Skip to main content

Advertisement

SpringerLink
Log in

Hydroxypropyl Beta Cyclodextrin as a Potential Surface Modifier for Paclitaxel Nanocrystals

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

Abstract

Paclitaxel (PTX) is a hydrophobic chemotherapeutic agent cytotoxic against many serious cancers. This study aimed at designing novel PTX nanocrystals (PTX-NCs) coated with the biocompatible and biodegradable hydroxypropyl-beta-cyclodextrin (HPβCD) polymer with specific characteristics through the formation of a non-inclusion complex. Briefly, PTX-NCs were prepared by the anti-solvent method followed by homogenization. Then, the surface of the prepared PTX-NCs was modified using the HPβCD coat (HPβCD-PTX-NCs). The prepared nanocrystals, both coated and uncoated, were characterized in terms of size, polydispersity index, charge, morphology, and stability. Moreover, the nanocrystals were investigated using powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), and Fourier transform infrared spectroscopy (FTIR). As well, the in vitro release of PTX from the nanocrystals was determined under conditions similar to the IV route of administration. Furthermore, the tendency of the nanocrystals to induce hemolysis was investigated. Results indicated that the size was about 241.4 and 310.5 nm, the polydispersity index was 0.14 and 0.21, and the zeta potential was about − 22.6 and − 16.4 mV for PTX-NCs and HPβCD-PTX-NCs, respectively. Additionally, the PXRD, FTIR, and DSC profiles can be explained by the NCs’ integrity and coat formation. The SEM images showed that both PTX-NCs and HPβCD-PTX-NCs have rod-like structures. Moreover, HPβCD-PTX-NCs had significantly superior in vitro release than both PTX-NCs and PTX. Interestingly, the hemolytic assay showed that HPβCD-PTX-NCs had a more efficient and safer profile than PTX-NCs. This study emphasized that HPβCD could be an interesting candidate for the surface modification of PTX-NCs providing superior properties such as release and safety profiles.

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

References

  1. Miele E, Spinelli GP, Miele E, Tomao F, Tomao S. Albumin-bound formulation of paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer. Int J Nanomed. 2009;4:99.

    CAS  Google Scholar 

  2. Heinig U, Scholz S, Jennewein S. Getting to the bottom of Taxol biosynthesis by fungi. Fungal diversity. 2013;60(1):161–70.

    Article  Google Scholar 

  3. Markman M. Managing taxane toxicities. Support Care Cancer. 2003;11(3):144–7.

    Article  PubMed  Google Scholar 

  4. Yoncheva K, Calleja P, Agüeros M, Petrov P, Miladinova I, Tsvetanov C, et al. Stabilized micelles as delivery vehicles for paclitaxel. Int J Pharm. 2012;436(1–2):258–64.

    Article  CAS  PubMed  Google Scholar 

  5. Haddad R, Alrabadi N, Altaani B, Li T. Paclitaxel drug delivery systems: focus on nanocrystals’ surface modifications. Polymers. 2022;14(4):658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Deepa G, Ashwanikumar N, J Pillai J, SV Kumar G. Polymer nanoparticles-a novel strategy for administration of paclitaxel in cancer chemotherapy. Current medicinal chemistry. 2012;19(36):6207–13.

  7. Ghadi R, Dand N. BCS class IV drugs: highly notorious candidates for formulation development. J Control Release. 2017;248:71–95.

    Article  CAS  PubMed  Google Scholar 

  8. Malingré MM, Beijnen JH, Schellens JH. Oral delivery of taxanes. Invest New Drugs. 2001;19(2):155–62.

    Article  PubMed  Google Scholar 

  9. Rowinsky EK, Cazenave LA, Donehower RC. Taxol: a novel investigational antimicrotubule agent. JNCI: Journal of the National Cancer Institute. 1990;82(15):1247–59.

  10. Hollis CP, Li T. Nanocrystals production, characterization, and application for cancer therapy. Pharmaceutical Sciences Encyclopedia: Drug Discovery, Development, and Manufacturing. 2010:1–26.

