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Nano-drug delivery system targeting FAP for the combined treatment of oral leukoplakia

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Abstract

Oral leukoplakia (OLK) has received much attention due to its potential risk of malignant transformation. Studies have shown that when drug therapy is combined with photothermal therapy (PTT), not only can the cytotoxicity of the drug be enhanced, but also the heat energy can be used to kill the lesion cells, so we can combine drug therapy with PTT to enhance the therapeutic effect on OLK. However, with certain drawbacks due to its lack of targeting, fibroblast activating protein (FAP) has become an attractive target for OLK combination therapy. In this study, we used NGO-PEG loaded with FAP-targeting peptide (F-TP) and celecoxib (CXB) to construct a nano-drug delivery system CGPF for targeting OLK with high FAP expression and confirmed the biocompatibility and therapeutic efficacy of CGPF by in vitro and in vivo experiments. Overall, the novel nano-drug delivery system CGPF proposed in this study showed a very significant potential for the combination therapy of OLK.

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Any data or material that supports the findings of this study can be made available by the corresponding author upon request.

References

  1. van der Waal I. Historical perspective and nomenclature of potentially malignant or potentially premalignant oral epithelial lesions with emphasis on leukoplakia-some suggestions for modifications. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125(6):577–81.

    Article  PubMed  Google Scholar 

  2. Ding T, Zou J, Qi J, et al. Mucoadhesive nucleoside-based hydrogel delays oral leukoplakia canceration. J Dent Res. 2022;101(8):921–30.

    Article  CAS  PubMed  Google Scholar 

  3. Holmstrup P, Vedtofte P, Reibel J, et al. Oral premalignant lesions: is a biopsy reliable? Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2007;36(5):262–6.

    Article  CAS  Google Scholar 

  4. Kerr AR, Lodi G. Management of oral potentially malignant disorders. Oral Dis. 2021;27(8):2008–25.

    Article  PubMed  Google Scholar 

  5. Annaji M, Poudel I, Boddu SHS, et al. Resveratrol-loaded nanomedicines for cancer applications. Cancer reports (Hoboken, NJ). 2021;4(3): e1353.

    Article  CAS  Google Scholar 

  6. Zhao M, Jing Z, Zhou L, et al. Pharmacokinetic research progress of anti-tumor drugs targeting for pulmonary administration. Curr Drug Metab. 2020;21(14):1117–26.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang H, Li Y, Pan Z, et al. Multifunctional nanosystem based on graphene oxide for synergistic multistage tumor-targeting and combined chemo-photothermal therapy. Mol Pharm. 2019;16(5):1982–98.

    Article  CAS  PubMed  Google Scholar 

  8. Cheng Y, Weng S, Yu L, et al. The role of hyperthermia in the multidisciplinary treatment of malignant tumors. Integr Cancer Ther. 2019;18:1534735419876345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lin L, Song C, Wei Z, et al. Multifunctional photodynamic/photothermal nano-agents for the treatment of oral leukoplakia. J Nanobiotechnology. 2022;20(1):106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li H, Sun J, Zhu H, et al. Recent advances in development of dendritic polymer-based nanomedicines for cancer diagnosis. Wiley interdisciplinary reviews. Nanomed Nanobiotechnol. 2021;13(2):e1670.

  11. Zhao L, Chen J, Pang Y, et al. Fibroblast activation protein-based theranostics in cancer research: a state-of-the-art review. Theranostics. 2022;12(4):1557–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Xi CR, Di Fazio A, Nadvi NA, et al. An improved production and purification protocol for recombinant soluble human fibroblast activation protein alpha. Protein Expr Purif. 2021;181: 105833.

    Article  CAS  PubMed  Google Scholar 

  13. Dendl K, Koerber S A, Kratochwil C, et al. FAP and FAPI-PET/CT in malignant and non-malignant diseases: a perfect symbiosis? Cancers. 2021;13(19).

