Phthalocyanine–Peptide Conjugates: Receptor-Targeting Bifunctional Agents for Imaging and Photodynamic Therapy

Abstract

The synthesis of a series of new zinc phthalocyanine-peptide conjugates targeting the gastrin-releasing peptide (GRP) and integrin receptors is reported. Two alternative synthetic methods based on Sonogashira cross-coupling of an iodinated zinc phthalocyanine with acetylenic bombesin or arginine-glycine-aspartic acid (RGD) derivatives, either in solution or on solid phase, are presented. The water-soluble conjugates were screened for their photodynamic efficacy against several cancer cell lines expressing different levels of GRP and integrin receptors, and their intracellular localization was evaluated via confocal fluorescence microscopy. Variations in photocytotoxicity between the conjugates correlate to differences in hydrophobicity as well as receptor-mediated cell uptake. In the case of the phthalocyanine-bombesin conjugate, competition experiments confirm the involvement of the GRP receptor in both the phototherapeutic activity as well as intracellular localization. These findings warrant further in vivo studies to evaluate the potential of this conjugate as photosensitizer for photodynamic therapy (PDT) of cancers overexpressing the GRP receptor.

Synthesis and Isolation of 2,9,17,23-Tetrakis[(3,5-dimethyl-1H-pyrazol-1-yl)phenoxy]phthalocyanine and Its Magnesium(II) and Zinc(II) Complexes

“…FT-IR, 1 H NMR, 13 C NMR, UV-Vis and ESI mass spectroscopy data confirm the proposed structures of the synthesized phthalocyanines. It is shown that the nature of metal and reaction condition do not influence on the synthesis and isolation of practically pure C S regioisomers.…”

“…These properties make them important candidates as potential agents for fluorescence imaging and photodynamic therapy of cancer. [12][13][14][15][16] Unsubstituted phthalocyanines are known to have low solubility in most organic solvents that restricts of their application. Introduction of aryl or heteroaryl substituents in phthalocyanine core enhances solubility of macroheterocycles in many organic solvents and gives them new functional properties.…”

Engineering of relevant photodynamic processes through structural modifications of metallotetrapyrrolic photosensitizers

“…Besides coordination with several metal ions, possible structural modification involves tailoring of hydrophilicity or hydrophobicity, shift of the maximum absorption to the near infrared, introduction of various functional groups and conjugation with nanoparticles or imaging agents [106][107][108][109][110][111][112][113][114]. Sterically-distorted phthalocyanines bearing n-butoxy groups in all the -benzo positions of the macrocycle ring, MPc(OBu) 8 combine absorption bands displaced to lower energies with photostability and the ability to generate high yields of singlet oxygen [122].…”

Synthetic approaches to asymmetric phthalocyanines and their analogues

“…In particular, as shown in the laboratories of Torres, van Lier, and many others, the mono-iodo A 3 B phthalocyanines 62 can easily be made to undergo a variety of coupling reactions (Scheme 23). 218,220,221,223,227,228,[236][237][238][239][240][241][242] This precursor can be used for the introduction of direct carboncarbon bonds as aryl, alkenyl, and alkynyl substituents. 217,219,220,226,234,235 In addition, the Buchwald reaction can be used for carbon-nitrogen bond formation.…”