Projects per year
Abstract
Over the past decade, porphyrin derivatives have emerged as invaluable synthetic building blocks and theranostic kits for the delivery of cellular fluorescence imaging and photodynamic therapy. Tetraphenylporphyrin (TPP), its metal complexes, and related derivatives have been investigated for their use as dyes in histology and as components of multimodal imaging probes. The photophysical properties of porphyrin–metal complexes featuring radiometals have been a focus of our attention for the realization of fluorescence imaging probes coupled with radioimaging capabilities and therapeutic potential having “true” theranostic promise. We report hereby on the synthesis, radiochemistry, structural investigations, and preliminary in vitro and in vivo uptake studies on a range of functionalized porphyrin-based derivatives. In pursuit of developing new porphyrin-based probes for multimodality imaging applications, we report new functionalized neutral, polycationic, and polyanionic porphyrins incorporating nitroimidazole and sulfonamide moieties, which were used as targeting groups to improve the notoriously poor pharmacokinetics of porphyrin tags. The resulting functional metalloporphyrin species were stable under serum challenges and the nitroimidazole and sulfonamide derivatives remained fluorescent, allowing in vitro confocal studies and visualization of the lysosomal uptake in a gallium(III) sulfonamide derivative. The molecular structures of selected porphyrin derivatives were determined by single crystal X-ray diffraction using synchrotron radiation. We also investigated the nature of the emission/excitation behavior of model functional porphyrins using in silico approaches such as TD DFT in simple solvation models. The conjugation of porphyrins with the [7-13] and [7-14] fragments of bombesin was also achieved, to provide targeting of the gastrin releasing peptide receptor (GRPR). Depending on the metal, probe conjugates of relevance for single photon emission computed tomography (SPECT) or positron emission tomography (PET) probes have been designed and tested hereby, using TPP and related functional free base porphyrins as the bifunctional chelator synthetic scaffold and 111In[In] or 68Ga[Ga], respectively, as the central metal ions. Interestingly, for simple porphyrin conjugates good radiochemical incorporation was obtained for both radiometals, but the presence of peptides significantly diminished the radio-incorporation yields. Although the gallium-68 radiochemistry of the bombesin conjugates did not show radiochemical incorporation suitable for in vivo studies, likely because the presence of the peptide changed the behavior of the TPP-NH2 synthon taken alone, the optical imaging assays indicated that the conjugated peptide tags do mediate uptake of the porphyrin units into cells.
Original language | English |
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Pages (from-to) | 1374-1392 |
Number of pages | 19 |
Journal | Bioconjugate Chemistry |
Volume | 32 |
Issue number | 7 |
Early online date | 1 Feb 2021 |
DOIs | |
Publication status | Published - 21 Jul 2021 |
Bibliographical note
Funding Information:This work was financially supported by Science & Technologies Facilities Council, EPSRC Centre for Doctoral Training Centre for Sustainable Chemical Technologies (EP/G03768X/1), ERC Consolidator grant scheme (O2Sense to S.I.P.) and ERC Proof-of-Concept grant Tools-To-Sense to S.I.P., and University of Bath, EPSRC Mass Spectrometry at Swansea. Also LASERLAB-EUROPE (grant agreement no. 654148), European Union’s Horizon 2020 research and innovation program is acknowledged. University of Catania is acknowledged for a travel and study grant to VC.
ASJC Scopus subject areas
- Biotechnology
- Bioengineering
- Biomedical Engineering
- Pharmacology
- Pharmaceutical Science
- Organic Chemistry
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Dive into the research topics of 'Structural Investigations, Cellular Imaging, and Radiolabeling of Neutral, Polycationic, and Polyanionic Functional Metalloporphyrin Conjugates'. Together they form a unique fingerprint.Projects
- 2 Finished
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Fluorescence Lifetime Imaging of New Functional Biomaterials Invasive Early Tumour Diagnosis
Pascu, S. (PI)
Science and Technology Facilities Council
1/11/12 → 16/03/14
Project: Research council
Equipment
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Avance 300 MHz Nuclear Magnetic Resonance (NMR) Spectrometer (1South)
Material and Chemical Characterisation (MC2)Facility/equipment: Equipment
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Confocal Laser Scanning Confocal Microscope (LSM)
Material and Chemical Characterisation (MC2)Facility/equipment: Equipment