  11. Lu Y, Chen Y, Gemeinhart RA, Wu W, Li T. Developing nanocrystals for cancer treatment. Nanomedicine. 2015;10(16):2537–52.

    Article  CAS  PubMed  Google Scholar 

  12. Gao W, Chen Y, Thompson DH, Park K, Li T. Impact of surfactant treatment of paclitaxel nanocrystals on biodistribution and tumor accumulation in tumor-bearing mice. J Control Release. 2016;237:168–76.

    Article  CAS  PubMed  Google Scholar 

  13. Lu Y, Wang Z-h, Li T, McNally H, Park K, Sturek M. Development and evaluation of transferrin-stabilized paclitaxel nanocrystal formulation. Journal of Controlled Release. 2014;176:76–85.

  14. Szejtli J. Introduction and general overview of cyclodextrin chemistry. Chem Rev. 1998;98(5):1743–54.

    Article  CAS  PubMed  Google Scholar 

  15. Larsen K. Large cyclodextrins. J Incl Phenom Macrocycl Chem. 2002;43(1–2):1–13.

    Article  CAS  Google Scholar 

  16. Tiwari G, Tiwari R, Rai A. Cyclodextrins in delivery systems: applications. Journal of pharmacy and bioallied sciences. 2010;2(2):72–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Abi-Mosleh L, Infante RE, Radhakrishnan A, Goldstein JL, Brown MS. Cyclodextrin overcomes deficient lysosome-to-endoplasmic reticulum transport of cholesterol in Niemann-Pick type C cells. Proc Natl Acad Sci. 2009;106(46):19316–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Crumling MA, King KA, Duncan RK. Cyclodextrins and iatrogenic hearing loss: new drugs with significant risk. Front Cell Neurosci. 2017;11:355.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Singhal A, Szente L, Hildreth JE, Song B. Hydroxypropyl-beta and-gamma cyclodextrins rescue cholesterol accumulation in Niemann-Pick C1 mutant cell via lysosome-associated membrane protein 1. Cell Death Dis. 2018;9(10):1–13.

    Article  CAS  Google Scholar 

  20. Kline MA, Butler EOC, Hinzey A, Sliman S, Kotha SR, Marsh CB, et al. A simple method for effective and safe removal of membrane cholesterol from lipid rafts in vascular endothelial cells: implications in oxidant-mediated lipid signaling. Free Radicals and Antioxidant Protocols. 610: Springer; 2010. p. 201–11.

  21. Wittkowski KM, Dadurian C, Seybold MP, Kim HS, Hoshino A, Lyden D. Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin as a treatment for breast cancer. PLoS ONE. 2018;13(7): e0199012.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Zhao Y, He L, Wang T, Zhu L, Yan N. 2-Hydroxypropyl-β-cyclodextrin regulates the epithelial to mesenchymal transition in breast cancer cells by modulating cholesterol homeostasis and endoplasmic reticulum stress. Metabolites. 2021;11(8):562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yokoo M, Kubota Y, Motoyama K, Higashi T, Taniyoshi M, Tokumaru H, et al. 2-Hydroxypropyl-β-cyclodextrin acts as a novel anticancer agent. PLoS ONE. 2015;10(11): e0141946.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gaspar J, Mathieu J, Alvarez P. 2-Hydroxypropyl-beta-cyclodextrin (HPβCD) reduces age-related lipofuscin accumulation through a cholesterol-associated pathway. Sci Rep. 2017;7(1):1–7.

    Article  Google Scholar 

  25. Sharma B, Agnihotri N. Role of cholesterol homeostasis and its efflux pathways in cancer progression. J Steroid Biochem Mol Biol. 2019;191: 105377.

    Article  CAS  PubMed  Google Scholar 

  26. Shelley H, Babu RJ. Role of cyclodextrins in nanoparticle-based drug delivery systems. J Pharm Sci. 2018;107(7):1741–53.

