Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis

• Published in: Nature communications 2017-03, Vol.8 (1), p.14179-14179, Article 14179
• Main Authors: Mitchell, Michael J., Webster, Jamie, Chung, Amanda, Guimarães, Pedro P. G., Khan, Omar F., Langer, Robert
• Format: Article
• Language: English
• Subjects: 101/62; 13/1; 13/2; 13/21; 13/31; 14/19; 14/5; 631/61/350; 631/67/1059; 639/925/352/152; 64/60; 96/106; 96/95; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Cancer; Cells; Cytokines; Drug Evaluation, Preclinical; Drug resistance; Drug Synergism; HT29 Cells; Humanities and Social Sciences; Humans; Ligands; Medical research; Mice; Molecular Targeted Therapy; multidisciplinary; Nanoparticles; Nanoparticles - therapeutic use; Natural products; Physiology; Polyethylene glycol; Polyethylene Glycols; Polymers - pharmacology; Polymers - therapeutic use; Science; Science (multidisciplinary); Shear stress; Stress, Mechanical; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TNF-Related Apoptosis-Inducing Ligand - therapeutic use; Toxicity; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14179

Physical forces affect tumour growth, progression and metastasis. Here, we develop polymeric mechanical amplifiers that exploit in vitro and in vivo physical forces to increase immune cytokine-mediated tumour cell apoptosis. Mechanical amplifiers, consisting of biodegradable polymeric particles tethered to the tumour cell surface via polyethylene glycol linkers, increase the apoptotic effect of an immune cytokine on tumour cells under fluid shear exposure by as much as 50% compared with treatment under static conditions. We show that targeted polymeric particles delivered to tumour cells in vivo amplify the apoptotic effect of a subsequent treatment of immune cytokine, reduce circulating tumour cells in blood and overall tumour cell burden by over 90% and reduce solid tumour growth in combination with the antioxidant resveratrol. The work introduces a potentially new application for a broad range of micro- and nanoparticles to maximize receptor-mediated signalling and function in the presence of physical forces. Fluid shear stress plays a critical role in receptor-mediated signalling and has been shown to sensitize cancer cells to apoptosis. Here, Mitchell et al . introduce polymer micro- and nanoparticles tethered to tumour cells to amplify fluid shear stress effects, and find that they can enhance immune cytokine-mediated apoptosis of tumour cells in vitro and in vivo .