Skip to main content

Folate-Functionalized Thiomeric Nanoparticles for Enhanced Docetaxel Cytotoxicity and Improved Oral Bioavailability


To achieve remotely directed delivery of anticancer drugs, surface-decorated nanoparticles with ligands are reported. In this study, folic acid– and thiol-decorated chitosan nanoparticles loaded with docetaxel (DTX-NPs) were prepared for enhanced cellular internalization in cancer cells and improved oral absorption. The DTX-NPs were explored through in vitro and in vivo parameters for various parameters. The DTX-NPs were found to be monodisperse nanoparticles with an average particle size of 158.50 ± 0.36 nm, a polydispersity index of 0.36 ± 0.0, a zeta potential of + 18.30 ± 2.52 mV, and an encapsulation efficiency of 71.47 ± 5.62%. The drug release from DTX-NPs followed the Korsmeyer-Peppas model with about 78% of drug release in 12 h. In in vitro cytotoxicity studies against folate receptor, positive MDA-MBB-231 cancerous cells showed improved cytotoxicity with IC50 of 0.58 μg/mL, which is significantly lower as compared to docetaxel (DTX). Ex vivo permeation enhancement showed an efflux ratio of 0.99 indicating successful transport across the intestine. Oral bioavailability was significantly improved as Cmax and AUC were higher than DTX suspension. Overall, the results suggest that DTX-NPs can be explored as a promising carrier for oral drug delivery.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6


  1. 1.

    Montero A, Fossella F, Hortobagyi G, Valero V. Docetaxel for treatment of solid tumours: a systematic review of clinical data. Lancet Oncol. 2005;6(4):229–39.

    CAS  Article  Google Scholar 

  2. 2.

    Kintzel PE, Michaud LB, Lange MK. Docetaxel-associated epiphora. Pharmacotherapy. 2006;26(6):853–67.

    CAS  Article  Google Scholar 

  3. 3.

    Gueritte-Voegelein F, Guenard D, Lavelle F, Le Goff MT, Mangatal L, Potier P. Relationships between the structure of taxol analogs and their antimitotic activity. J Med Chem. 1991;34(3):992–8.

    CAS  Article  Google Scholar 

  4. 4.

    Ringel I, Horwitz SB. Studies with RP 56976 (taxotere): a semisynthetic analogue of taxol. J Natl Cancer Inst. 1991;83(4):288–91.

    CAS  Article  Google Scholar 

  5. 5.

    Kuppens I, Bosch T, Van Maanen M, Rosing H, Fitzpatrick A, Beijnen J, et al. Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093). Cancer Chemother Pharmacol. 2005;55(1):72–8.

    CAS  Article  Google Scholar 

  6. 6.

    Gao K, Sun J, Liu K, Liu X, He Z. Preparation and characterization of a submicron lipid emulsion of docetaxel: submicron lipid emulsion of docetaxel. Drug Dev Ind Pharm. 2008;34(11):1227–37.

    CAS  Article  Google Scholar 

  7. 7.

    Sohail MF, Rehman M, Sarwar HS, Naveed S, Salman O, Bukhari NI, et al. Advancements in the oral delivery of docetaxel: challenges, current state-of-the-art and future trends. Int J Nanomedicine. 2018;13:3145–61.

    CAS  Article  Google Scholar 

  8. 8.

    Lee E, Kim H, Lee I-H, Jon S. In vivo antitumor effects of chitosan-conjugated docetaxel after oral administration. J Control Release. 2009;140(2):79–85.

    CAS  Article  Google Scholar 

  9. 9.

    Sohail MF, Javed I, Hussain SZ, Sarwar S, Akhtar S, Nadhman A, et al. Folate grafted thiolated chitosan enveloped nanoliposomes with enhanced oral bioavailability and anticancer activity of docetaxel. J Mater Chem B. 2016;4(37):6240–8.

    CAS  Article  Google Scholar 

  10. 10.

    Jain A, Thakur K, Kush P, Jain UK. Docetaxel loaded chitosan nanoparticles: formulation, characterization and cytotoxicity studies. Int J Biol Macromol. 2014;69:546–53.

    CAS  Article  Google Scholar 

  11. 11.

    Hassan S, Prakash G, Ozturk AB, Saghazadeh S, Sohail MF, Seo J, et al. Evolution and clinical translation of drug delivery nanomaterials. Nano Today. 2017;15:91–106.

    CAS  Article  Google Scholar 

  12. 12.

    Gao Y, Liu X-L, Li X-R. Research progress on siRNA delivery with nonviral carriers. Int J Nanomedicine. 2011;6:1017.

    CAS  Article  Google Scholar 

  13. 13.

    Mansouri S, Lavigne P, Corsi K, Benderdour M, Beaumont E, Fernandes JC. Chitosan-DNA nanoparticles as non-viral vectors in gene therapy: strategies to improve transfection efficacy. Eur J Pharm Biopharm. 2004;57(1):1–8.

    CAS  Article  Google Scholar 

  14. 14.

    Hamedi H, Moradi S, Hudson SM, Tonelli AE. Chitosan based hydrogels and their applications for drug delivery in wound dressings: a review. Carbohydr Polym. 2018;199:445–60.

    CAS  Article  Google Scholar 

  15. 15.

    Weitman SD, Lark RH, Coney LR, Fort DW, Frasca V, Zurawski VR, et al. Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res. 1992;52(12):3396–401.

    CAS  PubMed  Google Scholar 

  16. 16.

