Skip to main content

Advertisement

SpringerLink
Log in

Mucoadhesive Oro-Gel–Containing Chitosan Lipidic Nanoparticles for the Management of Oral Squamous Cell Carcinoma

  • Original Article
  • Published:
Journal of Pharmaceutical Innovation Aims and scope Submit manuscript

Abstract

Purpose

The aim of this research work was to develop a mucoadhesive oro-gel–containing resveratrol loaded folate conjugated chitosan-lipidic nanoparticles (RES-FA-LP-NPs) for targeted delivery to oral squamous cell carcinoma (OSCC).

Method

RES-FA-LP-NPs were prepared by hot homogenization followed by the ionic gelation method and were further incorporated in Carbopol® 971P gel. The in vitro cytotoxicity was assessed on folate receptor positive KB cell lines. The binding affinity of the folic acid (FA) ligand with the folate receptor was studied using Schrödinger, LLC, New York, NY, 2021.

Results

The optimized unconjugated nanoparticles exhibited an average particle size of 107.5 nm ± 10.7 nm, polydispersity index (PDI) of 0.241 ± 0.024, zeta potential of 28.7 mV ± 0.9 mV, and encapsulation efficiency of 60 ± 3%. Surface folate conjugation of the nanoparticles increased the particle size to 149.9 nm ± 13.4 nm with PDI of 0.275 ± 0.041 and zeta-potential of 29.4 mV ± 1.4 mV. The RES-FA-LP-NP-loaded mucoadhesive oro-gel was found to have excellent mucoadhesive properties. The cumulative release from ex vivo diffusion studies on goat buccal mucosa at pH 6.8 was about 48.755 ± 8.627% and 64.802 ± 1.305% of resveratrol and folic acid respectively at the end of 8 h. The results of the cell culture study suggests that the developed RES-FA-LP-NPs were able to arrest OSCC (IC50 61.51 ± 2.70 μM/ml) at G0/G1 growth phase (58.08% apoptosis) of cell division. The binding interactions revealed that the ligand had excellent shape complementarity and a high binding affinity towards folate receptors.

Conclusion

Preliminary results state that the developed RES-FA-LP-NP-loaded gel can serve as a promising drug delivery system for the management of OSCC; however, more detailed investigations are needed to support the hypothesis.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Data Availability

All datasets generated or analysed during this study are included in the article.

Abbreviations

OSCC:

Oral squamous cell carcinoma

RES:

Resveratrol

FA:

Folic acid

CHI:

Chitosan

NP:

Nanoparticles

TPP:

Sodium tripolyphosphate

DDA:

Degree of deacetylation

LP-NPs:

Chitosan-lipidic nanoparticles

RES-LP-NPs:

Resveratrol-loaded chitosan-lipidic nanoparticles

FA-LP-NPs:

Folate conjugated chitosan-lipidic nanoparticles

RES-FA-LP-NPs:

Resveratrol-loaded folate conjugated chitosan-lipidic nanoparticles

EE%:

Percent entrapment efficiency

FTIR:

Fourier transformed infrared spectroscopy

PDI:

Polydispersity index

References

  1. Sung H, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.

    Article  Google Scholar 

  2. Cancer Facts and Figures. 2022. https://doi.org/10.3238/arztebl.2008.0255.

  3. Li CC, Shen Z, Bavarian R, Yang F, Bhattacharya A. Oral cancer: genetics and the role of precision medicine. Dent Clin North Am. 2018;62(1):29–46. https://doi.org/10.1016/j.cden.2017.08.002.

    Article  PubMed  Google Scholar 

  4. Gharat SA, Momin M, Bhavsar C. Oral squamous cell carcinoma: current treatment strategies and nanotechnology-based approaches for prevention and therapy. Crit Rev Ther Drug Carrier Syst. 2016;33(4):363–400. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2016016272.

