Silk nanoparticles: proof of lysosomotropic anticancer drug delivery at single-cell resolution. (26th November 2017)

• Record Type: Journal Article
• Authors: Totten, John D.; Wongpinyochit, Thidarat; Seib, F. Philipp
• Is Part Of: Journal of drug targeting. Volume 25:Number 9/10(2017)
• Page Start: 865
• Page End: 872
• Publication Date: 2017-11-26
• Subjects: Fibroin -- endocytosis -- nanoparticle -- trafficking -- doxorubicin; Drug delivery systems -- Periodicals; Drug Delivery Systems; Vehicles; Drug Administration Routes; Drug Evaluation; 615.7
• DOI: 10.1080/1061186X.2017.1363212
• Languages: English
• ISSNs: 1061-186X

Abstract

Abstract: Silk nanoparticles are expected to improve chemotherapeutic drug targeting to solid tumours by exploiting tumour pathophysiology, modifying the cellular pharmacokinetics of the payload and ultimately resulting in trafficking to lysosomes and triggering drug release. However, experimental proof for lysosomotropic drug delivery by silk nanoparticles in live cells is lacking and the importance of lysosomal pH and enzymes controlling drug release is currently unknown. Here, we demonstrate, in live single human breast cancer cells, the role of the lysosomal environment in determining silk nanoparticle-mediated drug release. MCF-7 human breast cancer cells endocytosed and trafficked drug-loaded native and PEGylated silk nanoparticles (∼100 nm in diameter) to lysosomes, with subsequent drug release from the respective carriers and nuclear translocation within 5 h of dosing. A combination of low pH and enzymatic degradation facilitated drug release from the silk nanoparticles; perturbation of the acidic lysosomal pH and inhibition of serine, cysteine and threonine proteases resulted in a 42% ± 2.2% and 33% ± 3% reduction in nuclear-associated drug accumulation for native and PEGylated silk nanoparticles, respectively. Overall, this study demonstrates the importance of lysosomal activity for anticancer drug release from silk nanoparticles, thereby providing direct evidence for lysosomotropic drug delivery in live cells.