembly, and the subsequent cancer therapy of LFU20. (b) Inhibition ratios of different treatments to HeLa cells. Samples were diluted with DMEM culture medium (10% FBS) to the corresponding concentration, followed by addition to 96-well plates. Cells were cultured for an additional 48 h prior to cell viability assay. The concentration of free floxuridine is twenty-fold higher than that of the label on the X axis. (c) Tumor volumes of different treatments groups. Reproduced with permission [330]. Copyright 2018, German Chemical Society.