Elsevier

Life Sciences

Volume 298, 1 June 2022, 120500
Life Sciences

Ferulic acid nanocapsules as a promising treatment modality for colorectal cancer: Preparation and in vitro/in vivo appraisal

https://doi.org/10.1016/j.lfs.2022.120500Get rights and content

Abstract

Aims

Ferulic acid is a polyphenolic compound with proven anticancer properties, but it suffers from low solubility and bioavailability. In the current work, polymeric and lipidic nanocapsules of ferulic acid were prepared, characterized, and tested on colorectal cancer (CRC) cell lines (HCT-116 and Caco2 cells), with mechanistic anticancer elucidation using flow cytometry. The selected NCs formulation was further tested in vivo on rats after inducing CRC using 1,2 dimethylhydrazine (DMH), followed by biochemical analysis, molecular and histological examinations.

Key findings

Results revealed that both polymeric and lipidic nanocapsules showed favorable properties, but the latter was smaller in size and presented higher cumulative percent released of FA. The lipidic nanocapsules displayed better anticancer activity than the drug on both cell lines; with apoptosis being the dominant cell death mode. The in vivo study revealed that ferulic acid lipid NCs exhibited significant antioxidant and anti-inflammatory activities. They also downregulated cyclin D1, IGF II, and VEGF, and autoregulated the apoptotic/anti-apoptotic gene BAX/Bcl-2; indicating their apoptotic and anti-angiogenic potential, which was further confirmed by histological examination.

Significance

Findings prove that the proposed ferulic acid lipid nanocapsules are an ideal system for treatment of CRC, and can serve as a preventive measure against metastasis.

Introduction

Colorectal cancer is one of the most commonly diagnosed cancers, and is the second leading cause of cancer death worldwide [1]. Familial history, age, sex, genetic and environmental factors are associated with colon and rectal cancer. Surgical intervention is the first treatment option, although micrometastatic lesions may occur at the site of surgical operation [2]. Adjuvant chemotherapy is also used in the treatment of colon cancer in the advanced stages (Stage III and above) that include lymph node involvement or metastasis; however, this modality is associated with severe reported side effects.

Till current date, several studies have proven that the use of nanoparticles in cancer treatment could overcome several challenges within the tumor microenvironment such as immune suppression, vascular permeability, and tissue hypoxia, through passive targeting and enhanced permeability and retention (EPR effect) [3], [4], [5], and using specific targeting ligands [3], [6], [7]. Moreover, there is a great interest in the investigation of the potential role of herbal and complementary medicines in the treatment of different cancer subtypes, due to their immunoregulatory, tumor inhibitory properties, and antioxidant activities [8], [9]. Ferulic acid (FA) is a polyphenolic compound (4-hydroxy-3-methoxycinnamic acid), which exerts diverse therapeutic activities such as anti-inflammatory, antioxidant, and anticancer properties on several types of cancers [10], [11], [12]. FA is also able to decrease the occurrence of azoxymethane-induced large bowel neoplasms, hence manifesting chemopreventive potential on colonic neoplasia [13]. Despite of the pharmacological merits of FA, its low solubility and bioavailability in aqueous medium hinder its widespread application and clinical implementation. One of the proposed approaches to overcome the aforementioned problems is the formulation of FA in nanoparticulate carriers, such as nanoemulsions, chitosan nanoparticles and solid lipid nanoparticles [12], [14], [15].

Among the different types of nanoparticles, polymeric and lipidic nanocapsules hold great interest. Polymeric nanocapsules (PNCs) comprise a polymer coat surrounding an oil core [3]. Similarly, LNCs consist of an oily core surrounded by the amphiphilic surfactant solutol acting as a shell. LNCs are considered as stealth microemulsions with the added advantages of being small-sized nanocarriers, which makes them an excellent candidate for tumor targeting and uptake. Furthermore, LNCs hold further advantage over PNCs where the use of organic solvents is omitted; resulting in safer delivery systems for human use. To the best of our knowledge, no other studies reported the formulation of LNCs for FA till current date.

Therefore, following this context, the present work focused on preparing, characterizing and comparing PNCs and LNCs of FA, and studying the possible effects of the selected nanoencapsulated FA formulation against colon cancer both in vitro and in vivo.

