Nanocrystalline solid dispersions (NSD) of hesperetin (HRN) for prevention of 7, 12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in Sprague-Dawley (SD) rats

Sneha Sheokand; Umashanker Navik; Arvind K Bansal

doi:10.1016/j.ejps.2018.12.006

Nanocrystalline solid dispersions (NSD) of hesperetin (HRN) for prevention of 7, 12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in Sprague-Dawley (SD) rats

Eur J Pharm Sci. 2019 Feb 1:128:240-249. doi: 10.1016/j.ejps.2018.12.006. Epub 2018 Dec 12.

Authors

Sneha Sheokand¹, Umashanker Navik², Arvind K Bansal³

Affiliations

¹ Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Mohali, Punjab 160 062, India.
² Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Mohali, Punjab 160 062, India.
³ Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Mohali, Punjab 160 062, India. Electronic address: akbansal@niper.ac.in.

PMID: 30553062
DOI: 10.1016/j.ejps.2018.12.006

Abstract

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in females as per the global cancer project (GLOBOCAN 2018) estimates of breast cancer incidence and mortality produced by the International Agency for Research on Cancer (IARC). In 2018, there will be 2,088,849 new cases of breast cancer and 626,679 cases of deaths due to breast cancer in 5 regions (Americas, Africa, Europe, Asia and Oceania) at 20 sites of the world. Epidemiologic studies on diet and cancer have guided the search for some nutraceuticals acting as anti-cancer agents. Hesperetin (HRN), the aglycone of hesperidin, a glycoside found in citrus fruits, has been reported to have anti-cancer effects by apoptosis induction and inhibition of cell proliferation in cancer cells. However, poor solubility of HRN has limited its absorption while deviating from its therapeutic benefit. The present study aimed to develop nanocrystalline solid dispersions (NSD) of HRN and evaluating the oral bioavailability in rats. The study also evaluated the efficacy of NSDs against the carcinogenic activity of DMBA in female rats. NSDs were optimized using design of experiments (DoE) and multivariate analysis (MVA) tools. The optimized NSD formulation showed an average particle size (Z_avg) of 558.2 ± 68.1 nm and ~70% release in 30 min. The in vivo pharmacokinetic study also construed remarkable improvement (3.3 and 2.1-fold increase in C_max and AUC_0-∞) in rate and extent of absorption and 4-fold reduction in T_max by the optimized NSD formulation. In vivo chemoprevention study construed superior efficacy of the NSD formulation by reducing the tumor burden, delaying the onset of tumors and reducing the tumor weight and volume in DMBA-induced breast cancer rats. In conclusion, we present a simple NSD formulation of HRN with enhanced bioavailability and superior chemopreventive efficacy.

Keywords: Breast cancer; Chemoprevention; Hesperetin; NanoCrySP; Nanocrystalline solid dispersions; Optimization; Spray drying.

MeSH terms

Animals
Anthracenes / toxicity*
Female
Hesperidin / therapeutic use*
Mammary Neoplasms, Animal / chemically induced*
Mammary Neoplasms, Experimental / prevention & control*
Nanoparticles*
Piperidines / toxicity*
Random Allocation
Rats
Rats, Sprague-Dawley

Substances

3-(2,6-bis(4-fluorophenyl)-3-methylpiperidin-4-ylideneamino)-2-thioxoimidazolidin-4-one on 7,12-dimethylbenz(a)anthracene
Anthracenes
Piperidines
Hesperidin
hesperetin