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Nutrient-delivery and metabolism reactivation therapy for melanoma

Nature Nanotechnology (2024)Cite this article

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Abstract

To fulfil the demands of rapid proliferation, tumour cells undergo significant metabolic alterations. Suppression of hyperactivated metabolism has been proven to counteract tumour growth. However, whether the reactivation of downregulated metabolic pathways has therapeutic effects remains unexplored. Here we report a nutrient-based metabolic reactivation strategy for effective melanoma treatment. l-Tyrosine–oleylamine nanomicelles (MTyr–OANPs) were constructed for targeted supplementation of tyrosine to reactivate melanogenesis in melanoma cells. We found that reactivation of melanogenesis using MTyr–OANPs significantly impeded the proliferation of melanoma cells, primarily through the inhibition of glycolysis. Furthermore, leveraging melanin as a natural photothermal reagent for photothermal therapy, we demonstrated the complete eradication of tumours in B16F10 melanoma-bearing mice through treatment with MTyr–OANPs and photothermal therapy. Our strategy for metabolism activation-based tumour treatment suggests specific nutrients as potent activators of metabolic pathways.

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Fig. 1: Nutrient-based metabolism reactivation strategy for melanoma treatment.
Fig. 2: Stability, biocompatibility and delivery efficiency of MTyr–OANPs.
Fig. 3: Quantitative analysis of efficiency of MTyr–OANPs in promoting melanogenesis and inhibiting growth and migration of melanoma cells.
Fig. 4: MTyr–OANP-induced tyrosinase activation and glycolysis suppression.
Fig. 5: In vivo antitumour activity of MTyr–OANPs in melanoma-bearing mice.
Fig. 6: Pigmented cell phenotypes enhanced cell death in response to 808 nm laser irradiation.

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Data availability

All the data supporting the results are available within the paper and its Supplementary Information. The bulk RNA-seq data and clinical information of patients with SKCM were downloaded from The Cancer Genome Atlas (TCGA) database: https://portal.gdc.cancer.gov/. All raw sequencing data and associated processed data files that support the findings of this study have been deposited in the Gene Expression Omnibus under accession code GSE263497 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE263479). Source data are provided with this paper.

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Acknowledgements

This work is supported by the Key Program of National Natural Science Foundation of China (22235004) and Innovation Program of Shanghai Municipal Education Commission (2023ZKZD01) to W.B.; National Natural Science Foundation of China (grant numbers 82172091 and 82372122) and Shanghai Science and Technology Innovation Action Plan (grant numbers 23XD1422800 and 23S31900200) to Y. Wu; and National Science Foundation for the Young Scientists of China (grant number 32000948) and State Key Laboratory of Molecular Engineering of Polymers Project (Fudan University, grant number K2023-24) to Y.C.

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  1. These authors contributed equally: Yang Chen, Chaochao Wang, Yelin Wu.

Authors and Affiliations

  1. Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, School of Life Sciences and Technology, Tongji University, Shanghai, P. R. China

    Yang Chen, Chaochao Wang, Yelin Wu, Yun Meng, Jieyun Shi & Wenbo Bu

  2. Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, P. R. China

    Yang Chen, Chaochao Wang, Ya Wang, Fan Wu, Huilin Zhang, Xingwu Jiang, Huiyan Li, Peiran Zhao & Wenbo Bu

  3. Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, P. R. China

    Huilin Zhang, Jinfeng Wu & Wenbo Bu

  4. Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia

    Yuen Yee Cheng & Dayong Jin

  5. Cedars-Sinai Cancer Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Bin Zheng

  6. Eastern Institute for Advanced Study, Eastern Institute of Technology, Ningbo, P. R. China

    Dayong Jin

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Contributions

W.B., Y.C., J.W. and D.J. conceived the study. Y.C., C.W. and Y. Wu designed and performed the experiments. C.W., Y. Wang, P.Z. and H.Z. synthesized and characterized MTyr–OANPs. Y.C., Y.M. and F.W. performed cell- and tumour-bearing mice-related experiments. X.J. and J.S. assisted with cell biological and animal experiments. B.Z., H.L., C.W. and Y.C. analysed the data. W.B., Y.C., C.W., J.W., D.J. and Y.Y.C. wrote the paper. All authors interpreted data, discussed results and contributed to the review, revision and finalization of the paper.

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Correspondence to Jinfeng Wu, Dayong Jin or Wenbo Bu.

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Nature Nanotechnology thanks Yale Yue and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 MTyr-OANPs downregulated the expression of MMP9 and MMP2,and inhibited cell migration.

a, Immunofluorescence images of MMP9 and MMP2 in control and MTyr-OANPs treated cells (n = 3 biological replicates), scale bars, 50 μm. b and c, wound-healing assay in control and MTyr-OANPs treated cells (n = 3 biological replicates), scale bars, 50 μm. Data were represented as mean ± s.d., and P values were performed with one-way ANOVA followed by post hoc Tukey’s test.

