Research Article
Apigenin loaded nanoparticle delayed development of hepatocellular carcinoma in rats

https://doi.org/10.1016/j.nano.2018.05.011Get rights and content

Abstract

Hepatocellular carcinoma (HCC) is one of the major causes of cancer related death globally. Apigenin, a dietary flavonoid, possesses anti-tumor activity against HCC cells in-vitro. Development, physicochemical characterization of apigenin loaded nanoparticles (ApNp), biodistribution pattern and pharmacokinetic parameters of apigenin upon intravenous administration of ApNp, and effect of ApNp treatment in rats with HCC were investigated. Apigenin loaded nanoparticles had a sustained drug release pattern and successfully reached the hepatic cancer cells in-vitro as well as in liver of carcinogenic animals. ApNp predominantly delayed the progress of HCC in chemical induced hepatocarcinogenesis in rats. Quantification of apigenin by liquid chromatography–mass spectroscopy (LC-MS/MS) showed that apigenin availability significantly increased in blood and liver upon ApNp treatment. Apigenin loaded nanoparticle delivery substantially controlled the severity of hepatocellular carcinoma and could be a future hope for lingering the survival in hepatic cancer patients.

Graphical Abstract

Apigenin loaded PLGA nanoparticles successfully delayed hepatocellular carcinoma both in-vitro and in-vivo. Such strategic formulation of apigenin improved its bioavailability and made it more tumor site specific in nature. Again, various pharmacokinetic parameters and biodistribution of apigenin in mice plasma and liver were measured using LC-MS/MS and radiolabeling study. This study may help us to promote the usage of nanoformulations of dietary flavonoids such as apigenin in combating HCC along with the other medicines available in market.

Unlabelled Image
  1. Download : Download high-res image (343KB)
  2. Download : Download full-size image

Section snippets

Materials

Apigenin (4′, 5, 7-trihydroxyflavone, M.W 270.24) and PLGA {MW 50,000-75,000; poly (lactide-co-glycolide) ratio 85:15} were procured from Sigma-Aldrich Co, St Louis, MO, USA. Polyvinyl alcohol was purchased from S D Fine-Chemicals limited, Mumbai, India. Fluorescein isothiocyanate 98% (FITC) was purchased from HiMedia Laboratories, Mumbai, India. Dimethylsulfoxide (DMSO) and dicholoromethane (DCM) were procured from Merck Life Science Pvt. Ltd, Bengaluru, India. All other chemicals used in this

Fourier-transform infrared spectroscopy (FTIR) study

Presence of the characteristic peaks of apigenin [at wave number 1243 cm−1, responsible for C-C (O) –C stretching], PLGA (at wave number 2948 cm−1, responsible for –OH stretching) and PVA (at wave number 3426 cm−1, responsible for –OH stretching) in their physical mixture suggests that no chemical interaction took place between the drug and the excipients. However, absence of the characteristic peak of apigenin (at wave number 1243 cm−1) in apigenin loaded nanoparticles (Supplementary Figure 2)

Discussion

In recent times apigenin has gained much popularity as a naturally occurring flavonoid which has much lower intrinsic toxicity on normal cells compared to cancer cells while used as a tumor-suppressive agent.37 There are very few reports published to date, which showed tumor suppressive effect of apigenin against HCC in-vivo.14, 38, 39, 40 All these studies indicated a much higher dosing of apigenin required to acquire the therapeutic activity. To the best of our knowledge, this is the first

References (50)

  • H.L. Li et al.

    Poor prognosis for hepatocellular carcinoma with transarterial chemoembolization pre-transplantation: retrospective analysis

    World J Gastroenterol

    (2015)
  • L.A. Torre et al.

    Global cancer statistics, 2012

    CA Cancer J Clin

    (2015)
  • A.J. Sanyal et al.

    The etiology of hepatocellular carcinoma and consequences for treatment

    Oncologist

    (2010)
  • R.J. Smith

    Nutrition and metabolism in hepatocellular carcinoma

    Hepatobiliary Surg Nutr

    (2013)
  • A.V. Hootegem et al.

    Sorafenib-induced liver failure: a case report and review of the literature

    Case Rep Hepatol

    (2011)
  • Li Y. ZhouY et al.

    Dietary natural products for prevention and treatment of liver cancer

    Nutrients

    (2016)
  • B. Sung et al.

    Role of apigenin in cancer prevention via the induction of apoptosis and autophagy

    J Cancer Prev

    (2016)
  • T.N. Chinembiri et al.

    Review of natural compounds for potential skin cancer treatment

    Molecules

    (2014)
  • Y. Qin et al.

    Apigenin inhibits nf-κb and snail signaling, emt and metastasis in human hepatocellular carcinoma

    Oncotarget

    (2016)
  • N. Takagaki et al.

    Apigenin induces cell cycle arrest and p21/waf1 expression in a p53-independent pathway

    Int J Oncol

    (2005)
  • E.C. Lefort et al.

    Apigenin and its impact on gastrointestinal cancers

    Mol Nutr Food Res

    (2013)
  • H. Cao et al.

    Binding citrus flavanones to human serum albumin: effect of structure on affinity

    Mol Biol Rep

    (2011)
  • A. Gradolatto et al.

    Pharmacokinetics and metabolism of apigenin in female and male rats after a single oral administration

    Drug Metab Dispos

    (2004)
  • P.J. Das et al.

    Pulmonary delivery of voriconazole loaded nanoparticles providing a prolonged drug level in lungs: a promise for treating fungal infection

    Mol Pharm

    (2015)
  • M.S.T. Mirakabad et al.

    PLGA-based nanoparticles as cancer drug delivery systems

    Asian Pac J Cancer Prev

    (2014)
  • Cited by (0)

    Funding Source: This work was supported by Department of Science and Technology (Government of India), Grant no. DST/Inspire Fellowship/2012/691.

    Disclosure: The authors of this article have no conflicts of interest to declare.

    View full text