  14. Fitzgerald AA, Weiner LM. The role of fibroblast activation protein in health and malignancy. Cancer Metastasis Rev. 2020;39(3):783–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Givel AM, Kieffer Y, Scholer-Dahirel A, et al. miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. Nat Commun. 2018;9(1):1056.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Keane FM, Yao TW, Seelk S, et al. Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs. FEBS Open Bio. 2013;4:43–54.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Linz C, Brands RC, Kertels O, et al. Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity - initial experience and comparison to [(18)F]FDG PET/CT and MRI. Eur J Nucl Med Mol Imaging. 2021;48(12):3951–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sun Y, Liu N, Guan X, et al. Immunosuppression induced by chronic inflammation and the progression to oral squamous cell carcinoma. Mediators Inflamm. 2016;2016:5715719.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Das D, Maitra A, Panda CK, et al. Genes and pathways monotonically dysregulated during progression from normal through leukoplakia to gingivo-buccal oral cancer. NPJ Genom Med. 2021;6(1):32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tan P, Chen X, Zhang H, et al. Artificial intelligence aids in development of nanomedicines for cancer management. Semin Cancer Biol. 2023;89:61–75.

    Article  CAS  PubMed  Google Scholar 

  21. Mousavi SM, Hashemi SA, Ghasemi Y, et al. Applications of graphene oxide in case of nanomedicines and nanocarriers for biomolecules: review study. Drug Metab Rev. 2019;51(1):12–41.

    Article  CAS  PubMed  Google Scholar 

  22. Ma K, Fu D, Liu Y, et al. Cancer cell targeting, controlled drug release and intracellular fate of biomimetic membrane-encapsulated drug-loaded nano-graphene oxide nanohybrids. J Mater Chem B. 2018;6(31):5080–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. de Melo-Diogo D, Lima-Sousa R, Alves CG, et al. Graphene family nanomaterials for application in cancer combination photothermal therapy. Biomater Sci. 2019;7(9):3534–51.

    Article  PubMed  Google Scholar 

  24. Mo Y, Liu W, Liu P, et al. Multifunctional graphene oxide nanodelivery platform for breast cancer treatment. Int J Nanomed. 2022;17:6413–25.

    Article  Google Scholar 

  25. Jiang BP, Zhou B, Lin Z, et al. Recent Advances in Carbon Nanomaterials for Cancer Phototherapy. Chemistry (Weinheim an der Bergstrasse, Germany). 2019;25(16):3993–4004.

    CAS  PubMed  Google Scholar 

  26. Vacchi IA, Guo S, Raya J, et al. Strategies for the controlled covalent double functionalization of graphene oxide. Chemistry (Weinheim an der Bergstrasse, Germany). 2020;26(29):6591–8.

    CAS  PubMed  Google Scholar 

  27. Ding YF, Kwong CHT, Li S, et al. Supramolecular nanomedicine derived from cucurbit[7]uril-conjugated nano-graphene oxide for multi-modality cancer therapy. Biomater Sci. 2021;9(10):3804–13.

    Article  CAS  PubMed  Google Scholar 

  28. Guo S, Nishina Y, Bianco A, et al. A flexible method for covalent double functionalization of graphene oxide. Angew Chem Int Ed Engl. 2020;59(4):1542–7.

    Article  CAS  PubMed  Google Scholar 

  29. Lombardi L, Kovtun A, Mantovani S, et al. Visible-light assisted covalent surface functionalization of reduced graphene oxide nanosheets with arylazo sulfones. Chemistry (Weinheim an der Bergstrasse, Germany). 2022;28(26):e202200333.

    CAS  PubMed  Google Scholar 

  30. Mirrahimi M, Alamzadeh Z, Beik J, et al. A 2D nanotheranostic platform based on graphene oxide and phase-change materials for bimodal CT/MR imaging, NIR-activated drug release, and synergistic thermo-chemotherapy. Nanotheranostics. 2022;6(4):350–64.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Daniyal M, Liu B, Wang W. Comprehensive review on graphene oxide for use in drug delivery system. Curr Med Chem. 2020;27(22):3665–85.

    Article  CAS  PubMed  Google Scholar 

  32. Sugumaran PJ, Liu XL, Herng TS, et al. GO-functionalized large magnetic iron oxide nanoparticles with enhanced colloidal stability and hyperthermia performance. ACS Appl Mater Interfaces. 2019;11(25):22703–13.

    Article  CAS  PubMed  Google Scholar 

  33. Guo W, Chen Z, Feng X, et al. Graphene oxide (GO)-based nanosheets with combined chemo/photothermal/photodynamic therapy to overcome gastric cancer (GC) paclitaxel resistance by reducing mitochondria-derived adenosine-triphosphate (ATP). Journal of nanobiotechnology. 2021;19(1):146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hamson EJ, Keane FM, Tholen S, et al. Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy. Proteomics Clin Appl. 2014;8(5–6):454–63.

