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Folate-Decorated Polyamidoamine Dendrimer Nanoparticles for Head and Neck Cancer Gene Therapy

  • Leyuan Xu
  • Hu YangEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1974)

Abstract

Gene delivery systems have been developed on the basis of dendrimers and many other types of nanoparticle carriers, but few have been developed for head and neck squamous cell carcinomas (HNSCC). Herein, we describe the design and synthesis of fluorescently labeled, folic acid-decorated polyamidoamine (PAMAM) generation 4 (G4) dendrimer conjugates for HNSCC-targeted gene delivery. This delivery system comprises a dendrimer as the carrier that is conjugated with folic acid (FA) as HNSCC targeting moiety and imaging agents fluorescein isothiocyanate (FITC) or IRDye 800CW (NIR) for in vitro trafficking or bioimaging, respectively. By complexing with plasmid or siRNA, G4-FA/plasmid (or siRNA) significantly enhances gene transfection or knockdown efficiency in HNSCC cells. In a mouse xenograft model of HNSCC, this versatile G4-FA vector shows high biocompatibility, tumor targeting, high uptake, and sustained retention, making it a suitable platform for HNSCC gene therapy.

Keywords

Dendrimer Targeted delivery Gene therapy Folate receptor Head and neck cancer 

References

  1. 1.
    Harrington K, Alvarez-Vallina L, Crittenden M, Gough M, Chong H, Diaz RM, Vassaux G, Lemoine N, Vile R (2002) Cells as vehicles for cancer gene therapy: the missing link between targeted vectors and systemic delivery? Hum Gene Ther 13:1263–1280CrossRefPubMedGoogle Scholar
  2. 2.
    Brunotto M, Zarate AM, Bono A, Barra JL, Berra S (2014) Risk genes in head and neck cancer: a systematic review and meta-analysis of last 5 years. Oral Oncol 50:178–188CrossRefPubMedGoogle Scholar
  3. 3.
    Thomas SM, Grandis JR (2009) The current state of head and neck cancer gene therapy. Hum Gene Ther 20:1565–1575CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Dobbelstein M, Moll U (2014) Targeting tumour-supportive cellular machineries in anticancer drug development. Nat Rev Drug Discov 13:179–196CrossRefPubMedGoogle Scholar
  5. 5.
    Xu L, Yeudall WA, Yang H (2013) Dendrimer-based RNA interference delivery for cancer therapy. In: Scholz C, Kressler J (eds) Tailored polymer architectures for pharmaceutical and biomedical applications, vol 1135. American Chemical Society, Washington, DC, pp 197–213CrossRefGoogle Scholar
  6. 6.
    Ameyar-Zazoua M, Guasconi V, Ait-Si-Ali S (2005) siRNA as a route to new cancer therapies. Expert Opin Biol Ther 5:221–224CrossRefPubMedGoogle Scholar
  7. 7.
    Cabanillas R, Rodrigo JP, Astudillo A, Dominguez F, Suarez C, Chiara MD (2007) P53 expression in squamous cell carcinomas of the supraglottic larynx and its lymph node metastases: new results for an old question. Cancer 109:1791–1798CrossRefPubMedGoogle Scholar
  8. 8.
    Cardinali M, Jakus J, Shah S, Ensley JF, Robbins KC, Yeudall WA (1998) p21(WAF1/Cip1) retards the growth of human squamous cell carcinomas in vivo. Oral Oncol 34:211–218CrossRefPubMedGoogle Scholar
  9. 9.
    Ndoye A, Dolivet G, Hogset A, Leroux A, Fifre A, Erbacher P, Berg K, Behr JP, Guillemin F, Merlin JL (2006) Eradication of p53-mutated head and neck squamous cell carcinoma xenografts using nonviral p53 gene therapy and photochemical internalization. Mol Ther 13:1156–1162CrossRefPubMedGoogle Scholar
  10. 10.
    Morris JC, Wildner O (2000) Therapy of head and neck squamous cell carcinoma with an oncolytic adenovirus expressing HSV-tk. Mol Ther 1:56–62CrossRefPubMedGoogle Scholar
  11. 11.
    Xu L, Zhang H, Wu Y (2014) Dendrimer advances for the central nervous system delivery of therapeutics. ACS Chem Neurosci 5:2–13CrossRefPubMedGoogle Scholar
  12. 12.
    Yang H (2010) Nanoparticle-mediated brain-specific drug delivery, imaging, and diagnosis. Pharm Res 27:1759–1771CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kesharwani P, Iyer AK (2015) Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery. Drug Discov Today 20(5):536–547CrossRefPubMedGoogle Scholar
  14. 14.
    Lee CC, MacKay JA, Frechet JM, Szoka FC (2005) Designing dendrimers for biological applications. Nat Biotechnol 23:1517–1526CrossRefPubMedGoogle Scholar
  15. 15.
    Xu L, Bai Q, Zhang X, Yang H (2017) Folate-mediated chemotherapy and diagnostics: an updated review and outlook. J Control Release 252:73–82CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chen C, Ke J, Zhou XE, Yi W, Brunzelle JS, Li J, Yong EL, Xu HE, Melcher K (2013) Structural basis for molecular recognition of folic acid by folate receptors. Nature 500:486–489CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Xu L, Kittrell S, Yeudall WA, Yang H (2016) Folic acid-decorated polyamidoamine dendrimer mediates selective uptake and high expression of genes in head and neck cancer cells. Nanomedicine (Lond) 11:2959–2973CrossRefGoogle Scholar
  18. 18.
    Parker N, Turk MJ, Westrick E, Lewis JD, Low PS, Leamon CP (2005) Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal Biochem 338:284–293CrossRefPubMedGoogle Scholar
  19. 19.
    Elnakat H, Ratnam M (2004) Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev 56:1067–1084CrossRefPubMedGoogle Scholar
  20. 20.
    Ross JF, Chaudhuri PK, Ratnam M (1994) Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. Cancer 73:2432–2443CrossRefPubMedGoogle Scholar
  21. 21.
    Xu L, Yeudall WA, Yang H (2017) Folic acid-decorated polyamidoamine dendrimer exhibits high tumor uptake and sustained highly localized retention in solid tumors: its utility for local siRNA delivery. Acta Biomater 57:251–261CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kim SH, Jeong JH, Kim TI, Kim SW, Bull DA (2009) VEGF siRNA delivery system using arginine-grafted bioreducible poly(disulfide amine). Mol Pharm 6:718–726CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Guo S, Lin CM, Xu Z, Miao L, Wang Y, Huang L (2014) Co-delivery of cisplatin and rapamycin for enhanced anticancer therapy through synergistic effects and microenvironment modulation. ACS Nano 8:4996–5009CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Section of Nephrology, Department of Internal MedicineYale University School of MedicineNew HavenUSA
  2. 2.Department of Chemical and Life Science EngineeringVirginia Commonwealth UniversityRichmondUSA
  3. 3.Department of PharmaceuticsVirginia Commonwealth UniversityRichmondUSA
  4. 4.Massey Cancer CenterVirginia Commonwealth UniversityRichmondUSA

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