    Article  CAS  PubMed  Google Scholar 

  27. Shah M, Shah V, Ghosh A, Zhang Z, Minko T. Molecular inclusion complexes of β-cyclodextrin derivatives enhance aqueous solubility and cellular internalization of paclitaxel: Preformulation and in vitro assessments. Journal of pharmaceutics and pharmacology and therapeutics. 2015;2(2):8.

    Google Scholar 

  28. Zhang X-n, Tang L-h, Yan X-y, Zhang Q. Solubilization of hydropropyl-beta-cyclodextrin to paclitaxel and its relative molecular inclusion mechanism. Chinese Traditional and Herbal Drugs. 2007;38(9):1317.

  29. Shen Q, Shen Y, Jin F, Du Y-z, Ying X-y. Paclitaxel/hydroxypropyl-β-cyclodextrin complex-loaded liposomes for overcoming multidrug resistance in cancer chemotherapy. Journal of liposome research. 2020;30(1):12–20.

  30. Makhlof A, Miyazaki Y, Tozuka Y, Takeuchi H. Cyclodextrins as stabilizers for the preparation of drug nanocrystals by the emulsion solvent diffusion method. Int J Pharm. 2008;357(1–2):280–5.

    Article  CAS  PubMed  Google Scholar 

  31. D’Souza S. A review of in vitro drug release test methods for nano-sized dosage forms. Advances in Pharmaceutics. 2014;2014.

  32. Huang X, Shi Q, Du S, Lu Y, Han N. Poly-tannic acid coated paclitaxel nanocrystals for combinational photothermal-chemotherapy. Colloids Surf, B. 2021;197: 111377.

    Article  CAS  Google Scholar 

  33. Park J, Sun B, Yeo Y. Albumin-coated nanocrystals for carrier-free delivery of paclitaxel. J Control Release. 2017;263:90–101.

    Article  CAS  PubMed  Google Scholar 

  34. Tian J, Stella VJ. Degradation of paclitaxel and related compounds in aqueous solutions I: Epimerization. J Pharm Sci. 2008;97(3):1224–35.

    Article  CAS  PubMed  Google Scholar 

  35. Sohn JS, Yoon D-S, Sohn JY, Park J-S, Choi J-SJMS. Development and evaluation of targeting ligands surface modified paclitaxel nanocrystals. Materials Science and Engineering: C. 2017;72:228–37.

  36. Zhang H, Hollis CP, Zhang Q, Li T. Preparation and antitumor study of camptothecin nanocrystals. Int J Pharm. 2011;415(1–2):293–300.

    Article  CAS  PubMed  Google Scholar 

  37. Salari A, Young RE. Application of attenuated total reflectance FTIR spectroscopy to the analysis of mixtures of pharmaceutical polymorphs. Int J Pharm. 1998;163(1–2):157–66.

    Article  CAS  Google Scholar 

  38. Koester LcS, Xavier CR, Mayorga P, Bassani VL. Influence of β-cyclodextrin complexation on carbamazepine release from hydroxypropyl methylcellulose matrix tablets. European Journal of Pharmaceutics and Biopharmaceutics and drug disposition. 2003;55(1):85–91.

  39. León A, Reuquen P, Garín C, Segura R, Vargas P, Zapata P, et al. FTIR and Raman characterization of TiO2 nanoparticles coated with polyethylene glycol as carrier for 2-methoxyestradiol. Appl Sci. 2017;7(1):49.

    Article  Google Scholar 

  40. Kayal S, Ramanujan R. Doxorubicin loaded PVA coated iron oxide nanoparticles for targeted drug delivery. Mater Sci Eng, C. 2010;30(3):484–90.

    Article  CAS  Google Scholar 

  41. Craig DQ, Royall PG. The use of modulated temperature DSC for the study of pharmaceutical systems: potential uses and limitations. Pharm Res. 1998;15(8):1152.

