Curcumin-loaded self-nanomicellizing solid dispersion system: part II: in vivo safety and efficacy assessment against behavior deficit in Alzheimer disease

Abstract

Curcumin (CUR), a natural polyphenolic compound, is considered as one of the most potential candidates against Alzheimer disease (AD) by targeting multiple pathologies such as amyloid-beta, tau phosphorylation, and oxidative stress. Poor physicochemical profile and oral bioavailability (BA) are the major contributors to its failure in clinical trials. Lack of success in numerous drug clinical trials for the treatment of AD urges the need of repositioning of CUR. To overcome its limitation and enhance oral BA, Novel CUR Formulation (NCF) was developed using self-nanomicellizing solid dispersion strategy which displayed 117-fold enhancement in oral BA of CUR. NCF was tested using SH-SY5Y695 APP human neuroblastoma cell line against the cytotoxicity induced by copper metal ion, H2O2, and Aβ42 oligomer and compared with CUR control. The safety and efficacy of NCF on mice AD-like behavioral deficits (open field, novel objective recognition, Y-maze, and Morris water maze tests) were assessed in transgenic AD (APPSwe/PS1deE9) mice model. In SH-SY5Y695 APP human neuroblastoma cell line, NCF showed better safety and efficacy against the cytotoxicity due to the significantly enhancement of cellular uptake. It not only prevents the deterioration of cognitive functions of the aged APPSwe/PS1deE9 mice during aging but also reverses the cognitive functions to their much younger age which is also better than the currently available approved options. Moreover, NCF was proved as well tolerated with no appearance of any significant toxicity via oral administration. The results of the study demonstrated the potential of NCF to improve the efficacy of CUR without compromising its safety profile, and pave the way for clinical development for AD.

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Acknowledgments

Prof. Xin-Fu Zhou is grateful for the NHMRC fellowship. Ankit Parikh is obliged for the University President’s Scholarships from University of South Australia. Dr. Jintao Li is a visiting scholar and grateful for a scholarship under state scholarship fund organized by China Scholarship Council (CSC). We thank H. Md. Morshed Alam (BASF Australia Ltd.) for generously providing SOL, Rupal Pradhan and Andrew Beck from University of South Australia for technical support in hematological, coagulation parameters and histology study, Rebecca Summerton and Dr. Ian Beckman from Veterinary Diagnostic Laboratory, the University of Adelaide for providing technical support for serum biochemistry study, and Noralyn Manucat-Tan and Chun-Sheng Ruan for behavior tests. The Reid animal house staff members from University of South Australia are acknowledged for generous support in animal work.

Funding

This study received financial support from Fujian Kangshimei Co., China for the present research.

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Affiliations

Authors

Contributions

Sanjay Garg (SG) and Xin-Fu Zhou (XFZ) conceived the project. Ankit Parikh (AP), Krishna Kathawala (KK), Xia Cao (XC), XFZ, and SG designed the study. AP, KK, Chi Chen (CC), Jintao Li (JL), Zhengnan Shan (ZS), and XFZ performed the research. AP, KK, XFZ, and SG analyzed the data. AP, KK, XZ, and SG wrote the paper.

Corresponding authors

Correspondence to Xin-Fu Zhou or Sanjay Garg.

Ethics declarations

All breeding procedures were approved by the Animal Ethics Committee of the University of South Australia.

Conflict of interest

Ankit Parikh, Xin-Fu Zhou, and Sanjay Garg are the named inventors of Chinese patent 201610267974.5. Fujian Kangshimei Co., China owns the intellectual property. There is no other potential conflict of interest relevant to this article.

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Parikh, A., Kathawala, K., Li, J. et al. Curcumin-loaded self-nanomicellizing solid dispersion system: part II: in vivo safety and efficacy assessment against behavior deficit in Alzheimer disease. Drug Deliv. and Transl. Res. 8, 1406–1420 (2018). https://doi.org/10.1007/s13346-018-0570-0

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Keywords

  • Curcumin
  • Soluplus
  • APPSwe/PS1deE9 mice
  • Learning and memory
  • Safety assessment