Styrene maleic acid micelles as a nanocarrier system for oral anticancer drug delivery – dual uptake through enterocytes and M-cells

Abstract

Drug delivery systems could potentially overcome low bioavailability and gastrointestinal toxicity, which are the major challenges for the development of oral anticancer drugs. Herein, we demonstrate the ability of styrene maleic acid (SMA) nanomicelles encapsulating epirubicin to traverse in vitro and ex vivo models of the intestinal epithelium without affecting the tissue integrity. Further, SMA micelles encapsulating a fluorescent dye dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) showed twofold higher accumulation in the liver and spleen, 15-fold higher accumulation in the tumor, and sixfold higher accumulation in the lung as compared with the free DiI, following oral administration in a mice xenograft breast cancer model. Additionally, SMA micelles showed colocalization with microfold (M)-cells and accumulation in Peyer’s patches, which together confirms the M-cell mediated uptake and transport of SMA micelles. Our results indicate that SMA micelles, showing dual uptake by enterocytes and M-cells, are a potential tool for safe oral anticancer drug delivery.

Keywords:

• oral delivery
• anticancer nanomedicine
• enhanced permeability and retention effect
• EPR

Supplementary materials

Figure S1 Size distribution of 7.5% SMA-Epi was determined by TEM at concentration of 1 mg/mL in water with 1% phosphotungstic acid for staining.

Notes: Boxes indicate a single SMA micellar particle. The size of 7.5% SMA-Epi by TEM is calculated as the average of the four particles labeled in the figure.

Abbreviations: Epi, epirubicin; SMA, styrene maleic acid; TEM, transmission electron microscope.

Figure S2 The particle size distribution in the media from the lower compartment after a 3-hour incubation with 18% SMA-Epi micelles (green) and 18% SMA-Epi micelle in 0.1 M NaHCO₃ (red) was determined using a Malvern Zetasizer.

Abbreviations: Epi, epirubicin; SMA, styrene maleic acid.

Figure S3 Cytotoxicity of endocytosis inhibitors against Caco-2 cells, evaluated through MTT assay. The cytotoxicity of endocytosis inhibitors was assessed over 4 hours using MTT assay. Data expressed as mean ± SEM (n=4).

Abbreviations: MTT, (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide); SEM, standard error of the mean.

Acknowledgments

This work was supported by a 2014 University of Otago Research Grant (grant number 110273.01.R.LM) to KG. The authors would like to thank Professor Hamid Ghandehari for his kind gift of Caco-2 cells and Professor Rhonda Rosengren, Dr Sarah Baird, and Dr Gregory Giles for editing the paper.

Disclosure

The authors report no conflicts of interest with this work.