    Article  PubMed  Google Scholar 

  5. Ford PJ, Rich AM. Tobacco use and oral health. Addiction. 2021;116(12):3531–40. https://doi.org/10.1111/add.15513.

    Article  PubMed  Google Scholar 

  6. Ketabat, et al. Controlled drug delivery systems for oral cancer treatment—current status and future perspectives. Pharmaceutics. 2019;11(7):302. https://doi.org/10.3390/pharmaceutics11070302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pradhan R, Chatterjee S, Hembram KC, Sethy C, Mandal M, Kundu CN. Nano formulated Resveratrol inhibits metastasis and angiogenesis by reducing inflammatory cytokines in oral cancer cells by targeting tumor associated macrophages. J Nutr Biochem. 2021;92:1–14. https://doi.org/10.1016/j.jnutbio.2021.108624.

    Article  CAS  Google Scholar 

  8. Juneja A, Sultan A. Nanotechnology and nanobiomaterials: redefining ways of managing oral cancer. Online Turkish Journal of Health Sciences. 2020;5(4):693–700. https://doi.org/10.26453/otjhs.753846.

    Article  Google Scholar 

  9. Bharadwaj R, Medhi S. Oral squamous cell carcinoma and the cutting edge of nanotechnology. Multidisciplinary Cancer Investigation. 2020;4(2):36–45. https://doi.org/10.30699/mci.4.2.36.

    Article  Google Scholar 

  10. Wu D, et al. Phenolic-enabled nanotechnology: versatile particle engineering for biomedicine. Chem Soc Rev. 2021;50(7):4432–83. https://doi.org/10.1039/d0cs00908c.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tagde P, Kulkarni GT, Mishra DK, Kesharwani P. Recent advances in folic acid engineered nanocarriers for treatment of breast cancer. J Drug Deliv Sci Technol. 2020;56:101613. https://doi.org/10.1016/j.jddst.2020.101613.

  12. Mahmood L. The metabolic processes of folic acid and vitamin B12 deficiency. J Health Res Rev. 2014;1(1):5. https://doi.org/10.4103/2394-2010.143318.

    Article  Google Scholar 

  13. García-Gozalbo B, Cabañas-Alite L. A narrative review about nutritional management and prevention of oral mucositis in haematology and oncology cancer patients undergoing antineoplastic treatments. Nutrients. 2021;13:11. https://doi.org/10.3390/nu13114075.

  14. Thomsen M, Vitetta L. Adjunctive treatments for the prevention of chemotherapy- and radiotherapy-induced mucositis. Integr Cancer Ther. 2018;17(4):1027–47. https://doi.org/10.1177/1534735418794885.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mokbel K, Wazir U, Mokbel K. Chemoprevention of prostate cancer by natural agents: evidence from molecular and epidemiological studies. Anticancer Res. 2019;39(10):5231–59. https://doi.org/10.21873/anticanres.13720.

    Article  CAS  PubMed  Google Scholar 

  16. Almeida TC, et al. Resveratrol effects in oral cancer cells: a comprehensive review. Med Oncol. 2021;38(8):1–10. https://doi.org/10.1007/s12032-021-01548-0.

    Article  CAS  Google Scholar 

  17. Salehi B, et al. Resveratrol: a double-edged sword in health benefits. Biomedicines. 2018;6(3):1–20. https://doi.org/10.3390/biomedicines6030091.

    Article  CAS  Google Scholar 

  18. Basudkar V, Gharat S, Momin M, Shringarpure M. A review of anti-aging nanoformulations: recent developments in excipients for nanocosmeceuticals and regulatory guidelines. Crit Rev Ther Drug Carrier Syst. 2022;39(3):45–97. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2021039544.

    Article  PubMed  Google Scholar 

  19. Annaji M, Poudel I, Boddu SHS, Arnold RD, Tiwari AK, Babu RJ. Resveratrol-loaded nanomedicines for cancer applications. Cancer Rep. 2021;4:3. https://doi.org/10.1002/cnr2.1353.

  20. Gunes M, Karavana SY, Yapar EA. Buccal drug delivery system: an overview about dosage forms and recent studies. Universal Journal of Pharmaceutical Research. 2020;4(6):70–6.

