Original Article
Natural lipids enriched self-nano-emulsifying systems for effective co-delivery of tamoxifen and naringenin: Systematic approach for improved breast cancer therapeutics

https://doi.org/10.1016/j.nano.2017.03.003Get rights and content

Abstract

The nano-miceller drug delivery carriers of tamoxifen (TMX) having natural ingredients like polyunsaturated fatty acid (PUFA) with self-nano-emulsifying properties was developed with naringenin (NG) in a synergistic manner i.e. TMX-NG-SNEDDS. The optimized nano-formulation revealed complete drug release in 30 min and >80% permeation in 45 min. Superior cellular uptake potential (4.6–6.5-fold) of the TMX-NG–SNEDDS using Caco-2 cells while cytotoxicity study on MCF-7 cells indicated significant results (P < 0.05) of TMX-NG–SNEDDS. The in vivo pharmacokinetic study also construed remarkable improvement (7.3 and 11.4-fold increase in Cmax and AUC) in rate of drug absorption and 2-fold reduction in Tmax by optimized TMX-NG–SNEDDS. In vivo DMBA model construed superior efficacy of the formulation by reducing tumor size, and improved survival rate of the animals justifies its safety aspect as well.

Graphical Abstract

The oral administration of TMX-NG-SNEDDS leads to nano micelles formation in situ to owing to presence of the smart ingredients, which leads its lymphatic uptake, and multiple fold enhanced bioavailability revealed through pharmacokinetics parameters; the results corroborated the same using cell cytotoxicity on MCF-7 cells and flow cytometry of the samples with more than 84% apoptosis. The natural ingredients however, marked safe and effective role of the optimized formulation as evident from caco-2 cell line studies and Kaplan survival curve, % tumor burden after treatment period.

Image 2
  1. Download : Download high-res image (214KB)
  2. Download : Download full-size image

Section snippets

Materials

TMX was gifted by M/s Cipla Ltd., India, while NG was purchased from M/s Sigma Aldrich, India. Labrasol, Labrafil 1944 CS, Transcutol P, Acconon C 6, Capryol-90, were obtained ex-gratis from M/s Gattefosse, France. Various PUFA-rich oils viz. peanut oil, corn oil, sesame oil, soyabean oil, sunflower oil, and surfactants like PEG 400, Tween 80, Caproyl 90, Acconon CC-6, Acrysol EC-35 were procured from M/s S.D. Fine Chemicals, Mumbai, India and cosolvents like Transcutol P, Transcutol HP were

Formulation development and optimization

The formulations were prepared using apt combination of selected excipients (i.e., corn oil-lipid, labrasol-solvent, andtranscutol-P, i.e., co-solvent. And QbD-based D-optimal mixture design had provided the best optimal solution (supplementary data).

Characterization of the SNEDDS

The globule size diameter of the formulation was found to be ranging between 52 and 73 nm, thus confirming the nano-structured nature of the emulsion globules obtained after dilution in presence of SGF.18, 19, 20 The TEM images of the TMX-NG–SNEDDS

Discussion

The study is about the self-nano-emulsifying drug delivery system employing natural lipids and biocompatible, safe excipients, with enhanced bioavailability and bioflavonoid for synergistic anticancer potentials, with respect to TMX.28 The characterization revealed that the SNEDDS exhibited faster micelles forming efficiency, the drug release profiles showed immediate release exhibiting complete drug in <30 min.18 The in vitro cellular cytotoxicity studies on Caco-2 and MCF-7 cells showed

References (30)

  • F.E. Stuurman et al.

    Oral anticancer drugs: mechanisms of low bioavailability and strategies for improvement

    Clin Pharmacokinet

    (2013)
  • J. Zhang et al.

    Biodistribution, hypouricemic efficacy and therapeutic mechanism of morin phospholipid complex loaded self-nanoemulsifying drug delivery systems in an experimental hyperuricemic model in rats

    J Pharm Pharmacol

    (2016)
  • A.R. Patel et al.

    Edible oil structuring: an overview and recent updates

    Food Funct

    (2016)
  • B. Ramaiyan et al.

    Dietary omega-3 but not omega-6 fatty acids down-regulate maternal dyslipidemia induced oxidative stress: a three generation study in rats

    Biochem Biophys Res Commun

    (2016)
  • S.B. Tiwari et al.

    Improved oral delivery of paclitaxel following administration in nanoemulsion formulations

    J Nanosci Nanotechnol

    (2006)
  • Cited by (0)

    Conflict(s) of interest: The authors declare no conflict(s) of interest.

    View full text