Skip to main content

Advertisement

SpringerLink
Log in

Core Shell Lipid-Polymer Hybrid Nanoparticles for Oral Bioavailability Enhancement of Ibrutinib via Lymphatic Uptake

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The purpose of this research was to develop ibrutinib (IBR)-loaded lipid-polymer hybrid nanoparticles (IBR-LPHNPs) to improve oral absorption by intestinal lymphatic uptake. IBR-LPHNPs were fabricated by nanoprecipitation method using poly(lactic-co-glycolic acid), lipoid S 100, and DSPE-MPEG 2000. The IBR-LPHNPs showed particle size of 85.27±3.82 nm, entrapment efficiency of 97.70±3.85%, and zeta potential of −24.9±3.08 mV respectively. Fourier transform infrared spectroscopy and differential scanning calorimetry study revealed compatibility between IBR and excipients. X-ray diffraction study showed the conversion of IBR into amorphous form. High-resolution transmission electron microscopic image displayed spherical-shaped, discrete layered polymeric core and lipid shell structure. The drug release from IBR-LPHNPs exhibited prolong release profile up to 48 h and was best fitted to Korsmeyer–Peppas model. Higher fluorescence intensity at the end of 2 h in the intestinal tissue confirmed the uptake of LPHNPs by Peyer’s patches. The oral bioavailability of IBR was improved 22.52-fold with LPHNPs as compared to free IBR. The intestinal lymphatic uptake study in rats pretreated with cycloheximide confirmed the intestinal lymphatic uptake of IBR-LPHNPs. All the results conclusively showed that LPHNPs could be a promising approach to improve oral bioavailability of IBR.

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

Similar content being viewed by others

Data Availability

The authors confirmed that the data supporting the findings of this study are available in the article. Raw data that support findings of this study are available from corresponding author upon reasonable request.

References

  1. Mohanty A, Uthaman S, Park IK. Utilization of polymer-lipid hybrid nanoparticles for targeted anti-cancer therapy. Molecules. 2020;25(19):4377. https://doi.org/10.3390/molecules25194377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Elkateb H, Tatham LM, Cauldbeck H, Niezabitowska E, Owen A, Rannard S, McDonald T. Optimization of the synthetic parameters of lipid polymer hybrid nanoparticles dual loaded with darunavir and ritonavir for the treatment of HIV. Int J Pharm. 2020;588:119794. https://doi.org/10.1016/j.ijpharm.2020.119794.

    Article  CAS  PubMed  Google Scholar 

  3. Liu J, Cheng H, Han L, Qiang Z, Zhang X, Gao W, Zhao K, Song Y. Synergistic combination therapy of lung cancer using paclitaxel- and triptolide-coloaded lipid-polymer hybrid nanoparticles. Drug Des Devel Ther. 2018;25(12):3199–209. https://doi.org/10.2147/DDDT.S172199.

    Article  Google Scholar 

  4. Dali P, Shende P. Self-assembled lipid polymer hybrid nanoparticles using combinational drugs for migraine via intranasal route. AAPS PharmSciTech. 2023;24(1):20. https://doi.org/10.1208/s12249-022-02479-3.

    Article  CAS  Google Scholar 

  5. Zhang Z, Lu Y, Qi J, Wu W. An update on oral drug delivery via intestinal lymphatic transport. Acta Pharm Sin B. 2021;11(8):2449–68. https://doi.org/10.1016/j.apsb.2020.12.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. O’Driscoll CM. Lipid-based formulations for intestinal lymphatic delivery. Eur J Pharm Sci. 2002;15(5):405–15. https://doi.org/10.1016/s0928-0987(02)00051-9.

    Article  PubMed  Google Scholar 

  7. Ismail AI. Experimental and density functional theory characteristics of ibrutinib, a Bruton’s kinase inhibitor approved for leukemia treatment. J Spectrosc. 2021;1-8. https://doi.org/10.1155/2021/9968797.

  8. Parmar S, Patel K, Pinilla-Ibarz J. Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. P T. 2014;39(7):483–519.

    PubMed  PubMed Central  Google Scholar 

  9. Alshetaili AS, Ansari MJ, Anwer MK, Ganaie MA, Iqbal M, Alshahrani SM, Alalaiwe AS, Alsulays BB, Alshehri S, Sultan AS. Enhanced oral bioavailability of ibrutinib encapsulated poly (lactic-co- glycolic acid) nanoparticles: pharmacokinetic evaluation in rats. Curr Pharm Analysis. 2019;15(6):661–8. https://doi.org/10.2174/1573412915666190314124932.

    Article  CAS  Google Scholar 

  10. Shakeel F, Iqbal M, Ezzeldin E. Bioavailability enhancement and pharmacokinetic profile of an anticancer drug ibrutinib by self-nanoemulsifying drug delivery system. J Pharm Pharmacol. 2016;68(6):772–80. https://doi.org/10.1111/jphp.12550.