Source data

Extended Data Fig. 2 The metabolite analysis of B16F10 cells after MTyr-OANPs or MTyr-OANPs + α-Arbutin co-treatment.

a, Principal Component Analysis (PCA) of metabolites measured by LC-MS in MTyr-OANP (72h after co-incubation) versus control cells (n = 3 biological replicates). b, Intracellular melanin content of cell in control, MTyr-OANPs treated, MTyr-OANPs and α-Arbutin co-treated cells after 72 h (results were presented as percentage relative to control, n = 3 biological replicates, means ± s.d.). c, Heat map of glycolysis intermediate metabolites in MTyr-OANPs and α-Arbutin co-treated cells (72 h after co-incubation) (n = 3 biological replicates). Colour bar is Z-score. d, Pyruvate activities of B16F10 cells after incubation with melanin for 48 h (p > 0.05, n = 5 biological replicates, means ± s.d.). P values were performed with Student’s t test (unpaired, two-tailed) or one-way ANOVA followed by post hoc Tukey’s test.

Source data

Extended Data Fig. 3 LC-MS results of melanin intermediates including L-DOPA, 5,6-DHI and 5,6-DHICA after MTyr-OANPs treatment for 72 h.

a, Mass spectra of intracellular L-DOPA content by LC-MS (n = 3 independent experiments). b, Quantitative results based on peak intensity (n = 3 independent experiments, means ± s.d., P value was performed with Student’s t test (unpaired, two-tailed). c, The mass spectra of DHI and DHICA by LC-MS (n = 3 independent experiments).

Source data

Extended Data Fig. 4 MTyr-OANPs promote melanin synthesis and related gene expression in murine and human-derived melanoma.

Pictures of resected B16F10 tumors (a) and Fontana-Masson staining results for melanin of tumor tissue sections (b) with or without MTyr-OANPs treatment (n = 3 biological replicates, scale bars, 100 μm). Relative mRNA expression of Tyr, Tyrp1 and Tyrp2 (c), tyrosinase activity and total melanin content (d) in PBS and MTyr-OANPs treated mice tumor after three injections (n = 3 biological replicates). e, mRNA expression of Mitf in A375 and Mewo cells co-cultured with MTyr-OANPs for 24 h. f and g, Immunohistochemistry results of MITF in mice tumors (n = 3 biological replicates, scale bars, 200 μm). Data were represented as mean ± s.d., and P values were performed with Student’s t test (unpaired, two-tailed).

Source data

Extended Data Fig. 5 Enhanced anti-tumor efficiency under MTyr-OANPs and 808 nm laser irradiation co-treatment.

a, Fluorescent images of Calcein-AM/PI-stained B16F10 cells incubated with 1 mg/mL MTyr-OANPs for 72 h and/or treated with 808 nm laser for 5 min. (red represents dead cells, and green represents live cells) (n = 3 independent experiments, scale bars, 100 μm). b, Temperature increase curves vs. irradiation time of mice tumors (n = 3 biological replicates, means ± s.d. and P values were performed with Student’s t test (unpaired, two-tailed)). c) Representative images of tumor-bearing mice in different treated groups (n = 5 independent mice). d, Representative images of mice in ‘MTyr-OANPs + Laser group’ within 49 days of observation. e, H&E staining of tumors in each groups after 6 days of treatment (n = 5 independent experiments, scale bars, 100 μm).

Source data

Extended Data Fig. 6 The anti-tumor efficiency of photothermal effect after increasing melanin production.

Laser power intensity screening to achieve the same photothermal effect as that in ‘MTyr-OANPs + Laser’ group’. a, The tumor temperature increase curves versus irradiation time under different laser power intensity. b, Temperature increase curves versus irradiation time in tumors in ‘MTyr-OANPs + Laser (0.28 W/cm2)’ and ‘Laser (0.32 W/cm2)’ groups (n = 4 biological replicates, means ± s.d.). c, Relative infrared thermal images of mice (n = 4 biological replicates). Tumor Growth curves (V/V0) (d) and Kaplan–Meimer survival curves (e) of B16F10 tumor-bearing mice treated with PBS, MTyr-OANPs, Laser (0.32 W/cm2), and MTyr-OANPs + Laser (0.28 W/cm2), n = 6 biological replicates, means ± s.d. P values were performed with Student’s t test (unpaired, two-tailed) or one-way ANOVA followed by post hoc Tukey’s test. The differences of survival curves were determined by the two-side log-rank test.

Source data

Supplementary information

Supplementary Information

Additional methods and Supplementary Figs. 1–16.

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Supplementary Video 1

Body distribution of MTyr–OANPs in mice with time.

Statistical source data for Supplementary figures

Statistical source data for Supplementary Figs. 1–8, 11, 12 and 14.

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Source Data Fig. 2

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Source Data Fig. 4

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Source Data Fig. 6

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Source Data Figs. 3 and 6

Unprocessed western blots.

Source Data Extended Data Figs. 1–6

Statistical source data.

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Chen, Y., Wang, C., Wu, Y. et al. Nutrient-delivery and metabolism reactivation therapy for melanoma. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-024-01690-6

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