Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy

Abstract

Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen-sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the "lactate shuttle". Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species-related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field.

Keywords: glycolysis; lactate metabolism; nanoparticles; tumor therapy.

Figure 1

Schematic illustration of tumor treatment strategies based on nanomaterials interfering with lactate metabolism, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting “lactate shuttle”.

Figure 2

Lactate anabolism of tumor cells. Tumor cells are programmed to rely on aerobic glycolysis to support their proliferation. The abnormal metabolism of tumor cells causes a large accumulation of lactate in TME. Glucose transporters (i.e., GLUT1 and GLUT4) are responsible for the influx of glucose, which is then catalyzed by a series of glycolysis‐related enzymes to produce lactate. Following that, lactate is discharged into the extracellular environment through MCT4 on the cell membrane, leading to the increasement of lactate levels in TME. Enzymes that catalyze the metabolic reactions and corresponding inhibitors are shown in ovals and rectangles, respectively. GLUT1/GLUT4, glucose transporter 1/4; G6P, glucose‐6‐phosphate; F6P, fructose‐6‐phosphate; F1,6BP, fructose‐1,6‐bisphosphate; PEP, phosphoenolpyruvate; HK2, hexokinase 2; PFK1, phosphofructokinase 1; PKM1, pyruvate kinase 1; PKM2, pyruvate kinase 2; LDHA, lactate dehydrogenase A; MCT4, monocarboxylate transporter 4.

Figure 3

Nanomaterial‐mediated lactate anabolism inhibition by blocking glucose transport. A) Schematic illustration of P‐B‐D NPs, which are fabricated by coloading GLUT1 inhibitor (BAY‐876) and DOX prodrug (DOX‐Duplex) into a GSH‐responsive self‐assembled polymer nanoparticle. Reproduced with permission.^{[ 25 ]} Copyright 2021, Wiley‐VCH. B) Schematic diagram of iMD nanoparticle that inactivates multiple types of GLUTs on tumor cell membranes, which is composed of a core–shell UCNP with a thin layer of MnO₃‐ _X , protamine, photosensitizer eosin, and glucose phosphate. Reproduced with permission.^{[ 31 ]} Copyright 2021, American Chemical Society.

Figure 4

Alleviating hypoxia in TME to inhibit lactate anabolism. A) Scheme illustration of an “oxygen‐carrying” nanoplatform (PFB@PLLA) to downregulate glycolysis level and lactate secretion by alleviating hypoxia. B) Western blot analysis of HIF‐1α, HK2, GLUT1, and CAIX protein expressions. C) Lactate production of HepG2, MDA‐MB‐231 after different treatments. Reproduced with permission.^{[ 42 ]} Copyright 2019, Wiley‐VCH. D) Schematic design of the PLANT nanosystem fabricated by vegetable thylakoid and various nanoparticles. Under light irradiation, PLANT could produce O₂ in situ to normalize TME for antiangiogenesis therapy and enhanced PDT. E) O₂ generation capacity of different groups in real‐time. F) Lactate concentration of different groups in real‐time. Reproduced with permission.^{[ 52 ]} Copyright 2018, American Chemical Society.

Figure 5

Nanomaterial‐mediated lactate anabolism inhibition by inhibiting glycolysis‐related enzymes HK2 and PKM2. A) Scheme of the augmenting tumor‐starvation strategy by combining autophagy inhibitors (BP nanosheet) and HK2 inhibitors (2‐DG). B) Scheme of the supramolecular nanoplatform (CD‐Ce6‐3BP) combining 3‐BP with Ce6 for downregulating HK2 and GAPDH, which can inhibit lactate anabolism, and induce tumor cell apoptosis. Reproduced with permission.^{[ 63 ]} Copyright 2020, American Chemical Society. C) Schematic diagram of the mechanism of the hybrid albumin/lactoferrin nanosystem (BSA/LF), which codelivers PKM2 inhibitor SHK and ALDH1L1 inhibitor DSF to achieve dual restraint of glioma energy metabolism. D,E) Detection of (D) ALDH1L1 and (E) PKM2 expressions in normal cell lines and glioma cell lines by qPCR (n = 3). Reproduced with permission.^{[ 70 ]} Copyright 2022, Wiley‐VCH.

Figure 6

Nanomaterial‐mediated lactate anabolism inhibition by inhibiting glycolysis‐related enzymes LDHA and depleting key factors. A) Scheme of the RNAi nanoparticle‐mediated tumor acidity regulation. B) LDHA downregulation, lactate reduction, and acidity attenuation mediated by RNAi in vitro. Reproduced with permission.^{[ 78 ]} Copyright 2019, American Chemical Society. C) Scheme diagram of the H₂S‐depleting nanoplatform to inhibit glycolysis by downregulating GAPDH activity in tumor cells. Reproduced with permission.^{[ 79 ]} Copyright 2022, Springer Nature. D) Scheme of MSN‐based nanoplatform for codelivering rotenone and Mg²⁺ to downregulate glycolytic‐related enzymes for tumor therapy. Reproduced with permission^{[ 51 ]} under the terms of the CC BY 3.0 Creative Commons license (https://www.creativecommons.org/licenses/by/3.0/). Copyright 2018, Royal Society of Chemistry.