Section snippets

Materials

Ferulic acid was purchased from Skinactives Company, USA. Labrafac Lipophile WL 1349 oil was kindly gifted by Gattefossé Company, France. Soybean phosphatidylcholine (Epikuron E145V & Epikuron 200) were kindly gifted by Cargill Company, Germany. Polylactide-glycolide (PLGA) grade 7502 A was kindly gifted by Purac Company, Netherlands. Poloxamer P407 was kindly gifted by BASF Company, Germany. Potassium dihydrogen phosphate, tween 80, orthophosphoric acid, disodium hydrogen phosphate, as well as

Preparation and characterization of FA loaded PNCs and LNCs

Two types of NCs formulations of FA were prepared, characterized and compared in this study with the aim of identifying the best NCs formulation for enhancing the anticancer activity of FA against colon cancer cells. For the PNCs, they were prepared using the nanoprecipitation method [16], [17]. The previously reported biodegradability [29], [30] and biocompatibility of PLGA polymer delineated it as a promising platform for the preparation of PNCs for delivery of anticancer molecules [3], [21],

Conclusions

Two types of ferulic acid loaded nanocapsules; polymeric and lipidic were prepared and characterized in the current study. Lipidic nanocapsules were proven superior to polymeric nanocapsules on the cellular level, and their promising therapeutic potential were further delineated in an in vivo model of colorectal cancer. Results of the current study draw the attention to the importance of nutraceuticals such as ferulic acid in treatment of cancer, as well as the promising nature of lipidic

CRediT authorship contribution statement

Riham I. El-Gogary: Conceptualization, Data curation, Investigation, Formal analysis, Writing – original draft. Maha Nasr: Conceptualization, Data curation, Methodology, Validation, Writing – review & editing. Laila A. Rahsed: Conceptualization, Data curation, Investigation, Formal analysis, Writing – original draft. Mohamed A. Hamzawy: Conceptualization, Data curation, Investigation, Formal analysis, Writing – original draft.

Declaration of competing interest

This work was implemented with the support of the Arab-German Young Academy of Sciences and Humanities (AGYA), which draws on financial support from the German Federal Ministry of Education and Research (BMBF) grant 01DL20003.

References (55)

  • M. Nasr et al.

    Different modalities of NaCl osmogen in biodegradable microspheres for bone deposition of risedronate sodium by alveolar targeting

    Eur. J. Pharm. Biopharm.

    (2011)
  • A. Lamprecht et al.

    New lipid nanocapsules exhibit sustained release properties for amiodarone

    J. Control Rel.

    (2002)
  • A.S. Alazzouni et al.

    Ferulic acid as anticarcinogenic agent against 1, 2-dimethylhydrazine induced colon cancer in rats

    J. King Saud Univ. Sci.

    (2021)
  • E.A. Badr et al.

    A correlation between BCL-2 modifying factor, p53 and livin gene expressions in cancer colon patients

    Biochem. Biophys. Rep.

    (2020)
  • C.C. Peng et al.

    Ferulic acid is nephrodamaging while gallic acid is renal protective in long term treatment of chronic kidney disease

    Clin. Nutr.

    (2012)
  • N. Tsakiris et al.

    Combinational drug-loaded lipid nanocapsules for the treatment of cancer

    Int. J. Pharm.

    (2019)
  • H. Sung et al.

    Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

    CA Cancer J. Clin.

    (2021)
  • R.I. El-Gogary et al.

    Polyethylene glycol conjugated polymeric nanocapsules for targeted delivery of quercetin to folate-expressing cancer cells in vitro and in vivo

    ACS Nano

    (2014)
  • M.A. Hamzawy et al.

    Antitumor activity of intratracheal inhalation of temozolomide (TMZ) loaded into gold nanoparticles and/or liposomes against urethane-induced lung cancer in BALB/c mice

    Drug Deliv.

    (2017)
  • L. Ramzy et al.

    Novel thymoquinone lipidic core nanocapsules with anisamide-polymethacrylate shell for colon cancer cells overexpressing sigma receptors

    Sci. Rep.

    (2020)
  • M. Bayoumi et al.

    Nobiletin-loaded composite penetration enhancer vesicles restore the normal miRNA expression and the chief defence antioxidant levels in skin cancer

    Sci. Rep.

    (2021)
  • S. Wang et al.

    Positive role of chinese herbal medicine in cancer immune regulation

    Am. J. Chin. Med.

    (2020)
  • B. Janicke et al.

    The antiproliferative effect of dietary fiber phenolic compounds ferulic acid and p-coumaric acid on the cell cycle of Caco-2 cells

    Nutr. Cancer

    (2011)
  • R. Panwar et al.

    Characterization and anticancer potential of ferulic acid-loaded chitosan nanoparticles against ME-180 human cervical cancer cell lines

    Appl. Nanosci.

    (2016)
  • H. Mori et al.

    Chemopreventive effects of ferulic acid on oral and rice germ on large bowel carcinogenesis

    Anticancer Res.

    (1999)
  • R.I. El-Gogary et al.

    Polymeric nanocapsular baicalin: chemometric optimization, physicochemical characterization and mechanistic anticancer approaches on breast cancer cell lines

    Sci. Rep.

    (2019)
  • L. Mazzarino et al.

    Curcumin-loaded polymeric and lipid nanocapsules: preparation, characterization and chemical stability evaluation

    Lat. Am. J. Pharm.

    (2010)
  • Cited by (28)

    • Update on Mucoadhesive Approaches to target Drug Delivery in Colorectal Cancer

      2023, Journal of Drug Delivery Science and Technology
    View all citing articles on Scopus
    View full text