Studies on Iron and Cobalt Complexes for Cellular Imaging and Photodynamic Therapy

Abstract

Redox-active transition metal-based prodrug complexes hold great promise as drug delivery systems (DDS) to circumvent drug related toxicity and enhance the overall efficacy of the cytotoxic agents. In this context, bioessential 3d-block elements like iron and cobalt are more advantageous compared to heavy metal like Pt, Ru, or Ir, which induced metal-related dark toxicity. The present work explores the prodrug approach in photodynamic therapy, that uses localized light to activate a photosensitizer with high spatio-temporal selectivity to produce reactive oxygen species (ROS) leading to cancer cell death. Although boron-dipyrromethene (BODIPY) dyes are excellent for cellular imaging and photodynamic therapy, their clinical applications are limited due to their hydrophobicity, poor aqueous solubility and bioavailability. The present research is focused on designing iron and cobalt chaperones of photochemotherapeutic natural product curcumin and BODIPY photosensitizers to selectively deliver the pharmacophore in cancer cells for targeted cancer therapy. Here, heteroleptic iron complexes of curcumin (Hcur) having ancillary tetradentate tris(2-pyridylmethyl)amine (TPA), N,N-bis(2-pyridylmethyl)-N-(2-hydroxybenzyl)amine (HPBPA), and N,N-dimethyl-N',N'-bis(4,6-ditertiarybutyl-2-hydroxybenzyl)ethylenediamine (H2BPEN) ligands, namely, [FeII(TPA)(cur)]Cl (1), [FeIII(PBPA)(cur)]Cl (2) and [FeIII(BPEN)(cur)] (3) are synthesized and their photobiological properties investigated. The complexes exhibited efficient release of curcumin ligand upon exposure to visible light or in the presence of biological reducing agents like ascorbic and glutathione (GSH) with improved photocytotoxic effect than curcumin alone. Next, a series of Co(III) complexes having acetylacetonate-linked BODIPY ligand (acac-BOD or acac-diiodo-BOD) and tetradentate TPA or 2-((bis-(2-pyridylmethyl)amino)methyl)isonicotinic acid (4-COOH-TPA) ligands, viz. [Co(TPA)(acac-BOD)](ClO4)2 (4), [Co(4-COOH-TPA)(acac-BOD)](ClO4)2 (5), [Co(TPA)(acac-diiodo-BOD)]Cl2 (6) and [Co(4-COOH-TPA)(acac-diiodo-BOD)]Cl2 (7) are synthesized and their photophysical and phototherapeutic features are explored. Upon visible-light activation or in a reducing environment, complexes 4 and 5 released the acac-BODIPY ligand in vitro. Complex 7 exhibited remarkable photocytotoxicity in HeLa cancer cells (IC50 ~ 0.007 M, PI >7,000). In a subsequent study Co(III) complexes, viz. [CoIII(TPA)(acac-RBOD)](ClO4)2 (8) and [CoIII(TPA)(acac-diBr-RBOD)](ClO4)2 (9) having di-styryl BODIPY derivatives are investigated for prodrug activation via photoreduction in the phototherapeutic window (600-850 nm) or in the hypoxic tumor microenvironment. Finally, Co(III) chaperones of HPBPA and N,O-donor 8-hydroxyquinoline (HQ) and its BODIPY (HQ-BOD) or dibromo-BODIPY (HQ-diBr-RBOD) analogues, namely, [Co(PBPA)(Q)]ClO4 (10), [Co(PBPA)(Q-BOD)]ClO4 (11), and [Co(PBPA)(Q-diBr-RBOD)]Cl (12) were investigated to establish a structure-activity relationship for Co(III)-BODIPY conjugates in the field of stimuli responsive metal-based prodrug strategy. In summary, this work presents systematic developments of iron(II/II)-curcumin conjugates and BODIPY appended cobalt(III) prodrug chaperones as novel photosensitizers and photo-diagnostic agents for phototherapeutic applications.