    Article  CAS  PubMed  Google Scholar 

  11. Qiu Q, Lu M, Li C, Luo X, Liu X, Hu L, et al. Novel self-assembled ibrutinib-phospholipid complex for potently peroral delivery of poorly soluble drugs with pH-dependent solubility. AAPS PharmSciTech. 2018;19(8):3571–83. https://doi.org/10.1208/s12249-018-1147-4.

    Article  CAS  PubMed  Google Scholar 

  12. Rangaraj N, Pailla SR, Chowta P, Sampathi S. Fabrication of ibrutinib nanosuspension by quality by design approach: intended for enhanced oral bioavailability and diminished fast fed variability. AAPS PharmSciTech. 2019;2019(20):1–18. https://doi.org/10.1208/s12249-019-1524-7.

    Article  CAS  Google Scholar 

  13. Shi X, Song S, Ding Z, Fan B, Huang W, Xu T. Improving the solubility, dissolution, and bioavailability of ibrutinib by preparing it in a Coamorphous state with saccharin. J Pharm Sci. 2019;108:3020–8. https://doi.org/10.1016/j.xphs.2019.04.031.

    Article  CAS  PubMed  Google Scholar 

  14. Rangaraj N, Pailla SR, Shah S, Prajapati S, Sampathi S. QbD aided development of ibrutinib-loaded nanostructured lipid carriers aimed for lymphatic targeting: evaluation using chylomicron flow blocking approach. Drug Deliv Transl Res. 2020;10(5):1476–94. https://doi.org/10.1007/s13346-020-00803-7.

    Article  CAS  PubMed  Google Scholar 

  15. Jain S, Patil SR, Swarnakar NK, Agrawal AK. Oral delivery of doxorubicin using novel polyelectrolyte-stabilized liposomes (layersomes). Mol Pharm. 2012;9(9):2626–35. https://doi.org/10.1021/mp300202c.

    Article  CAS  PubMed  Google Scholar 

  16. Hu L, Xing Q, Meng J, Shang C. Preparation and enhanced oral bioavailability of cryptotanshinone-loaded solid lipid nanoparticles. AAPS PharmSciTech. 2010;11:582–7. https://doi.org/10.1208/s12249-010-9410-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yuan Y, Chiba P, Cai T, Callaghan R, Bai L, Cole SPC, Cai Y. Fabrication of psoralen-loaded lipid-polymer hybrid nanoparticles and their reversal effect on drug resistance of cancer cells. Oncol Rep. 2018;40(2):1055–63. https://doi.org/10.3892/or.2018.6492.

    Article  CAS  PubMed  Google Scholar 

  18. Patel P, Patel M. Enhanced oral bioavailability of nintedanib esylate with nanostructured lipid carriers by lymphatic targeting: In vitro, cell line and in vivo evaluation. Eur J Pharm Sci. 2021;159:105715. https://doi.org/10.1016/j.ejps.2021.105715.

    Article  CAS  PubMed  Google Scholar 

  19. Zeng C, Zheng R, Yang X, Du Y, Xing J, Lan W. Improved oral delivery of tilianin through lipid-polymer hybrid nanoparticles to enhance bioavailability. Biochem Biophys Res Commun. 2019;519(2):316–22. https://doi.org/10.1016/j.bbrc.2019.09.004.

    Article  CAS  PubMed  Google Scholar 

  20. Bao X, Qian K, Yao P. Insulin- and cholic acid-loaded zein/casein-dextran nanoparticles enhance the oral absorption and hypoglycemic effect of insulin. J Mater Chem B. 2021;9(31):6234–45. https://doi.org/10.1039/d1tb00806d.

    Article  CAS  PubMed  Google Scholar 

  21. Fang RH, Aryal S, Hu CM, Zhang L. Quick synthesis of lipid-polymer hybrid nanoparticles with low polydispersity using a single-step sonication method. Langmuir. 2010;26(22):16958–169562. https://doi.org/10.1021/la103576a.

    Article  CAS  PubMed  Google Scholar 

  22. Wang Q, Alshaker H, Böhler T, Srivats S, Chao Y, Cooper C, Pchejetski D. Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer. Sci Rep. 2017;7(1):5901. https://doi.org/10.1038/s41598-017-06142-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Khan A, Mudassir J, Mohtar N, Darwis Y. Advanced drug delivery to the lymphatic system: lipid-based nanoformulations. Int J Nanomedicine. 2013;8:2733–44. https://doi.org/10.2147/IJN.S41521.

    Article  CAS  PubMed Central  Google Scholar 

  24. Mare R, Da H, Fresta M, Cosco D, Awasthi V. Anchoring property of a novel hydrophilic lipopolymer, HDAS-SHP, post-inserted in preformed liposomes. Nanomaterials (Basel). 2019;9(9):1185. https://doi.org/10.3390/nano9091185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Leal J, Smyth HDC, Ghosh D. Physicochemical properties of mucus and their impact on transmucosal drug delivery. Int J Pharm. 2017;532(1):555–72. https://doi.org/10.1016/j.ijpharm.2017.09.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tahir N, Madni A, Correia A, Rehman M, Balasubramanian V, Khan MM, Santos HA. Lipid-polymer hybrid nanoparticles for controlled delivery of hydrophilic and lipophilic doxorubicin for breast cancer therapy. Int J Nanomed. 2019;14:4961–74. https://doi.org/10.2147/IJN.S209325.