Figure 7

Nanomaterial‐mediated promotion of lactate catabolism. A) Scheme of metal–phenol network encapsulated with LOX and ATO for efficient consumption of lactate. Reproduced with permission.^{[ 104 ]} Copyright 2021, American Chemical Society. B) Scheme of Cu²⁺‐chelated mesoporous polydopamine (mPDA) nanoparticles encapsulated with LOX to achieve closed‐loop catalysis of lactate consumption in tumor tissues. Reproduced with permission.^{[ 107 ]} Copyright 2022, American Chemical Society. C) Scheme of SnSe@ABS NSs with LDHB‐like activity to ameliorate the acidic TME. Reproduced with permission.^{[ 110 ]} Copyright 2022, American Chemical Society. D) Schematic illustration of the bioreactor SO@MDH for active tumor targeting and anaerobical lactate depletion. Reproduced with permission.^{[ 113 ]} Copyright 2021, American Chemical Society.

Figure 8

Nanomaterial‐mediated lactate production inhibiting and depletion promoting. A) Schematic illustration of the cascade catalytic nanosystem (PMLR) to efficiently deplete intra/extracellular lactate in TME. B) Lactate concentration in solution of PMR and PMLR nanosystems. Reproduced with permission.^{[ 120 ]} Copyright 2019, Wiley‐VCH. C) Schematic diagram of the antitumor mechanism of Bac@MnO₂. D) Bac@MnO₂ mediated lactate concentration in CT26 tumor tissues. Reproduced with permission.^{[ 117a ]} Copyright 2020, Wiley‐VCH.

Figure 9

Lactate shuttles between tumor cells. Tumor cells far from the vessels opt for glycolysis instead of OXPHOS to provide a vast amount of energy for rapid proliferation due to the shortage of oxygen, increasing lactate production. Lactate is then discharged into the extracellular environment through monocarboxylic acid transporter 4 (MCT4), ultimately acidifying the TME. The catabolites lactate is in turn acquired by tumor cells closer to the vessels through monocarboxylic acid transporter 1 (MCT1), then entered into the tricarboxylic acid (TCA) cycle to fuel mitochondrial metabolism for energy generation.

Figure 10

Nanomaterial‐mediated disruption of lactate efflux. A) cheme of TerBio self‐assembled by Ce6, Lon, and SB for lactate efflux inhibition and enhanced tumor treatment. Reproduced with permission.^{[ 131 ]} Copyright 2022, American Chemical Society. B) The antitumor mechanism of the cascaded responsive nanoplatform HMONs@HCPT–BSA–PEI–CDM–PEG@siMCT4. Reproduced with permission.^{[ 132 ]} Copyright 2020, American Chemical Society. C) Scheme of Me&Flu@MSN@MnO₂‐FA interfering with lactate metabolism to induce intracellular acidosis to suppress metastasis. Reproduced with permission.^{[ 133c ]} Copyright 2020, Royal Society of Chemistry. D) Schematic illustration of PCA nanomotor for tumor metabolism symbiosis disruption. Reproduced with permission.^{[ 133b ]} Copyright 2021, Wiley‐VCH.

Figure 11

Nanomaterial‐mediated disruption of lactate influx. A) Schematic illustration of the porphyrinic MOF nanoplatform for interfering with the lactate uptake to enhance tumor treatment. B) Lactate concentration of cells after different treatments. Reproduced with permission.^{[ 144 ]} Copyright 2018, Wiley‐VCH. C) Schematic illustration of the tumor therapeutic mechanisms of CHC/GOX@ZIF‐8. D) Lactate consumption profile of cells in different groups. Reproduced with permission.^{[ 146 ]} Copyright 2021, Wiley‐VCH.

Figure 12

Strategies that combine lactate metabolic modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy (PTT), ROS‐related therapies, and others.

Figure 13

Nanomaterial‐mediated therapy strategies combined lactate metabolic regulation with chemotherapies. A) Schematic diagram of the construction of DOX‐loaded ACC/PAA nanoparticles and their regulation mechanism on tumor cells. Different amounts of Sr²⁺ or Mg²⁺ doped in ACC lead to different degradation curves of nanoparticles, indicating that the pH response of drug release is adjustable. B) Relative tumor volumes with different treatments (n = 5). Reproduced with permission.^{[ 155 ]} Copyright 2019, Wiley‐VCH. C) Scheme of the fabrication of LOX/TPZ@Lips‐LA and its mediated combined therapy. D) Intracellular lactate concentration after different treatments for 12 h. Reproduced with permission.^{[ 98 ]} Copyright 2020, Wiley‐VCH.

Figure 14

A) Schematic diagram of the construction of D/B/CQ/ZIF‐8@CS and its synergetic mechanism for starvation therapy and lactate metabolic regulation. B) Extracellular lactate level of 4T1 cells after various treatments for 24 h. (1) PBS, (2) B@ZIF‐8@CS, (3) D@ZIF‐8@CS, (4) D/B@ZIF‐8@CS, and (5) D/B/CQ@ZIF‐8@CS. Reproduced with permission.^{[ 165 ]} Copyright 2022, American Chemical Society. C) Scheme of the fibrin gel containing aCD47@CaCO₃ nanoparticles for the combination of H⁺ neutralization and immune system awakening. D) aCD47 release profiles from fibrin in solutions at pH 6.5 and 7.4. Reproduced with permission.^{[ 164 ]} Copyright 2018, Springer Nature.

Figure 15

A) Scheme of the synthesis process of LND@HMPB‐Zn and its synergistic mechanism for glycolytic inhibition and PTT. B) Lactate concentration in the culture medium of B16 cells in different treatment groups. Reproduced with permission.^{[ 30 ]} Copyright 2022, Elsevier. C) Scheme of the synthesis of PTFL nanoparticles and their synergistic mechanisms for lactate metabolic regulation and CDT. D) Lactate level in the culture medium of 4T1 cells in different groups for 48 h. Reproduced with permission.^{[ 178 ]} Copyright 2021, Wiley.