    Hilgenbrink AR, Low PS. Folate receptor-mediated drug targeting: from therapeutics to diagnostics. J Pharm Sci. 2005;94(10):2135–46.

    CAS  Article  Google Scholar 

  17. 17.

    Sudimack J, Lee RJ. Targeted drug delivery via the folate receptor. Adv Drug Deliv Rev. 2000;41(2):147–62.

    CAS  Article  Google Scholar 

  18. 18.

    Mislick KA, Baldeschwieler JD, Kayyem JF, Meade TJ. Transfection of folate-polylysine DNA complexes: evidence for lysosomal delivery. Bioconjug Chem. 1995;6(5):512–5.

    CAS  Article  Google Scholar 

  19. 19.

    Sohail MF, Hussain SZ, Saeed H, Javed I, Sarwar HS, Nadhman A, et al. Polymeric nanocapsules embedded with ultra-small silver nanoclusters for synergistic pharmacology and improved oral delivery of docetaxel. Sci Rep. 2018;8(1):13304.

    Article  Google Scholar 

  20. 20.

    Shahnaz G, Perera G, Sakloetsakun D, Rahmat D, Bernkop-Schnürch A. Synthesis, characterization, mucoadhesion and biocompatibility of thiolated carboxymethyl dextran–cysteine conjugate. J Control Release. 2010;144(1):32–8.

    CAS  Article  Google Scholar 

  21. 21.

    Saremi S, Atyabi F, Akhlaghi SP, Ostad SN, Dinarvand R. Thiolated chitosan nanoparticles for enhancing oral absorption of docetaxel: preparation, in vitro and ex vivo evaluation. Int J Nanomedicine. 2011;6:119.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Kafedjiiski K, Krauland AH, Hoffer MH, Bernkop-Schnürch A. Synthesis and in vitro evaluation of a novel thiolated chitosan. Biomaterials. 2005;26(7):819–26.

    CAS  Article  Google Scholar 

  23. 23.

    Iqbal J, Shahnaz G, Perera G, Hintzen F, Sarti F, Bernkop-Schnürch A. Thiolated chitosan: development and in vivo evaluation of an oral delivery system for leuprolide. Eur J Pharm Biopharm. 2012;80(1):95–102.

    CAS  Article  Google Scholar 

  24. 24.

    Jiang L, Li X, Liu L, Zhang Q. Thiolated chitosan-modified PLA-PCL-TPGS nanoparticles for oral chemotherapy of lung cancer. Nanoscale Res Lett. 2013;8(1):1–11.

    CAS  Article  Google Scholar 

  25. 25.

    Wang C, Huang Y. Facile preparation of fluorescent Ag-clusters–chitosan-hybrid nanocomposites for bio-applications. New J Chem. 2014;38(2):657–62.

    CAS  Article  Google Scholar 

  26. 26.

    Ibrahim WM, AlOmrani AH, Yassin AEB. Novel sulpiride-loaded solid lipid nanoparticles with enhanced intestinal permeability. Int J Nanomedicine. 2014;9:129.

    PubMed  Google Scholar 

  27. 27.

    Shahnaz G, Vetter A, Barthelmes J, Rahmat D, Laffleur F, Iqbal J, et al. Thiolated chitosan nanoparticles for the nasal administration of leuprolide: bioavailability and pharmacokinetic characterization. Int J Pharm. 2012;428(1–2):164–70.

    CAS  Article  Google Scholar 

  28. 28.

    Laffleur F, Hintzen F, Rahmat D, Shahnaz G, Millotti G, Bernkop-Schnürch A. Enzymatic degradation of thiolated chitosan. Drug Dev Ind Pharm. 2013;39(10):1531–9.

    CAS  Article  Google Scholar 

  29. 29.

    Carron P, Crowley A, O’Shea D, McCann M, Howe O, Hunt M, et al. Targeting the folate receptor: improving efficacy in inorganic medicinal chemistry. Curr Med Chem. 2018;25:2675–708.

    CAS  Article  Google Scholar 

  30. 30.

    Fang G, Tang B, Chao Y, Xu H, Gou J, Zhang Y, et al. Cysteine-functionalized nanostructured lipid carriers for oral delivery of docetaxel: a permeability and pharmacokinetic study. Mol Pharm. 2015;12(7):2384–95.

    CAS  Article  Google Scholar 

  31. 31.

    Gaikwad VL, Bhatia MS. Polymers influencing transportability profile of drug. Saudi Pharm J. 2013;21(4):327–35.

    Article  Google Scholar 

  32. 32.

    Javed I, Hussain SZ, Ullah I, Khan I, Ateeq M, Shahnaz G, et al. Synthesis, characterization and evaluation of lecithin-based nanocarriers for the enhanced pharmacological and oral pharmacokinetic profile of amphotericin B. J Mater Chem B. 2015;3(42):8359–65.

    CAS  Article  Google Scholar 

  33. 33.

    Saremi S, Dinarvand R, Kebriaeezadeh A, Ostad SN, Atyabi F. Enhanced oral delivery of docetaxel using thiolated chitosan nanoparticles: preparation, in vitro and in vivo studies. Biomed Res Int. 2013;2013:1–8.

    Article  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Muhammad Farhan Sohail.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sajjad, M., Khan, M.I., Naveed, S. et al. Folate-Functionalized Thiomeric Nanoparticles for Enhanced Docetaxel Cytotoxicity and Improved Oral Bioavailability. AAPS PharmSciTech 20, 81 (2019).

Download citation


  • docetaxel
  • nanoparticles
  • thiolated chitosan
  • folic acid
  • oral bioavailability