    Article  CAS  Google Scholar 

  27. Freag MS, Elnaggar YS, Abdallah OY. Lyophilized phytosomal nanocarriers as platforms for enhanced diosmin delivery: optimization and ex vivo permeation. Int J Nanomed. 2013;8:2385–97. https://doi.org/10.2147/ijn.s45231.

    Article  Google Scholar 

  28. Yu F, Ao M, Zheng X, Li N, Xia J, Li Y, Li D, Hou Z, Qi Z, Chen XD. PEG-lipid-PLGA hybrid nanoparticles loaded with berberine-phospholipid complex to facilitate the oral delivery efficiency. Drug Deliv. 2017;24(1):825–33. https://doi.org/10.1080/10717544.2017.1321062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Le L, Bokare A, Erogbogbo F. Hand powered, cost effective, 3D printed nanoparticle synthesizer: effects of polymer end caps, drugs, and solvents on lipid polymer hybrid nanoparticles. Mater Res Express. 2018;2018(6):025403–12. https://doi.org/10.1088/2053-1591/aaed72.

    Article  CAS  Google Scholar 

  30. Jain A, Sharma G, Kushwah V, Garg NK, Kesharwani P, Ghoshal G, Singh B, Shivhare US, Jain S, Katare OP. Methotrexate and beta-carotene loaded-lipid polymer hybrid nanoparticles: a preclinical study for breast cancer. Nanomedicine. 2017;12(15):1851–72. https://doi.org/10.2217/nnm-2017-0011.

    Article  CAS  PubMed  Google Scholar 

  31. Tunsirikongkon A, Pyo YC, Kim DH, Lee SE, Park JS. Optimization of polyarginine-conjugated PEG lipid grafted proliposome formulation for enhanced cellular association of a protein drug. Pharmaceutics. 2019;11(6):272. https://doi.org/10.3390/pharmaceutics11060272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jadon RS, Sharma M. Docetaxel-loaded lipid-polymer hybrid nanoparticles for breast cancer therapeutics. J Drug Deliv Sci Tech. 2019;51:475–84. https://doi.org/10.1016/j.jddst.2019.03.039.

    Article  CAS  Google Scholar 

  33. Zeng SQ, Chen YZ, Chen Y, Liu H. Lipid-polymer hybrid nanoparticles for synergistic drug delivery to overcome cancer drug resistance. New J Chem. 2017;41:1518–25. https://doi.org/10.1039/C6NJ02819E.

    Article  CAS  Google Scholar 

  34. Bachhav SS, Dighe VD, Devarajan PV. Rifampicin lipid-polymer hybrid nanoparticles (LIPOMER) for enhanced Peyer’s patch uptake. Int J Pharm. 2017;532(1):612–22. https://doi.org/10.1016/j.ijpharm.2017.09.040.

    Article  CAS  PubMed  Google Scholar 

  35. Zhang RX, Dong K, Wang Z, Miao R, Lu W, Wu XY. Nanoparticulate drug delivery strategies to address intestinal cytochrome P450 CYP3A4 metabolism towards personalized medicine. Pharmaceutics. 2021;13(8):1261. https://doi.org/10.3390/pharmaceutics13081261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shakweh M, Ponchel G, Fattal E. Particle uptake by Peyer’s patches: a pathway for drug and vaccine delivery. Expert Opin Drug Deliv. 2004;1(1):141–63. https://doi.org/10.1517/17425247.1.1.141.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Zydus Lifescience Ltd. (Ahmedabad) for providing ibrutinib as a gift sample. We also thank Lipoid GmbH (Germany) for providing gift samples of lipoid S 100 and DSPE MPEG 2000.

Author information

Authors and Affiliations

  1. Maliba Pharmacy College, Uka Tarsadia University, Bardoli, 394350, Gujarat, India

    Mitali Patel, Ayushi Desai, Vrushti Kansara & Bhavin Vyas

Authors
  1. Mitali Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayushi Desai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vrushti Kansara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bhavin Vyas
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Mitali Patel: investigation; resources; data analysis; writing—review and editing; supervision. Ayushi Desai: investigation and data collection. Vrushti Kansara: writing—original draft; visualization; revising manuscript. Bhavin Vyas: revising manuscript.

Corresponding author

Correspondence to Mitali Patel.

Ethics declarations

Conflict of 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

Patel, M., Desai, A., Kansara, V. et al. Core Shell Lipid-Polymer Hybrid Nanoparticles for Oral Bioavailability Enhancement of Ibrutinib via Lymphatic Uptake. AAPS PharmSciTech 24, 142 (2023). https://doi.org/10.1208/s12249-023-02586-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-023-02586-9

Keywords

Search

Navigation