Skip to main content
SpringerLink
Log in

Paclitaxel-loaded Nanolipidic Carriers with Improved Oral Bioavailability and Anticancer Activity against Human Liver Carcinoma

  • Research Article
  • Theme: Lipid-Based Drug Delivery Strategies for Oral Drug Delivery
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The poorly water-soluble chemotherapeutic agents, paclitaxel (PTX), exhibit serious clinical side effects upon oral administration due to poor aqueous solubility and a high degree of toxic effects due to non-specific distribution to healthy tissues. In our efforts, we formulated biocompatible dietary lipid-based nanostructured lipidic carriers (NLCs) to enhance the oral bioavailability of PTX for treatment of the liver cancer. A three-factor, three-level Box–Behnken design was employed for formulation and optimization of PTX-loaded NLC formulations. PTX-loaded NLC formulation prepared by melt-emulsification in which glyceryl monostearate (GMS) was used as solid lipid and soybean oil as liquid lipid, while poloxamer 188 and Tween 80 (1:1) incorporated as a surfactant. In vitro drug release investigation was executed by dialysis bag approach, which indicated initial burst effect with > 60% drug release within a 4-h time period. Moreover, PTX-NLCs indicated high entrapment (86.48%) and drug loading efficiency (16.54%). In vitro cytotoxicity study of PTX-NLCs performed on HepG2 cell line by MTT assay indicated that PTX-NLCs exhibited comparatively higher cytotoxicity than commercial formulation (Intaxel®). IC50 values of PTX-NLCs and Intaxel® after 24-h exposure were found to be 4.19 μM and 11.2 μM. In vivo pharmacokinetic study in Wistar rats also indicated nearly 6.8-fold improvement in AUC and Cmax of the drug from the PTX-NLCs over the PTX suspension. In a nutshell, the observed results construed significant enhancement in the biopharmaceutical attributes of PTX-NLCs as a potential therapy for the management of human liver carcinoma.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Best J, Schotten C, Theysohn JM, Wetter A, Müller S, Radünz S, et al. Novel implications in the treatment of hepatocellular carcinoma. Ann Gastroenterol. 2017;30(1):23–32.

    PubMed  Google Scholar 

  2. Li S, Zheng L. Effect of combined treatment using wilfortrine and paclitaxel in liver cancer and related mechanism. Med Sci Monit. 2016;22:1109–14.

    Article  CAS  Google Scholar 

  3. Soni K, Rizwanullah M, Kohli K. Development and optimization of sulforaphane-loaded nanostructured lipid carriers by the Box-Behnken design for improved oral efficacy against cancer: in vitro, ex vivo and in vivo assessments. Artif Cells Nanomed Biotechnol. 2017:1–17. https://doi.org/10.1080/21691401.2017.1408124.

  4. Porter CJ, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov. 2007;6(3):231–48.

    Article  CAS  Google Scholar 

  5. Yang XY, Li YX, Li M, Zhang L, Feng LX, Zhang N. Hyaluronic acid coated nanostructured lipid carriers for targeting paclitaxel to cancer. Cancer Lett. 2013;334(2):338–45.

    Article  CAS  Google Scholar 

  6. Sandhu PS, Beg S, Mehta F, Singh B, Trivedi P. Novel dietary lipid-based selfnanoemulsifying drug delivery systems of paclitaxel with p-gp inhibitor: implications on cytotoxicity and biopharmaceutical performance. Expert Opin Drug Deliv. 2013;12(11):1809–22.

    Article  Google Scholar 

  7. Rivkin I, Cohen K, Koffler J, Melikhov D, Peer D, Margalit R. Paclitaxel clusters coated with hyaluronan as selective tumor-targeted nanovectors. Biomaterials. 2010;31(27):7106–14.

    Article  CAS  Google Scholar 

  8. Akhter MH, Rizwanullah M, Ahmad J, Ahsan MJ, Mujtaba MA, Amin S. Nanocarriers in advanced drug targeting: setting novel paradigm in cancer therapeutics. Artif Cells Nanomed Biotechnol. 2018;46(5):873–84.

    Article  CAS  Google Scholar 

  9. Ahmad J, Akhter S, Rizwanullah M, Amin S, Rahman M, Ahmad MZ, et al. Nanotechnology-based inhalation treatments for lung cancer: state of the art. Nanotechnol Sci Appl. 2015;8:55–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Beg S, Saini S, Bandopadhyay S, Katare OP, Singh B. QbD-driven development and evaluation of nanostructured lipid carriers (NLCs) of olmesartan medoxomil employing multivariate statistical techniques. Drug Dev Ind Pharm. 2018;44(3):407–20.

