Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis.
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.
Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts 02139, USA.
Michael J
0000-0002-3628-2244
MJ
Mitchell
Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts 02139, USA.
Jamie
J
Webster
Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts 02139, USA.
Amanda
A
Chung
Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts 02139, USA.
Pedro P G
PP
Guimarães
Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts 02139, USA.
Omar F
0000-0003-3811-2369
OF
Khan
Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts 02139, USA.
Robert
R
Langer
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000627:therapeutic use; D011092:Polyethylene Glycols; D011108:Polymers / Q000494:pharmacology* / Q000627:therapeutic use; D013314:Stress, Mechanical; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011108:Polymers; D053221:TNF-Related Apoptosis-Inducing Ligand; D011092:Polyethylene Glycols