Small molecular chelator for comprehensive regulation of tumor lactate levels in synergy with photodynamic therapy for cancer treatment

Abstract

An increasing number of studies have focused on depleting lactate and modulating the tumor's lactic microenvironment to interfere with tumor progression, particularly in breast cancer. Lactate accumulation in tumors contributes to a highly acidic microenvironment that promotes cancer cell survival and resistance to therapies. However, existing lactate depletion agents, primarily enzymes and macromolecules, fall short of clinical applications due to poor stability and their ability to only perform solitary lactate depletion without interfering with the transport process. Consequently, the development of stable molecules that deplete lactate and interfere with lactate transport is critically needed. Therefore, in this study, chlorin e6 (Ce6)-gadolinium chloride (GdCl₃)-flavin adenine dinucleotide (FAD)/tamoxifen (TAM) molecular chelates were prepared. The chelates fully interfered with lactate transport, depleted lactate in the tumor microenvironment, mitigated photodynamic therapy resistance, and realized synergistic photodynamic-hormonal therapy. FAD has promising capabilities in regulating lactate levels and mitigating acidic microenvironments. However, a strategy for depleting lactate by chelating the coenzyme FAD to form nanoparticles has not yet been reported. Tamoxifen disrupts tumor development and interferes with lactate transport by binding to estrogen receptor and inhibiting the expression of monocarboxylate transporter. In addition, coupling with Gd³⁺ increased the solubility of Ce6, thereby improving the photodynamic therapy effectiveness. This innovative strategy improves therapeutic efficacy and offers a promising approach for breast cancer treatment.

Keywords

Nano drug delivery system / Lactate depletion / Lactate modulation / Hormone therapy / Photodynamic therapy

Conflicts of interest

The authors declare that there is no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 82373206), Zhejiang Provincial Natural Science Foundation of China under Grant No LHDMZ24H300002, and National Key Research and Development Program of China (No. 2022YFE0107800, 2023YFA1008603).

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ajps.2025.101059. The figures with "S" before the serial number are included in the Supplementary data.

References

[1] Chua CYX, Ho J, Demaria S, Ferrari M, Grattoni A. Emerging technologies for local cancer treatment. Adv Ther 2020; 3(9):2000027.

[2] Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023;73( 1):17-48.

[3] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71( 3):209-49.

[4] Li T, Akinade T, Zhou J, Wang H, Tong Q, He S, et al. Therapeutic nanocarriers inhibit chemotherapy-induced breast cancer metastasis. Adv Sci 2022; 9(33):2203949.

[5] Loibl S, Poortmans P, Morrow M, Denkert C, Curigliano G. Breast cancer. Lancet 2021; 397(10286):1750-69.

[6] Servetto A, Kollipara R, Formisano L, Lin CC, Lee KM, Sudhan DR, et al. Nuclear FGFR1 regulates gene transcription and promotes antiestrogen resistance in ER+ breast cancer. Clin Cancer Res 2021; 27(15):4379-96.

[7] Farrar MC, Jacobs TF. Tamoxifen. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.

[8] Rossi V, Govoni M, Farabegoli F, Di Stefano G. Lactate is a potential promoter of tamoxifen resistance in MCF7 cells. Biochim Biophys Acta Gen Subj 2022; 1866(9):130185.

[9] Ippolito L, Morandi A, Giannoni E, Chiarugi P. Lactate: a metabolic driver in the tumour landscape. Trends Biochem Sci 2019; 44(2):153-66.

[10] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5):646-74.

[11] Heiden MGV, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324(5930):1029-33.

[12] Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, et al. Lactate metabolism in human lung tumors. Cell 2017; 171(2):358-71.

[13] Polet F, Feron O. Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force. J Intern Med 2013; 273(2):156-65.

[14] Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF- $\kappa \mathrm{b} / \mathrm{IL}-8$ pathway that drives tumor angiogenesis. Cancer Res 2011; 71(7):2550-60.

