Original Article
Novel osteoprotective nanocochleate formulation: A dual combination therapy-codelivery system against glucocorticoid induced osteoporosis

https://doi.org/10.1016/j.nano.2020.102273Get rights and content

Abstract

Phosphatidylserine nanocochleates (Nanocochs) are novel delivery systems that may play a prominent osteoprotective role with their cargo, vitamin D3 (Vit-D3), against osteoporosis. Therefore, this study was conducted to characterize a Nanococh containing vitamin D3 (Nanococh-D3) and investigate its potential role in improving GIO in a rat model. Roll-shaped Nanococh-D3 particles were obtained in a size range of 320 nm with a sustained release performance. Oral Nanococh-D3 significantly increased the bioavailability of Vit-D3, enhanced bone mechanical strength, and improved osteogenic biomarkers including B-ALP, osteocalcin, Ca, and OPG in GIO rats. This formulation markedly suppressed gene expression of RANK and RANKL in treated rats. Histomorphometric analysis showed significant repairs in bone tissues and TRAP staining indicated a significant decrease in osteoclasts using Nanococh-D3 in osteoporotic rats. Nanococh alone similar to Nanococh-D3 acted better than AL as a standard anti-osteoporotic drug in the improvement of bone strength. In conclusion, our results established the potential role of Nanococh-D3 against osteoporosis in rats.

Graphical Abstract

Nanocochleate containing vitamin D3 was formulated efficiently with sustained-release behavior, improved bioavailability, and increased drug targeting. Interestingly, nanocochleate exhibited an anti-osteoporotic potentiation which acted better than alendronate as a standard drug in this study.

Unlabelled Image
  1. Download : Download high-res image (224KB)
  2. Download : Download full-size image

Section snippets

Chemicals

Phosphatidylserine was manufactured by Pharmin USA, LLC (USA). Sodium alendronate hydrate was purchased from Dr. Abidi Pharmaceutical Company, Tehran, Iran. Methylprednisolone sodium succinate (MP) was used as glucocorticoid and purchased from Pfizer Pharmaceuticals (USA). Amicon Ultra 10 kDa filter centrifuge tubes were purchased from EMD-Millipore (Billerica, USA).

Nanocochleate preparation and characterization

A modified method adapted from previous studies was applied to prepare Nanococh using nontoxic chemical agents.14,23

PS (200 mg)

Characterization and in vitro sustained release of Nanococh-D3

Particle size analysis of Nanococh-D3 showed that z-average size of nanocochleates was in the range of 319.4 ± 27.3 nm with a good polydispersity index of 0.38 ± 0.08 and surface charge of −11.8 ± 1.2 mV using DLS. The entrapment efficiency percentage was also estimated at a range of 98.2 ± 3.3 in Nanococh-D3 formulation as given in Figure 1. FESEM technique showed that the morphology of Nanococh subunits at high magnification was as rolled stacks dispersed in the submicron size range (Figure 1

Discussion

Cochleates containing phosphatidylserine are versatile carriers for advanced oral administration of active compounds against serious illnesses with reduced drug toxicity and increased drug efficacy.15., 16., 17., 18. Furthermore, due to their spirally rolled bilayer, highly stable Nanococh structures, they protect their cargo from destruction while producing long-lasting drug release in the circulation.26,27

In the current study, a role-shaped Nanococh containing vitamin D was produced in a size

Acknowledgments

This research has been supported by Tehran University of Medical Sciences and Health Services grant (No. 95-03-158-33113).

This research has been also financially sustained by Iran National Science Foundation grant (No. 95848872).

Authorship contribution

Maryam Eskandarynasab: Conceptualization, InvestigationWriting - original draft.

Shahroo Etemad-Moghadam: Formal analysis, Data curation.

Mojgan Alaeddini: Formal analysis, Data curation.

Amir Hossein Doustimotlagh: Methodology, Software.

Ali Nazeri: Methodology, Software.

Ahmad Reza Dehpour: Data validation, Visualization.

Ramin Goudarzi: Review & editing.

Alireza Partoazar: Supervision, Conseptualization, Methodology, Funding acquisition, Writing - review & editing,

References (50)

  • J.C. Gallagher et al.

    Molecular biology of bone remodeling: implications for new therapeutic targets for osteoporosis

    Maturitas

    (2010)
  • L. Hymøller et al.

    Vitamin D analysis in plasma by high performance liquid chromatography (HPLC) with C30 reversed phase column and UV detection—easy and acetonitrile-free

    J Chromatogr A

    (2011)
  • D. Mukherjee et al.

    Improvement of bone microarchitecture in methylprednisolone induced rat model of osteoporosis by using thiolated chitosan-based risedronate mucoadhesive film

    Drug Dev Ind Pharm

    (2018)
  • D. Prieto-Alhambra et al.

    In-hospital care, complications, and 4-month mortality following a hip or proximal femur fracture: the Spanish registry of osteoporotic femur fractures prospective cohort study

    Archives of osteoporosis

    (2018)
  • E. Canalis

    Mechanisms of glucocorticoid action in bone

    Curr Osteoporos Rep

    (2005)
  • J.S. Siffledeen et al.

    Bones and Crohn's. Risk factors associated with low bone mineral density in patients with Crohn's disease

    Inflamm Bowel Dis

    (2004)
  • P. Dhawan et al.

    Novel regulation of 25-hydroxyvitamin D3 24-hydroxylase (24(OH)ase) transcription by glucocorticoids: cooperative effects of the glucocorticoid receptor, C/EBP beta, and the vitamin D receptor in 24(OH)ase transcription

    J Cell Biochem

    (2010)
  • S. Christakos et al.

    New insights into the mechanisms of vitamin D action

    J Cell Biochem

    (2003)
  • B. Li et al.

    Bisphosphonates, specific inhibitors of osteoclast function and a class of drugs for osteoporosis therapy

    J Cell Biochem

    (2011)
  • C. Reyes et al.

    Risks and benefits of bisphosphonate therapies

    J Cell Biochem

    (2016)
  • U.P.S.T. Force

    Screening for osteoporosis in postmenopausal women: recommendations and rationale

    AJN The American Journal of Nursing

    (2003)
  • K. Nagarsekar et al.

    Understanding cochleate formation: insights into structural development

    Soft Matter

    (2016)
  • K. Nagarsekar et al.

    Micro-spherical cochleate composites: method development for monodispersed cochleate system

    J Liposome Res

    (2017)
  • S. Campo et al.

    Efficacy of a nanocochleate-encapsulated 3,5-diaryl-s-triazole derivative in a murine model of graft-versus-host disease

    Transplantation

    (2008)
  • O. Coban et al.

    Efficacy of targeted liposomes and nanocochleates containing imatinib plus dexketoprofen against fibrosarcoma

    Drug Dev Res

    (2019)
  • Cited by (6)

    Conflict of interest: The authors confirm that they never have conflict of interest.

    View full text