    Google Scholar 

  21. Ashri LY, Amal El Sayeh F, Ibrahim MA, Alshora DH Naguib MJ. Optimization and evaluation of chitosan buccal films containing tenoxicam for treating chronic periodontitis: in vitro and in vivo studies. J Drug Deliv Sci Technol. 2020;57:101720. https://doi.org/10.1016/j.jddst.2020.101720.

  22. Ways TMM, Lau WM, Khutoryanskiy VV. Chitosan and its derivatives for application in mucoadhesive drug delivery systems. Polymers. 2018;10:3. https://doi.org/10.3390/polym10030267.

  23. Abouhussein D, El Nabarawi MA, Shalaby SH, El-Bary AA. Cetylpyridinium chloride chitosan blended mucoadhesive buccal films for treatment of pediatric oral diseases. J Drug Deliv SciTechnol. 2020;57:101676. https://doi.org/10.1016/j.jddst.2020.101676.

  24. Kristó K, et al. Investigation of surface properties and free volumes of chitosan-based buccal mucoadhesive drug delivery films containing ascorbic acid. Pharmaceutics. 2022;14:2. https://doi.org/10.3390/pharmaceutics14020345.

  25. Parhi R. Drug delivery applications of chitin and chitosan: a review. Environ Chem Lett. 2020;18(3):577–94. https://doi.org/10.1007/s10311-020-00963-5.

    Article  CAS  Google Scholar 

  26. Calixto GMF, Victorelli FD, Dovigo LN, Chorilli M. Polyethyleneimine and chitosan polymer-based mucoadhesive liquid crystalline systems intended for buccal drug delivery. AAPS PharmSciTech. 2018;19(2):820–36. https://doi.org/10.1208/s12249-017-0890-2.

    Article  CAS  PubMed  Google Scholar 

  27. Shakil MS, et al. Using chitosan or chitosan derivatives in cancer therapy. Polysaccharides. 2021;2(4):795–816. https://doi.org/10.3390/polysaccharides2040048.

    Article  CAS  Google Scholar 

  28. Akbarian A, Ebtekar M, Pakravan N, Hassan ZM. Folate receptor alpha targeted delivery of artemether to breast cancer cells with folate-decorated human serum albumin nanoparticles. Int J Biol Macromol. 2020;152:90–101. https://doi.org/10.1016/j.ijbiomac.2020.02.106.

    Article  CAS  PubMed  Google Scholar 

  29. Maiyo F, Singh M. Polymerized selenium nanoparticles for folate-receptor-targeted delivery of anti-Luc-siRNA: Potential for Gene Silencing. Biomedicines. 2020;8(4):76. https://doi.org/10.3390/biomedicines8040076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Abbas H, Kamel R, El-Sayed N. Dermal anti-oxidant, anti-inflammatory and anti-aging effects of compritol ATO-based resveratrol colloidal carriers prepared using mixed surfactants. Int J Pharm. 2018;541(1–2):37–47. https://doi.org/10.1016/j.ijpharm.2018.01.054.

    Article  CAS  PubMed  Google Scholar 

  31. Gokce EH, Korkmaz E, Dellera E, Sandri G, Cristina Bonferoni M, Ozer O. Resveratrol-loaded solid lipid nanoparticles versus nanostructured lipid carriers: Evaluation of antioxidant potential for dermal applications. Int J Nanomedicine. 2012;7:1841–1850. https://doi.org/10.2147/IJN.S29710.

  32. Hajj Ali H, Michaux F, Khanji AN, Jasniewski J, Linder M. Chitosan - Shea butter solid nanoparticles assemblies for the preparation of a novel nanoparticles in microparticles system containing curcumin. Colloids Surf A Physicochem Eng Asp. 2018;553:359–367. https://doi.org/10.1016/j.colsurfa.2018.05.075.

