Towards the Synthesis of New Tumor Targeting Photosensitizers for Photodynamic Therapy and Imaging Applications

Abstract

The synthesis of three complexes, which bear tumor-targeting peptide and which are suitable for imaging applications might act at the same time, is reported. Their structure contain a PS (a porphyrin or a fulleropyrrolidine derivative), a [1,4,7]-triazacyclononane (TACN) chelator suitable for coordination, and a bombesin BN[7-14] as a targeting peptide. Overall, this work paves the way for the preparation of theranostic complexes although the yields will need to be seriously improved and the synthetic process optimized.\ud Targeting peptides are very promising molecules to increase tumor selectivity of anticancer drugs. Herein, we report the synthesis of three complexes, which might act at the same time as photosensitizers (PSs) for cancer photodynamic therapy (PDT), as delivery systems of Re(I)/99mTc(I) fragments into tumor cells as well as targeting agents for prostate cancer cells. To this aim, we designed a structure containing a PS such as a water soluble +3-charged tris-methylpyridinium porphyrin or a fulleropyrrolidine derivative, a [1,4,7]-triazacyclononane (TACN) chelator suitable for coordination, and a bombesin BN[7-14] as a targeting peptide. Their syntheses were performed using two different approaches: the first one was based on a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC, “click reaction”) in solution, that led to compound 1, and the second one based on coupling reactions on the solid phase, that led to compounds 2 and 3. We could successfully prepare molecules bearing tumor-targeting PSs and which are suitable for imaging applications. Overall, this work paves the way for the synthesis of theranostic complexes although the yields will need to be seriously improved and the synthetic process optimized

Porphyrinoid biohybrid materials as an emerging toolbox for biomedical light management

“…Many functional peptide libraries have actually been described in the literature, with different sequences and functions, offering a versatile platform of delivery agents to localize PS conjugates in different kinds of cells and tissues. 48 Covalently linked PS-peptide biohybrids can be synthesized, taking advantage of mild synthetic organic methodologies such as amide [49][50][51][52][53]77,78,81,[85][86][87]89,[91][92][93]95,97,104,105 or sulphonamide 54 bond formation, palladium-catalysed cross-coupling reactions, 55,56 click-chemistry reactions [57][58][59]81,94 and isothiocyanate chemistry, 60,82 among other strategies. Supramolecular approaches have also been used toward self-assembled peptide nanofibers, 61 nanodots, 62 vesicles, 63 light harvesting complexes, 64 arrays 65 or polymeric micelles with a peptide-decorated surface, 66 among others.…”

“…In 2017, Giuliana et al synthesized two additional conjugates composed of bombesin and an asymmetric Zn(II)Por, linked to a chelator that allows metal coordination, in order to target prostate cancer cells for PDT and imaging applications. 81 The preparation of such PS was carried out by click chemistry and amide coupling reactions, yet the compounds were obtained in very low yields and with a laborious HPLC purification. In order to achieve higher yields, the authors suggested that the choice of the PS might be a critical point.…”

Fullerenes in biology and medicine

“…80 reported the synthesis of fullerene compound 35 (Fig. 6) for photodynamic therapy and imaging applications.…”

Modifications of Porphyrins and Hydroporphyrins for their Solubilization in Aqueous Media

“…The water-soluble derivatives were purified by normal phase silica gel column chromategraphy (CH2Cl2/MeOH mixtures). These types of compounds can also be conjugated to cancer-targeting peptides for use in cancer therapy [83]. Cu(II)-based acylhydrazone porphyrin-derivatives 37m and 37n could be obtained using a similar strategy [84].…”