Minimally-invasive Theranostics based on Triplet-Triplet Annihilation
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Abstract
Simultaneous and real-time sensing of specific cellular parameters can be achieved by the use of multifunctional nanocarriers. Multifunctional nanocarriers combine multiple properties in single particles, and enable minimally invasive and all-optical monitoring of specific physiological parameters at a cellular level with unprecedented efficiency and sensitivity.
This study is devoted to the synthesis of entirely organic upconversion nanoparticles (UCNPs) and to the investigation of their unique optical properties and cytotoxic effects. These UCNPs provide an excellent platform to construct multifunctional nanocarriers for various biomedical applications, because of their anti-Stokes luminescence properties and strong dependence of the efficiency of triplet-triplet annihilation assisted upconversion (TTA-UC) on the local temperature and oxygen content.
This thesis includes an up-to-date literature review on the application of UCNPs as a therapy and diagnostics (theranostic) platform. The thesis also describes: i) the fundamental theoretical aspects of the TTA-UC; ii) the advantages of the use of this TTA-UC process for biosensing purposes; iii) the requirements to the structural and energetic characteristics of the couples of sensitizer/emitter; iv) and a theoretical prediction for the maximal quantum yields of delayed emitter fluorescence (dEF) and residual sensitizer phosphorescence (rSPh).
The selected matrix composition for UCNPs formation is entirely biocompatible, mostly consisting of natural waxes and vegetable oils. Spectroscopic techniques were used to assess the effectiveness of the TTA-UC process in organogel matrix and UCNPs. The matrix material ensures the significant increase of the rotational diffusion of the optically active molecules for a temperature interval centered at 36 °C. The optimal UCNP-composition (Y-894 / DBOV-Mes in rice bran oil 30 wt.% / squalene 30 wt.% / carnauba wax 40 wt.% / Tween-20) demonstrates the monotonic increase of the dEF-signal and decrease of the rSPh-signal at monotonically increasing the sample temperature, that leads to exclusively sustainable T-calibration curve. The obtained UCNP-composition demonstrates highly stable dispersions with pronounced oxygen scavenging ability.
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We have determined the cytotoxicity of the UCNPs and their optimal concentration for efficient intracellular T-sensing through the cooperation with the biologists from our group. The upper limit of the solid content of the sensing UСNPs (1250 μg mL-1) demonstrates high T-sensitivity – up to 250 mK, optically achieved in the ambient environment, around the life-science relevant temperature of T = 36 °C. The UCNPs are well tolerated by bio-objects and highly suited for biomedical applications as suggested by the fluorescence microscopy of cellular uptake process and cytotoxicity test.
Additionally, we studied external-stimuli responsive protection of excited triplet states against deactivation by singlet oxygen. The sacrificial singlet oxygen scavenging capability of N-butyl-2-pyridone provides long-term protection of the triplet-triplet annihilation photon energy upconversion process against photooxidation.