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ENS Cachan - Institut d'Alembert

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This project aims at designing an efficient gene delivery cargo based on gold nanorods (GNRs). Gene therapy can revolutionize the treatment of cancer by replacing or deactivating a defective gene. However, prior to any clinical application, unavoidable roadblocks need to be removed: the oligonucleotide has to be selectively transported to cancer cells while preventing its degradation during the journey and an on-command switch has to release the active oligonucleotides only after reaching the targeted cells. Gold nanoparticles (GNPs) are easily functionalized with multiple bio-molecules, exhibit low cytotoxicity when specifically functionalized and are readily internalized by cancer cells because of their high membrane permeability. On the other hand, when light of an appropriate wavelength is absorbed by GNPs, the incident energy is efficiently converted into heat that can be localized close to the particle's surface. These properties may be used in biology to release small molecules anchored to nanoparticles or to induce cell death. GNRs permit studies in the transparency spectral domain suited for biological applications and are more effective than nanospheres for photo-thermal conversion. With this project, we propose a highly detailed study, which will optimize the photo-release of a single strand DNA (ssDNA) by controlling the melting of the GNR-functionalized double-strand DNA (dsDNA).

To obtain the sensitivity necessary for reliable quantification of the released DNA both in vitro and in vivo, we will take advantage of the induced fluorescent enhancement properties of GNRs.
The LBPA team has recently developed an original in house surface chemistry allowing the control of both the density and the orientation of dsDNA immobilized on the GNRs surface. By combining the enhanced sensitivity with the nano-heat source size obtained with the GNRs we intend to probe not only the complete denaturation of the dsDNA strands and the MB but to characterize the intermediate states upon denaturation and renaturation or folding.
With the high sensitivity of detection coupled with the PPSM FLIM setup that collates all collected photons with time information on a range of picosecond to second, this project offers a unique opportunity to follow microsecond kinetics. Probing the time evolution of a sample by FLIM after a perturbation (warming of the GNP) has never been done. We shall make movies of the relaxation of the system after the repetitive thermal perturbation.
In addition, the expertise of the LPQM team in analyzing the thermal energy generated with light will allow mapping of the temperature gradient from GNRs surface to the solution as a function of laser energy and pulse duration so we can predict optimum conditions for in vivo experiments. Such a level of sensitivity of detection opens up new perspectives for correlating the release of an active drug with its impact on cell gene expression both in space and in time.