A new generation of molecular probes with red-shifted emission towards effective fluorescence imaging and treatment of cancer cells

Date

2023-9

Author

Atakan Alkan, Gizem

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Cancer is still among the leading health issues today, considering the complexity of detection/treatment methods and survival rates. Florescence imaging agents emerged as an important alternative due to the current state of the art owing to their spatial and temporal resolution, high sensitivity and selectivity, and ease of modification. In addition to imaging, light-based treatment technique, photodynamic therapy (PDT), attained remarkable attention, as it is minimally invasive and has fewer side effects compared to the current standard of care treatments. Even though fluorescence imaging and PDT have these significant advantages, light that needs to excite the agent has limited penetration in tissues, hindering widespread utilization. Hybrid xanthene dyes, particularly ones bearing silicon or phosphine oxide as the bridging unit of xanthene moiety, gained significant interest not only due to their excellent photochemical properties, high fluorescence quantum yield, photostability but also their red-shifted absorption and emission maxima. Here, the design and synthesis strategies of a series of advanced fluorophores that combine the two contradicting entities – absorption in red-shifted region (>650 nm) and low Mws – was aimed using novel design approaches towards creating a new series of PDT agents that can penetrate the blood brain barrier for glioblastoma treatment. A novel dye series with red-shifted absorption and low molecular weights was developed. Our design strategy involved incorporating two single atom modifications at the bridging sp2 carbon and the oxygen atom modifications of fluorescein-based cores and four peculiar dyes were pursued. Silicon containing derivative IDC1 was successfully synthesized and proved our theory that the red-shifting effect of each single atom modification was in fact additive. To best of our knowledge this resulted in the realization of smallest molecular weight xanthene-based dye to exhibit absorption above 650 nm which marks the starting point for therapeutic window, a range of wavelengths that are suitable for PDT action for deeper tumors. While the effectiveness of the approach was proven, lack of fluorescence in IDC1 hindered its utilization for imaging and PDT applications. To address these problems, synthetic efforts were made to synthesize a methyl derivative, Me-SiNO. The major steps of the synthetic pathway are outlined, although the synthesis was not completed. Simultaneously, efforts were made to realize an azasilane PDT agent, Me-SiNN. The phosphorus containing analogue, IDC2, was synthesized successfully. IDC2 showed absorption at 617 nm and emission in the NIR region (710 nm). Due to its fluorescence characteristics synthetic efforts were directed towards the realization of its PDT agent by heavy atom decoration. These modifications proved difficult, and several approaches proved unfruitful. Several other approached are currently being pursued. Synthetic efforts were also established towards realization of the annulated derivatives of IDC1 and IDC2, IDC1A and IDC2A respectively, to further extent the absorption into the NIR range. Additional efforts were made to realize PDT agents using well-established phosphorous containing fluorescein and rhodamine derivatives. A novel pathway was designed for PCO. Although the efforts did not yield the desired results, the dedicated synthetic efforts are important guidelines for devising novel pathways. Successfully, the synthesis of PCN was achieved by modifying literature pathways. This marks the first successful synthesis of a phosphorous-containing xanthene-based PDT agent.

Subject Keywords

NIR-Fluorophores, NIR-Photosensitizers, Photodynamic Therapy

URI

https://hdl.handle.net/11511/106358

Collections

Graduate School of Natural and Applied Sciences, Thesis