    Article  CAS  Google Scholar 

  11. Barkat MA, Harshita, Ahmad J, Khan MA, Beg S, Ahmad FJ. Insights into the targeting potential of Thymoquinone for therapeutic intervention against triple-negative. Breast Cancer Curr Drug Targets 2018;19(1):70–80.

  12. Hussain A, Wais M, Singh SK, Samad A, Nazish I, Beg S. Nanostructured lipidic carriers for oral bioavailability enhancement. Recent Pat Nanomed. 2015;5(2):78–86.

    Article  CAS  Google Scholar 

  13. Granja A, Vieira AC, Chaves LL, Nunes C, Neves AR, Pinheiro M, et al. Folate-targeted nanostructured lipid carriers for enhanced oral delivery of epigallocatechin-3-gallate. Food Chem. 2017;237:803–10.

    Article  CAS  Google Scholar 

  14. Gao X, Zhang J, Xu Q, Huang Z, Wang Y, Shen Q. Hyaluronic acid-coated cationic nanostructured lipid carriers for oral vincristine sulfate delivery. Drug Dev Ind Pharm. 2017;43(4):661–7.

    Article  CAS  Google Scholar 

  15. Sun B, Luo C, Li L, Wang M, Du Y, Di D, et al. Core-matched encapsulation of an oleate prodrug into nanostructured lipid carriers with high drug loading capability to facilitate the oral delivery of docetaxel. Colloids Surf B Biointerfaces. 2016;143:47–55.

    Article  CAS  Google Scholar 

  16. Aditya NP, Shim M, Lee I, Lee Y, Im MH, Ko S. Curcumin and genistein coloaded nanostructured lipid carriers: in vitro digestion and antiprostate cancer activity. J Agric Food Chem. 2013;61(8):1878–83.

    Article  CAS  Google Scholar 

  17. Beg S, Rahman M, Kohli K. Quality-by-design approach as a systematic tool for the development of nanopharmaceutical products. Drug Discov Today. 2018.

  18. Beg S, Rahman M, Rahman Z, Akhter S. Perspectives of quality by design approach in nanomedicines development. Curr Nanomed. 2017;7:191–7.

    Article  CAS  Google Scholar 

  19. Singh B, Raza K, Beg S. Developing “optimized” drug products employing “designed” experiments. Chem Ind Digest. 2013;23:70–6.

    Google Scholar 

  20. Singh B, Beg S. Attaining product development excellence and federal compliance employing quality by design (QbD) paradigms. Pharma Rev. 2015;13(9):35–44.

    Google Scholar 

  21. Singh B, Beg S. Product development excellence and federal compliance via QbD. Chronicle Pharmabiz. 2014;15(10):30–5.

    Google Scholar 

  22. Singh B, Beg S. Quality by design in product development life cycle. Chronicle Pharmabiz. 2013;22:72–9.

    Google Scholar 

  23. Rizwanullah M, Amin S, Ahmad J. Improved pharmacokinetics and antihyperlipidemic efficacy of rosuvastatin-loaded nanostructured lipid carriers. J Drug Target. 2017;25(1):58–74.

    Article  CAS  Google Scholar 

  24. Qidwai A, Khan S, Md S, Fazil M, Baboota S, Narang JK, et al. Nanostructured lipid carrier in photodynamic therapy for the treatment of basal-cell carcinoma. Drug Deliv. 2016;23(4):1476–85.

    Article  CAS  Google Scholar 

  25. Xu W, Lee MK. Development and evaluation of lipid nanoparticles for paclitaxel delivery: a comparison between solid lipid nanoparticles and nanostructured lipid carriers. J Pharm Investig. 2015;45(7):675–80.

    Article  CAS  Google Scholar 

  26. Barkat MA, Harshita AI, Ali R, Singh SP, Pottoo FH, et al. Nanosuspension-based aloe vera gel of silver sulfadiazine with improved wound healing activity. AAPS PharmSciTech. 2017;18(8):3274–85.

    Article  Google Scholar 

  27. Ahamad MS, Siddiqui S, Jafri A, Ahmad S, Afzal M, Arshad M. Induction of apoptosis and antiproliferative activity of naringenin in human epidermoid carcinoma cell through ROS generation and cell cycle arrest. PLoS One. 2014;9(10):e110003.