    Article  CAS  PubMed  Google Scholar 

  35. Wang L, Yu D, Dai R, et al. PEGylated doxorubicin cloaked nano-graphene oxide for dual-responsive photochemical therapy. Int J Pharm. 2019;557:66–73.

    Article  CAS  PubMed  Google Scholar 

  36. Li R, Wang Y, Du J, et al. Graphene oxide loaded with tumor-targeted peptide and anti-cancer drugs for cancer target therapy. Sci Rep. 2021;11(1):1725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li R, Gao R, Wang Y, et al. Gastrin releasing peptide receptor targeted nano-graphene oxide for near-infrared fluorescence imaging of oral squamous cell carcinoma. Sci Rep. 2020;10(1):11434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dash BS, Lu YJ, Chen HA, et al. Magnetic and GRPR-targeted reduced graphene oxide/doxorubicin nanocomposite for dual-targeted chemo-photothermal cancer therapy. Mater Sci Eng C Mater Biol Appl. 2021;128:112311.

  39. Jiang Z, Zhang C, Wang X, et al. A borondifluoride-complex-based photothermal agent with an 80 % photothermal conversion efficiency for photothermal therapy in the NIR-II window. Angew Chem Int Ed Engl. 2021;60(41):22376–84.

    Article  CAS  PubMed  Google Scholar 

  40. Wang C, Niu W, Chen H, et al. Nicotine suppresses apoptosis by regulating α7nAChR/Prx1 axis in oral precancerous lesions. Oncotarget. 2017;8(43):75065–75.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Nagao T, Warnakulasuriya S, Nakamura T, et al. Treatment of oral leukoplakia with a low-dose of beta-carotene and vitamin C supplements: a randomized controlled trial. Int J Cancer. 2015;136(7):1708–17.

    Article  CAS  PubMed  Google Scholar 

  42. Yu CH, Chen HM, Hung HY, et al. Photodynamic therapy outcome for oral verrucous hyperplasia depends on the clinical appearance, size, color, epithelial dysplasia, and surface keratin thickness of the lesion. Oral Oncol. 2008;44(6):595–600.

    Article  CAS  PubMed  Google Scholar 

  43. Jiang GM, Xu W, Du J, et al. The application of the fibroblast activation protein α-targeted immunotherapy strategy. Oncotarget. 2016;7(22):33472–82.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Garin-Chesa P, Old LJ, Rettig WJ. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA. 1990;87(18):7235–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ren J, Smid M, Iaria J, et al. Cancer-associated fibroblast-derived gremlin 1 promotes breast cancer progression. Breast cancer research : BCR. 2019;21(1):109.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Dourado RC, Porto LPA, Leitão ÁCGH, et al. Immunohistochemical characterization of cancer-associated fibroblasts in oral squamous cell carcinoma. Appl Immunohistochem Mol Morphol : AIMM. 2018;26(9):640–7.

    Article  CAS  PubMed  Google Scholar 

  47. Wang Y, Jing Y, Ding L, et al. Epiregulin reprograms cancer-associated fibroblasts and facilitates oral squamous cell carcinoma invasion via JAK2-STAT3 pathway. J Exp Clin Cancer Res : CR. 2019;38(1):274.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Crusz SM, Balkwill FR. Inflammation and cancer: advances and new agents. Nat Rev Clin Oncol. 2015;12(10):584–96.

    Article  CAS  PubMed  Google Scholar 

  49. Zi F, He J, He D, et al. Fibroblast activation protein α in tumor microenvironment: recent progression and implications (review). Mol Med Rep. 2015;11(5):3203–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ding H, Tan P, Fu S, et al. Preparation and application of pH-responsive drug delivery systems. Journal of controlled release : official journal of the Controlled Release Society. 2022;348:206–38.

    Article  CAS  PubMed  Google Scholar 

  51. Li S, Zheng J, Chen D, et al. Yolk-shell hybrid nanoparticles with magnetic and pH-sensitive properties for controlled anticancer drug delivery. Nanoscale. 2013;5(23):11718–24.