[15] Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M, Senbabaoglu Y, et al. CTLA-4 blockade drives loss of T(reg) stability in glycolysis-low tumours. Nature 2021; 591(7851):652-8.

[16] Elia I, Rowe JH, Johnson S, Joshi S, Notarangelo G, Kurmi K, et al. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells. Cell Metab 2022; 34(8):1137-50.

[17] Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 2022; 40(2):201-18.

[18] Watson MJ, Vignali PDA, Mullett SJ, Overacre-Delgoffe AE, Peralta RM, Grebinoski S, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 2021; 591(7851):645-51.

[19] Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature 2019; 574(7779):575-80.

[20] Liu N, Luo J, Kuang D, Xu S, Duan Y, Xia Y, et al. Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2 a-mediated tumor progression. J Clin Invest 2019; 129(2):631-46.

[21] de la Cruz-Lopez KG, Castro-Munoz LJ, Reyes-Hernandez DO, Garcia-Carranca A, Manzo-Merino J. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front Oncol 2019; 9:1143.

[22] Li XL, Yang YY, Zhang B, Lin XT, Fu XX, An Y, et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther 2022; 7(1):372.

[23] Zhou X, Zhao W, Wang M, Zhang S, Li Y, Hu W, et al. Dual-modal therapeutic role of the lactate oxidase-embedded hierarchical porous zeolitic imidazolate framework as a nanocatalyst for effective tumor suppression. ACS Appl Mater Interfaces 2020; 12(29):32278-88.

[24] He R, Zang J, Zhao Y, Liu Y, Ruan S, Zheng X, et al. Nanofactory for metabolic and chemodynamic therapy: pro-tumor lactate trapping and anti-tumor ROS transition. J Nanobiotechnol 2021; 19(1):426.

[25] Jayabalan R, Sathishkumar M, Jeong ES, Mun SP, Yun SE. Immobilization of flavin adenine dinucleotide (FAD) onto carbon cloth and its application as working electrode in an electroenzymatic bioreactor. Bioresour Technol 2012; 123:6869.

[26] Satomura T, Kawakami R, Sakuraba H, Ohshima T. A novel flavin adenine dinucleotide (FAD) containing d-lactate dehydrogenase from the thermoacidophilic crenarchaeota Sulfolobus tokodaii strain 7: purification, characterization and expression in Escherichia coli. J Biosci Bioeng 2008; 106(1): 16-21.

[27] Xie X, Hao F, Chen R, Wang J, Wei Y, Liu J, et al. Nicotinamide adenine dinucleotide-dependent flavin oxidoreductase of Mycoplasma hyopneumoniae functions as a potential novel virulence factor and not only as a metabolic enzyme. Front Microbiol 2021; 12:747421.

[28] Furman E, Rushkin E, Margalit R, Bendel P, Degani H. Tamoxifen induced changes in MCF7 human breast cancer: in vitro and in vivo studies using nuclear magnetic resonance spectroscopy and imaging. J Steroid Biochem Mol Biol 1992; 43(1):189-95.

[29] Frisardi V, Canovi S, Vaccaro S, Frazzi R. The significance of microenvironmental and circulating lactate in breast cancer. Int J Mol Sci 2023; 24(20):15369.

[30] Shi X, Yang W, Ma Q, Lu Y, Xu Y, Bian K, et al. Hemoglobinmediated biomimetic synthesis of paramagnetic O2evolving theranostic nanoprobes for MR imaging-guided enhanced photodynamic therapy of tumor. Theranostics 2020; 10(25):11607-21.

[31] Sun R, Xiang J, Zhou Q, Piao Y, Tang J, Shao S, et al. The tumor EPR effect for cancer drug delivery: current status, limitations, and alternatives. Adv Drug Deliv Rev 2022; 191:114614.

[32] Bian Q, Huang LL, Xu YH, Wang RX, Gu YT, Yuan AR, et al. A facile low-dose photosensitizer-incorporated dissolving microneedles-based composite system for eliciting antitumor immunity and the abscopal effect. ACS Nano 2022; 16(8):13255-68.