Abstract
HypothesisOne of the main challenges in cancer therapy is the poor water solubility of many anticancer drugs which results in low bioavailability at the tumour sites and reduced efficacy. The currently available polymer-based anticancer drug delivery systems often suffer from low encapsulation efficiency, uncontrolled release, and lack of long-term stability. Herein, we report the development of novel stiffness-tuneable core–shell nanocarriers composed of naturally derived polymers silk fibroin (SF) and sodium alginate (SA) inside a liposomal shell for enhanced cellular uptake and controlled release of hydrophobic anticancer agent ASC-J9 (Dimethylcurcumin). It is anticipated that the stiffness of the nanocarriers has a significant effect on their cellular uptake and anticancer efficacy. ExperimentsThe nanocarriers were prepared by thin film hydration method followed by extrusion and cross-linking of SA to obtain a uniform size and shape, avoiding harsh processing conditions. The structural transformation of SF in the nanocarriers induced by SA crosslinking was determined using Fourier transform infrared (FTIR) spectroscopy. The size, zeta potential, morphology and stiffness of the nanocarriers were measured using dynamic light scattering (DLS), transmission electron microscopy (TEM) and atomic force microscopy (AFM). Drug loading and release were measured using UV–Vis spectrophotometry. The cellular uptake and anticancer efficacy of the nanocarriers were studied in HCT 116 human colorectal adenocarcinoma cells and 3D tumour spheroids using high content microscopy. FindingsThe synthesized nanocarriers had high encapsulation efficiency (62–78%) and were physically stable for up to 5 months at 4 ˚C. The release profile of the drug from the nanocarriers was directed by their stiffness and was easily tuneable by changing the ratio of SF to SA in the core. Furthermore, the designed nanocarriers improved the cellular uptake and anticancer activity of ASC-J9, and enhanced its tumour penetration in HCT 116 3D colorectal cancer spheroids. These findings suggest that the designed core–shell nanocarriers can be used as a highly efficient drug delivery system for cancer therapy.
Highlights
One of the main obstacles to overcome in cancer therapy is designing non-toxic and biodegradable carriers for safe and efficient anticancer drug delivery
ASC-J9 increases the downstream apoptotic markers to a higher extent compared to curcumin, which results in enhanced anticancer activity [7]
The present work was aimed at developing nanocarriers with tuneable properties for enhanced loading, improved aqueous solubility and enhanced cellular uptake of ASC-J9 before it is cleared from the body
Summary
One of the main obstacles to overcome in cancer therapy is designing non-toxic and biodegradable carriers for safe and efficient anticancer drug delivery. T1/2 of the hydrophobic anticancer agent ASC-J9 was found to be less than 6 h following an intravenous injection in mouse, which reduces the bioactivity in certain tissues [11]. Increasing the exposure time of ASC-J9 to the cancer cells reduces the half maximal inhibitory concentration (IC50) values due to the cumulative cytotoxic effect [12]. The development of novel drug delivery systems (DDSs) for efficient loading, enhanced aqueous solubility, and improved cellular uptake of hydrophobic anticancer agents within the elimination time window has received more attention over the past decade [13,14,15]
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