Year-end Sale % OFF 
Abstract
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.
Highlights
Physical forces affect tumour growth, progression and metastasis
We assessed whether shear force exposure increased tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via caspase-mediated signalling, which is triggered upon TRAIL binding to death receptors death receptors 4 (DR4) and DR5
In summary, we have demonstrated that functionalization of the tumour cell surface with polymeric particles can amplify TRAILmediated tumour cell killing in the presence of fluid shear stress both in vitro and in vivo in mice
Summary
We develop polymeric mechanical amplifiers that exploit in vitro and in vivo physical forces to increase immune cytokine-mediated tumour cell apoptosis. Receptor-mediated signalling in response to mechanical forces is under intense study, and plays an important role in embryonic development and adult physiology, while contributing to numerous diseases including atherosclerosis, osteoporosis and cancer[7]. Malignant cells are exposed to a wide range of physiological fluid shear forces in vivo, including high shear stress (0.5–30.0 dyn cm À 2) in the circulation generated by blood flow and low shear stress (B0.1 dyn cm À 2) in soft tissues generated by interstitial flow[10] Such forces can trigger mechanotransduction in tumour cells at the receptor level both in vitro and in vivo, which can affect tumour progression[11,12,13,14,15]. Numerous groups have studied the effect of chemical sensitizers, to our knowledge no one has explored leveraging mechanical stimulation as a means to increase TRAIL sensitivity while sparing normal cells in vivo
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
