Delivery of Docetaxel to Brain Employing Piperine-Tagged PLGA-Aspartic Acid Polymeric Micelles: Improved Cytotoxic and Pharmacokinetic Profiles

Abstract

In this study, poly-(lactic-co-glycolic) acid (PLGA) was conjugated with aspartic acid and was characterized by nuclear magnetic resonance and Fourier transform infrared spectroscopy. Docetaxel-loaded polymeric micelles were prepared, and piperine was tagged. The neuroblastoma cytotoxicity studies revealed a substantially higher cytotoxic potential of the developed system to that of plain docetaxel, which was further corroborated by cellular uptake employing confocal laser scanning microscopy. The hemocompatible system was able to enhance the pharmacokinetic profile in terms of 6.5-fold increment in bioavailability followed by a 3.5 times increase in the retention time in comparison with the plain drug. The single-point brain bioavailability of docetaxel was amplified by 3.3-folds, signifying a better uptake and distribution to brain employing these carriers. The findings are unique as the physically adsorbed piperine was released before the DTX, increasing the propensity of curbing the CYP3A4 enzyme, which plays a vital role in the degradation of docetaxel. Meanwhile, piperine might have compromised the P-gp efflux mechanism, which can be ascribed to the enhanced retention of the drug at the target site. The elevated target site concentrations and extended residence by a biocompatible nanocarrier supplemented with co-delivery of piperine inherit immense promises to deliver this BCS class IV drug more safely and effectively.

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

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

References

  1. 1.

    Hines DJ, Kaplan DL. Poly(lactic-co-glycolic) acid-controlled-release systems: experimental and modeling insights. Crit Rev Ther Drug Carrier Syst. 2013;30:257–76.

    CAS  Article  Google Scholar 

  2. 2.

    Lü J-M, Wang X, Marin-Muller C, Wang H, Lin PH, Yao Q, et al. Current advances in research and clinical applications of PLGA-based nanotechnology. Expert Rev Mol Diagn. 2009;9:325–41.

    Article  Google Scholar 

  3. 3.

    Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Préat V. PLGA-based nanoparticles: an overview of biomedical applications. J Control Release. 2012;161:505–22.

    CAS  Article  Google Scholar 

  4. 4.

    Raza K, Kumar N, Misra C, Kaushik L, Guru SK, Kumar P, et al. Dextran-PLGA-loaded docetaxel micelles with enhanced cytotoxicity and better pharmacokinetic profile. Int J Biol Macromol. 2016;88:206–12.

    CAS  Article  Google Scholar 

  5. 5.

    Han S, Zhang X, Li M. Progress in research and application of PLGA embolic microspheres. Front Biosci. 2016;21:931–40.

    CAS  Article  Google Scholar 

  6. 6.

    Low SA, Yang J, Kopeček J. Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics. Bioconjug Chem. 2014;25:2012–20.

    CAS  Article  Google Scholar 

  7. 7.

    Prasad BB, Jaiswal S, Singh K. Ultra-trace analysis of d-and l-aspartic acid applying one-by-one approach on a dual imprinted electrochemical sensor. Sensors Actuators B Chem. 2017;240:631–9.

    CAS  Article  Google Scholar 

  8. 8.

    Melville GW, Siegler JC, Marshall PW. Three and six grams supplementation of d-aspartic acid in resistance trained men. J Int Soc Sports Nutr. 2015;12:15.

    Article  Google Scholar 

  9. 9.

    Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T, van den Broek NJF, et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature. 2017;544:372–6.

    CAS  Article  Google Scholar 

  10. 10.

    Kratochvilova M, Raudenska M, Heger Z, Richtera L, Cernei N, Adam V, et al. Amino acid profiling of zinc resistant prostate cancer cell lines: associations with cancer progression. Prostate. 2017;77:604–16.

    CAS  Article  Google Scholar 

  11. 11.

    Zhang J, Pavlova NN, Thompson CB. Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. EMBO J. 2017;36:1302–15.

    CAS  Article  Google Scholar 

  12. 12.

    Thotakura N, Sharma G, Singh B, Kumar V, Raza K. Aspartic acid derivatized hydroxylated fullerenes as drug delivery vehicles for docetaxel: an explorative study. Artif Cells Nanomed Biotechnol. 2017;46(8):1763–72.

    PubMed  Google Scholar 

  13. 13.

    Madhwi KR, Kumar P, Singh B, Sharma G, Katare OP, et al. In vivo pharmacokinetic studies and intracellular delivery of methotrexate by means of glycine-tethered PLGA-based polymeric micelles. Int J Pharm. 2017;519:138–44.

    CAS  Article  Google Scholar 

  14. 14.

    Dong X. Current strategies for brain drug delivery. Theranostics. 2018;8:1481–93.

    CAS  Article  Google Scholar 

  15. 15.

    Raza K, Kumar D, Kiran C, Kumar M, Guru SK, Kumar P, et al. Conjugation of docetaxel with multiwalled carbon nanotubes and co-delivery with piperine: implications on pharmacokinetic profile and anti-cancer activity. Mol Pharm. 2016;13:2423–32.

    CAS  Article  Google Scholar 

  16. 16.

    Dogra RK, Khanna S, Shanker R. Immunotoxicological effects of piperine in mice. Toxicology. 2004;196:229–36.

    CAS  Article  Google Scholar 

  17. 17.

    Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J Pharmacol Exp Ther. 2002;302:645–50.

    CAS  Article  Google Scholar 

  18. 18.

    Unger JM, Hershman DL, Martin D, Etzioni RB, Barlow WE, LeBlanc M, et al. The diffusion of docetaxel in patients with metastatic prostate cancer. J Natl Cancer Inst. 2015;107.