  33. Anwer MK, et al. Development of lipomer nanoparticles for the enhancement of drug release, anti-microbial activity and bioavailability of delafloxacin. Pharmaceutics. 2020;12(3):1–13. https://doi.org/10.3390/pharmaceutics12030252.

    Article  CAS  Google Scholar 

  34. Shtenberg Y, et al. Mucoadhesive alginate pastes with embedded liposomes for local oral drug delivery. Int J Biol Macromol. 2018;111:62–9. https://doi.org/10.1016/j.ijbiomac.2017.12.137.

    Article  CAS  PubMed  Google Scholar 

  35. İnce İ, et al. Synthesis and characterization of folic acid-chitosan nanoparticles loaded with thymoquinone to target ovarian cancer cells. J Radioanal Nucl Chem. 2020;324(1):71–85. https://doi.org/10.1007/s10967-020-07058-z.

    Article  CAS  Google Scholar 

  36. Khan T, Gharat S, Chalke M, Momin M. Development of simultaneous spectrophotometric method for quantification of resveratrol and folic acid in an orogel. Int J Pharmaceutic Sci Res. 2019;10(4):2035–2039. https://doi.org/10.13040/IJPSR.0975-8232.10(4).2035-39.

  37. Gupta S, Ghoshal S, Mishra MK, Kesharwani M, Gupta N, Dubey D. Formulation, evaluation and comparative study of the effect of different gelling agent on oxaprozin loaded topical emulgel. 2022;31.

  38. Mutimer MN, Riffkin C, Hill JA, Glickman ME, Cyr GN. Modem ointment base technology II.:comparative evaluation of bases*. J Am Pharm Assoc (Scientific ed). 1956;45(4):212–8. https://doi.org/10.1002/jps.3030450406.

    Article  CAS  Google Scholar 

  39. Ghafar H, et al. Development and characterization of bioadhesive film embedded with lignocaine and calcium fluoride nanoparticles. AAPS PharmSciTech. 2020;21(2):1–12. https://doi.org/10.1208/s12249-019-1615-5.

    Article  CAS  Google Scholar 

  40. Kumar N, Salar RK, Prasad M, Ranjan K. Synthesis, characterization and anticancer activity of vincristine loaded folic acid-chitosan conjugated nanoparticles on NCI-H460 non-small cell lung cancer cell line. Egypt J Basic Appl Sci. 2018;5(1):87–99. https://doi.org/10.1016/j.ejbas.2017.11.002.

    Article  Google Scholar 

  41. Kumar CS, Thangam R, Mary SA, Kannan PR, Arun G, Madhan B. Targeted delivery and apoptosis induction of trans-resveratrol-ferulic acid loaded chitosan coated folic acid conjugate solid lipid nanoparticles in colon cancer cells. Carbohydr Polym. 2020;231:115682. https://doi.org/10.1016/j.carbpol.2019.115682.

Download references

Acknowledgements

All images and graphical abstract were prepared using the Biorender (Trial version).

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, University of Mumbai, Mithibai College Campus, Gate No. 2, Mumbai, Maharashtra, India

    Sankalp Gharat, Vivek Basudkar & Munira Momin

  2. SVKM’s Shri C B Patel Research, Center for Chemistry and Biological Sciences, Mithibai College Campus, Gate No. 2, V. M. Road, Vile Parle (W), Mumbai, Maharashtra, India

    Munira Momin

  3. Department of Quality Assurance, SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, University of Mumbai, Mithibai College Campus, Gate No. 2, V. M. Road, Vile Parle (W), Mumbai, Maharashtra, India

    Arati Prabhu

Authors
  1. Sankalp Gharat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vivek Basudkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Munira Momin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arati Prabhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sankalp Gharat.

Ethics declarations

Competing Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gharat, S., Basudkar, V., Momin, M. et al. Mucoadhesive Oro-Gel–Containing Chitosan Lipidic Nanoparticles for the Management of Oral Squamous Cell Carcinoma. J Pharm Innov 18, 1298–1315 (2023). https://doi.org/10.1007/s12247-023-09724-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12247-023-09724-7

Keywords

Search

Navigation