Stimuli-Responsive Chromophores

Stimuli-Responsive Chromophores

02/07/2023

Seminar room

9:30

Mr. Vinay Kumar Sharma Gross Group

Stimuli-Responsive Chromophores
Balancing between safety and efficacy of cancer chemotherapeutics is one very significant challenge. Stimuli-responsive molecules, whose cytotoxic properties are activated only in response to a specific stimulus, are promising approaches toward meeting such goals. Porphyrins and related macrocycles like corroles have the advantage of being detectable and activated by various stimuli, of which the most common is irradiation by visible light.
The goal of my PhD research was to design corrole nanoparticles (NPs) whose cancer detection/treatment features will come into effect by triggering de-aggregation of the NPs by either endogenous (low pH of cancer cells) and/or exogenous (light or ultrasound) stimuli. My work started with the preparation of corroles with quite different physical properties and examination of their response to different stimuli: light, pH, and ultrasonication. This revealed that ultrasonication of corrole-containing aqueous solutions initiated the formation of singlet oxygen, thus suggesting that they may be of utility as reagents for sonodynamic therapy (SDT).1 This was followed by a collaborative in vivo study which exposed the efficacy of corrole NPs for SDT of chemotherapy-resistant human pancreatic cancer.2
A corrole containing an imidazole moiety was prepared for examining the pH-responsiveness strategy. Its corresponding gallium and aluminum complexes formed coordination-based dimers, which we have introduced as synthetic analogs of chlorophylls special pair.3 The same corrole was also used for the preparation of the trans-difluorophosphorus complex (PC-Im), which is substitution-inert and does not form dimers. Its properties were compared to two analogous complexes, one without any pH-responsive moiety (PC) and one with a permanently charged imidazolium moiety (PC-ImM+). Structure/activity relationships, via comparison with PC-ImM+ and PC, uncovered the exceptional features of PC-Im: nanoparticular and monomeric at neutral and low pH, respectively, 10-fold increased light-induced singlet oxygen production at acidic pH, internalization into malignant cells within minutes, and selective accumulation within lysosomes. Submillimolar PC-Im concentrations were found to be tolerable in the dark, while illumination induced nanomolar cytotoxic activity.4
Much smaller corroles (about 500 Dalton), capable of spontaneously conjugating a cancer-targeting protein, were also synthesized. The resulting bio-conjugates were used in in vivo studies for selective delivery to the breast tumor site, for both imaging and therapeutic interventions.5
References:
1. V. K. Sharma, A. Mahammed, M. Soll, B. Tumanskii and Z. Gross, Chem. Commun., 2019, 55, 12789–12792.
2. M. Soll, V. K. Sharma, S. Khoury, Y. G. Assaraf, and Z. Gross, J. Med. Chem., 2023, 66, 766–776.
3. V. K. Sharma, A. Mahammed, A. Mizrahi, M. Morales, N. Fridman, H. B. Gray, and Z. Gross, J. Am. Chem. Soc., 2021, 143, 9450–9460.
4. V. K. Sharma, M. Stark, N. Fridman, Y. G Assaraf, and Z. Gross, J. Med. Chem., 2022, 65, 6100–6115.
5. V. K. Sharma, S. Mikhael, H. B. Gray, L. Medina-Kauwe, and Z. Gross (in preparation).