Synthesis, Characterization,
and Nanoencapsulation
of Tetrathiatriarylmethyl and Tetrachlorotriarylmethyl (Trityl) Radical
DerivativesA Study To Advance Their Applicability as in Vivo
EPR Oxygen Sensors
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Abstract
Tissue oxygenation
plays an important role in the pathophysiology
of various diseases and is often a marker of prognosis and therapeutic
response. EPR (ESR) is a suitable noninvasive oximetry technique.
However, to reliably deploy soluble EPR probes as oxygen sensors in
complex biological systems, there is still a need to investigate and
improve their specificity, sensitivity, and stability. We reproducibly
synthesized various derivatives of tetrathiatriarylmethyl and tetrachlorotriarylmethyl
(trityl) radicals. Hydrophilic radicals were investigated in aqueous
solution mimicking physiological conditions by, e.g., variation of
viscosity and ionic strength. Their specificity was satisfactory,
but the oxygen sensitivity was low. To enhance the capability of trityl
radicals as oxygen sensors, encapsulation into oily core nanocapsules
was performed. Thus, different lipophilic triesters were prepared
and characterized in oily solution employing oils typically used in
drug formulations, i.e., middle-chain triglycerides and isopropyl
myristate. Our screening identified the deuterated ethyl ester of
D-TAM (radical <b>13</b>) to be suitable. It had an extremely
narrow single EPR line under anoxic conditions and excellent oxygen
sensitivity. After encapsulation, it retained its oxygen responsiveness
and was protected against reduction by ascorbic acid. These biocompatible
and highly sensitive nanosensors offer great potential for future
EPR oximetry applications in preclinical research