    Article  CAS  PubMed  Google Scholar 

  52. Pan Q, Peng X, Cun J-E, et al. In-situ drug generation and controllable loading: rational design of copper-based nanosystems for chemo-photothermal cancer therapy. Chem Eng J. 2021;409:128222.

  53. Chen Q, Dan H, Tang F, et al. Photodynamic therapy guidelines for the management of oral leucoplakia. Int J Oral Sci. 2019;11(2):14.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Li Q, Dong H, Yang G, et al. Mouse tumor-bearing models as preclinical study platforms for oral squamous cell carcinoma. Front Oncol. 2020;10:212.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Barcessat AR, Huang I, Rabelo GD, et al. Systemic toxic effects during early phases of topical 4-NQO-induced oral carcinogenesis in rats. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2014;43(10):770–7.

    Article  CAS  Google Scholar 

  56. Vered M, Yarom N, Dayan D. 4NQO oral carcinogenesis: animal models, molecular markers and future expectations. Oral Oncol. 2005;41(4):337–9.

    Article  CAS  PubMed  Google Scholar 

  57. Kong X, Yang X, Zhou J, et al. Analysis of plasma metabolic biomarkers in the development of 4-nitroquinoline-1-oxide-induced oral carcinogenesis in rats. Oncol Lett. 2015;9(1):283–9.

    Article  PubMed  Google Scholar 

  58. Ludwig S, Hong CS, Razzo BM, et al. Impact of combination immunochemotherapies on progression of 4NQO-induced murine oral squamous cell carcinoma. Cancer Immunol Immunother : CII. 2019;68(7):1133–41.

    Article  PubMed  Google Scholar 

  59. Gumus R, Capik O, Gundogdu B, et al. Low vitamin D and high cholesterol facilitate oral carcinogenesis in 4NQO-induced rat models via regulating glycolysis. Oral Dis. 2023;29(3):978–89.

    Article  PubMed  Google Scholar 

  60. Wang X, Yuan Z, Tao A, et al. Hydrogel-based patient-friendly photodynamic therapy of oral potentially malignant disorders. Biomaterials. 2022;281:121377.

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Funding

This study was supported by the Shanxi Province Basic Research Program (20210302123311), the Research Project Supported by the Shanxi Scholarship Council of China (2021-087), Fund Program for the Scientific Activities of Selected Returned Overseas Professionals in Shanxi Province (20220020), Teaching Reform and Innovation Programs of Higher Education Institutions in Shanxi (J20220404), the Science and Technology Innovation Leader and Key Talent Team Project of Shanxi Province (202204051002034), and the 2022 Innovation Project of Postgraduate Education in Shanxi Province (Master).

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Authors and Affiliations

  1. Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, China

    Ran Li, Yingjiao Zhao, Tiantian Liu, Yanwei Li, Chaoqiong Wan, Ruifang Gao, Chen Liu, Xianqi Li & Bing Li

  2. Department of Pediatric and Preventive Dentistry, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, China

    Ran Li, Yingjiao Zhao, Tiantian Liu, Yanwei Li, Chaoqiong Wan, Ruifang Gao & Chen Liu

  3. Department of Oral and Maxillofacial Surgery, School of Dentistry, Matsumoto Dental University, Shiojiri, 399-0781, Japan

    Xianqi Li

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  1. Ran Li
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  2. Yingjiao Zhao
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Contributions

R.L. and Y.Z. contributed equally to this work. R.L.: validation, writing—review & editing, supervision, conceptualization, project administration, and funding acquisition. Y.Z.: data curation, methodology, formal analysis, investigation, writing—original draft, and visualization. T.L.: methodology, resources, and writing—review & editing. Y.L.: writing—review & editing. C.W.: resources and writing—review & editing. R.G.: validation, and writing—review & editing. C.L.: resources. X.L.: conceptualization. B.L.: conceptualization.

Corresponding author

Correspondence to Ran Li.

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All institutional and national guidelines for the care and use of laboratory animals were followed. All human OLK and NOM samples were obtained and used under informed written patient consent and local ethical committee approval.

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The authors declare no competing interests.

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Li, R., Zhao, Y., Liu, T. et al. Nano-drug delivery system targeting FAP for the combined treatment of oral leukoplakia. Drug Deliv. and Transl. Res. 14, 247–265 (2024). https://doi.org/10.1007/s13346-023-01397-6

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