    Article  Google Scholar 

  28. Siddiqui S, Ahmad E, Gupta M, Rawat V, Shivnath N, Banerjee M, et al. Cissus quadrangularis Linn exerts dose-dependent biphasic effects: osteogenic and anti-proliferative, through modulating ROS, cell cycle and Runx2 gene expression in primary rat osteoblasts. Cell Prolif. 2015;48:443–54.

    Article  CAS  Google Scholar 

  29. Ahmad J, Mir SR, Kohli K, Chuttani K, Mishra AK, Panda AK, et al. Solid-nanoemulsion preconcentrate for oral delivery of paclitaxel: formulation design, biodistribution, and γ-scintigraphy imaging. Biomed Res Int. 2014;2014:984756.

    Article  Google Scholar 

  30. Tan SW, Billa N, Roberts CR, Burley JC. Surfactant effects on the physical characteristics of amphotericin-B containing nanostructured lipid carriers. Colloids Surf A Physicochem Eng Asp. 2010;372(1–3):73–9.

    Article  CAS  Google Scholar 

  31. Liu J, Gong T, Wang C, Zhong Z, Zhang Z. Solid lipid nanoparticles loaded with insulin by sodium cholate-phosphatidylcholine-based mixed micelles: preparation and characterization. Int J Pharm. 2007;340(1–2):153–62.

    Article  CAS  Google Scholar 

  32. Rahman Z, Zidan AS, Khan MA. Non-destructive methods of characterization of risperidone solid lipid nanoparticles. Eur J Pharm Biopharm. 2010;76(1):127–37.

    Article  CAS  Google Scholar 

  33. Mishra A, Imam SS, Aqil M, Ahad A, Sultana Y, Ameeduzzafar, et al. Carvedilolnano lipid carriers: formulation, characterization and in-vivo evaluation. Drug Deliv. 2016;23(4):1486–94.

    Article  CAS  Google Scholar 

  34. Moghddam SM, Ahad A, Aqil M, Imam SS, Sultana Y. Optimization of nanostructured lipid carriers for topical delivery of nimesulide using Box-Behnken design approach. Artif Cells Nanomed Biotechnol. 2017;45(3):617–24.

    Article  CAS  Google Scholar 

  35. Alam S, Aslam M, Khan A, Imam SS, Aqil M, Sultana Y, et al. Nanostructured lipid carriers of pioglitazone for transdermal application: from experimental design to bioactivity detail. Drug Deliv. 2016;23(2):601–9.

    Article  CAS  Google Scholar 

  36. Khan A, Imam SS, Aqil M, Ahad A, Sultana Y, Ali A, et al. Brain targeting of temozolomide via the intranasal route using lipid-based nanoparticles: brain pharmacokinetic and scintigraphic analyses. Mol Pharm. 2016;13(11):3773–82.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Gattefosse for providing gift samples of oils and co-surfactants, and Fresenius Kabi India Pvt. Ltd. for PTX. The authors also acknowledge the kind help from Dr. M. Arshad, Deptt. Zoology, Lucknow University, India, for in vitro cell culture studies.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, School of Medical & Allied Sciences, K.R. Mangalam University, Gurgaon, Sohna, Haryana, India

    Harshita & Md Abul Barkat

  2. Department of Pharmaceutics, Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, Uttar Pradesh, India

    Md Abul Barkat

  3. Nanomedicine Research Lab, Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India

    Md Abul Barkat, Sarwar Beg & Farhan J. Ahmad

  4. Formulation Research Lab, Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India

    Md Rizwanullah

  5. Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University (Formerly University of Dammam), 31441, Dammam, Saudi Arabia

    Faheem Hyder Pottoo

  6. Department of Biotechnology, Era’s Lucknow Medical College & Hospital, Era University, Lucknow, 226003, India

    Sahabjada Siddiqui

Authors
  1. Harshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Md Abul Barkat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Md Rizwanullah
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarwar Beg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Faheem Hyder Pottoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sahabjada Siddiqui
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Farhan J. Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Md Abul Barkat, Sarwar Beg or Farhan J. Ahmad.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interests.

Additional information

Guest Editor: Sanyog Jain

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Harshita, Barkat, M.A., Rizwanullah, M. et al. Paclitaxel-loaded Nanolipidic Carriers with Improved Oral Bioavailability and Anticancer Activity against Human Liver Carcinoma. AAPS PharmSciTech 20, 87 (2019). https://doi.org/10.1208/s12249-019-1304-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-019-1304-4

KEY WORDS

Search

Navigation