  19. 19.

    Raza K, Thotakura N, Kumar P, Joshi M, Bhushan S, Bhatia A, et al. C60-fullerenes for delivery of docetaxel to breast cancer cells: a promising approach for enhanced efficacy and better pharmacokinetic profile. Int J Pharm. 2015;495:551–9.

    CAS  Article  Google Scholar 

  20. 20.

    Hirth J, Watkins PB, Strawderman M, Schott A, Bruno R, Baker LH. The effect of an individual’s cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res. 2000;6:1255–8.

    CAS  PubMed  Google Scholar 

  21. 21.

    Misra C, Thotakura N, Kumar R, Singh B, Sharma G, Katare OP, et al. Improved cellular uptake, enhanced efficacy and promising pharmacokinetic profile of docetaxel employing glycine-tethered C 60-fullerenes. Mater Sci Eng C. 2017;76:501–8.

    CAS  Article  Google Scholar 

  22. 22.

    Zhang L, Shen Y, Qiu L. Loading docetaxel in β-cyclodextrin-based micelles for enhanced oral chemotherapy through inhibition of P-glycoprotein mediated efflux transport. RSC Adv. 2017;7:26161–9.

    CAS  Article  Google Scholar 

  23. 23.

    Due-Hansen ME, Pandey SK, Christiansen E, Andersen R, Hansen SVF, Ulven T. A protocol for amide bond formation with electron deficient amines and sterically hindered substrates. Org Biomol Chem. 2015;14:430.

    Article  Google Scholar 

  24. 24.

    Hait SK, Moulik SP. Determination of critical micelle concentration (CMC) of nonionic surfactants by donor-acceptor interaction with lodine and correlation of CMC with hydrophile-lipophile balance and other parameters of the surfactants. J Surfactant Deterg. 2001;4:303–9.

    CAS  Article  Google Scholar 

  25. 25.

    Mourya V, Inamdar N. Polymeric micelles: general considerations and their applications. Indian J Pharm Educ Res. 2011;45(2):128–38.

    Google Scholar 

  26. 26.

    Joshi M, Kumar P, Kumar R, Sharma G, Singh B, Katare OP, et al. Aminated carbon-based “cargo vehicles” for improved delivery of methotrexate to breast cancer cells. Mater Sci Eng C. 2017;75:1376–88.

    CAS  Article  Google Scholar 

  27. 27.

    Huang Z, Hua S, Yang Y, Fang J. Development and evaluation of lipid nanoparticles for camptothecin delivery: a comparison of solid lipid nanoparticles, nanostructured lipid carriers, and lipid emulsion. Acta Pharmacol Sin. 2008;29:1094–102.

    CAS  Article  Google Scholar 

  28. 28.

    Kumar P, Sharma G, Kumar R, Malik R, Singh B, Katare OP, et al. Vitamin-derived nanolipoidal carriers for brain delivery of dimethyl fumarate: a novel approach with preclinical evidence. ACS Chem Neurosci. 2017;8(6):1390–6.

    CAS  Article  Google Scholar 

  29. 29.

    Kumar P, Kumar R, Singh B, Malik R, Sharma G, Chitkara D, et al. Biocompatible phospholipid-based mixed micelles for tamoxifen delivery: promising evidences from in-vitro anticancer activity and dermatokinetic studies. AAPS PharmSciTech. 2016:1–8.

  30. 30.

    Pavia DL, Lampman GM, Kriz GS, Vyvyan J. Introduction to spectroscopy. Brooks/Cole, Cengage Learning; 2009.

  31. 31.

    Zhang H, Li R, Lu X, Mou Z, Lin G. Docetaxel-loaded liposomes: preparation, pH sensitivity, pharmacokinetics, and tissue distribution. J Zhejiang Univ Sci B. 2012;13:981–9.

    CAS  Article  Google Scholar 

  32. 32.

    Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm. 2010;67:217–23.

    CAS  PubMed  Google Scholar 

  33. 33.

    Singla S, Harjai K, Raza K, Wadhwa S, Katare OP, Chhibber S. Phospholipid vesicles encapsulated bacteriophage: a novel approach to enhance phage biodistribution. J Virol Methods. 2016;236:68–76.

    CAS  Article  Google Scholar 

  34. 34.

    Chen Y, Sha X, Zhang W, Zhong W, Fan Z, Ren Q, et al. Pluronic mixed micelles overcoming methotrexate multidrug resistance: in vitro and in vivo evaluation. Int J Nanomedicine. 2013;8:1463–76.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Kumar P, Sharma G, Kumar R, Malik R, Singh B, Katare OP, et al. Enhanced brain delivery of dimethyl fumarate employing tocopherol-acetate-based nanolipidic carriers: evidence from pharmacokinetic, biodistribution, and cellular uptake studies. ACS Chem Neurosci. 2017;8:860–5.

    CAS  Article  Google Scholar 

Download references

Funding

The study was financially supported by the Science and Engineering Research Board, Department of Science and Technology (DST), New Delhi, India (YSS/2014/000485).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Kaisar Raza.

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

Singh, A., Thotakura, N., Singh, B. et al. Delivery of Docetaxel to Brain Employing Piperine-Tagged PLGA-Aspartic Acid Polymeric Micelles: Improved Cytotoxic and Pharmacokinetic Profiles. AAPS PharmSciTech 20, 220 (2019). https://doi.org/10.1208/s12249-019-1426-8

Download citation

KEY WORDS

  • bioavailability
  • aspartic acid conjugation
  • co-administration
  • anticancer activity
  • brain delivery