    Article  CAS  PubMed  Google Scholar 

  42. George S, Vasudevan D. Studies on the preparation, characterization, and solubility of 2-HP-β-cyclodextrin-meclizine HCI inclusion complexes. J Young Pharm. 2012;4(4):220–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bandi N, Wei W, Roberts CB, Kotra LP, Kompella UB. Preparation of budesonide–and indomethacin–hydroxypropyl-β-cyclodextrin (HPBCD) complexes using a single-step, organic-solvent-free supercritical fluid process. Eur J Pharm Sci. 2004;23(2):159–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liggins RT, Hunter W, Burt HM. Solid-state characterization of paclitaxel. J Pharm Sci. 1997;86(12):1458–63.

    Article  CAS  PubMed  Google Scholar 

  45. Jacob S, Nair AB. Cyclodextrin complexes: perspective from drug delivery and formulation. Drug Dev Res. 2018;79(5):201–17.

    Article  CAS  PubMed  Google Scholar 

  46. Liu J, Tu L, Cheng M, Feng J, Jin Y. Mechanisms for oral absorption enhancement of drugs by nanocrystals. Journal of Drug Delivery Science and Technology. 2020;56: 101607.

    Article  CAS  Google Scholar 

  47. Pan D, Vargas-Morales O, Zern B, Anselmo AC, Gupta V, Zakrewsky M, et al. The effect of polymeric nanoparticles on biocompatibility of carrier red blood cells. PLoS ONE. 2016;11(3): e0152074.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Ziglari T, Anderson DS, Holian A. Determination of the relative contribution of the non-dissolved fraction of ZnO NP on membrane permeability and cytotoxicity. Inhalation Toxicol. 2020;32(2):86–95.

    Article  CAS  Google Scholar 

  49. Amin K, Dannenfelser RM. In vitro hemolysis: guidance for the pharmaceutical scientist. J Pharm Sci. 2006;95(6):1173–6.

    Article  CAS  PubMed  Google Scholar 

  50. Shahbazi MA, Hamidi M, Mäkilä EM, Zhang H, Almeida PV, Kaasalainen M, et al. The mechanisms of surface chemistry effects of mesoporous silicon nanoparticles on immunotoxicity and biocompatibility. Biomaterials. 2013;34(31):7776–89.

    Article  CAS  PubMed  Google Scholar 

  51. Vader P, Fens MH, Sachini N, Van Oirschot BA, Andringa G, Egberts AC, et al. Taxol®-induced phosphatidylserine exposure and microvesicle formation in red blood cells is mediated by its vehicle Cremophor® EL. Nanomedicine. 2013;8(7):1127–35.

    Article  CAS  PubMed  Google Scholar 

  52. Mameri A, Bournine L, Mouni L, Bensalem S, Iguer-Ouada M. Oxidative stress as an underlying mechanism of anticancer drugs cytotoxicity on human red blood cells’ membrane. Toxicol In Vitro. 2021;72: 105106.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research was funded by the Deanship of Research at Jordan University of Science and Technology, grant number (298/2021).

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 22110, Jordan

    Razan Haddad, Bashar Altaani & Majed Masadeh

  2. Department of Pharmacology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, 22110, Jordan

    Nasr Alrabadi

  3. Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana, 47907, USA

    Tonglei Li

Authors
  1. Razan Haddad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nasr Alrabadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bashar Altaani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Majed Masadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tonglei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, R.H. and N.A.; methodology, R.H., B.A., N.A., and M.M.; software, R.H.; validation, R.H., N.A., B.A., M.M., and T.L.; formal analysis, R.H. and N.A.; investigation, R.H.; resources, R.H.; data curation, R.H., N.A., B.A., M.M., and T.L.; writing—original draft preparation, R.H.; writing—review and editing, N.A., B.A., M.M., and T.L.; visualization, N.A.; supervision, N.A., B.A., M.M., and T.L.; project administration, N.A. and B.A.; funding acquisition, N.A. and B.A. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Razan Haddad or Nasr Alrabadi.

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 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

Haddad, R., Alrabadi, N., Altaani, B. et al. Hydroxypropyl Beta Cyclodextrin as a Potential Surface Modifier for Paclitaxel Nanocrystals. AAPS PharmSciTech 23, 219 (2022). https://doi.org/10.1208/s12249-022-02373-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-022-02373-y

Keywords

Search

Navigation