Rational Molecular Designing of Aggregation-Enhanced Emission (AEE) Active Red-Emitting Iridium(III) Complexes: Effect of Lipophilicity and Nanoparticle Encapsulation on Photodynamic Therapy Efficacy

Abstract

Two "aggregation-enhanced emission" (AEE) active cyclometalated phosphorescent iridium(III) complexes, SM2 and SM4, were synthesized to evaluate the influence of lipophilicity on photodynamic therapy efficacy. Compared to SM2, SM4 had a higher logP due to the presence of naphthyl groups. As observed by confocal microscopy, this increased lipophilicity of SM4 significantly enhanced its cellular uptake in breast cancer cells. Both the molecules were found to be noncytotoxic under nonirradiating conditions. However, with light irradiation, SM4 exhibited significant cytotoxicity at a 500 nM dose, whereas SM2 remained noncytotoxic, signifying the influence of lipophilicity on cellular internalization and cytotoxicity. Mechanistically, light-irradiated SM4-treated cancer cells exhibited a significant increase in the intracellular reactive oxygen species (ROS) level. Neutralizing ROS with N-acetylcysteine (NAC) pretreatment partly abolished the cytotoxic ability, indicating ROS as one of the major effectors of cell cytotoxicity. Two nanoparticle (NP) formulations of SM4 were developed to improve the intracellular delivery: a PLGA-based NP and a Soluplus-based micelle. Interestingly, PLGA and Soluplus NP formulations exhibited a 10-and 22-fold increased emission intensity, respectively, compared to SM4. There was also an increase in the excited-state lifetime. Additionally, the Soluplus-based micelles encapsulating SM4 exhibited enhanced cellular uptake and increased cytotoxicity compared to the PLGA NPs encapsulating SM4. Altogether, the current study indicates the importance of rational molecular designing and the significance of a proper delivery vector for improving photodynamic therapy efficacy.

Ru(II) Phenanthroline-Based Oligothienyl Complexes as Phototherapy Agents

“…In addition, PDT can induce hypoxia as oxygen is consumed during irradiation. , Decreased generation of ROS limits damage to cancerous cells. To address this, there is motivation to develop light-triggered compounds that exploit oxygen-independent mechanisms for phototoxicity. − In this context, metal complexes such as Ru(II) polypyridyl systems have attracted considerable attention. ,,,− Judicious choice of ligand–metal combinations provides access to a variety of excited-state configurations with characteristic photophysical properties and reactivities. Strategies have included photorelease of bulky ligands to reveal phototoxic metals and/or ligands, ,,,,,− photocaging of chemotherapeutics and enzyme inhibitors, ,,,,,− …”

Ligand Dictated Photosensitization of Iridium(III) Dithiocarbamate Complexes for Photodynamic Therapy

“…The UV–visible absorption spectra of all of the complexes in dry acetonitrile (CH 3 CN) and DMSO–water (0.4%, v/v) at 298 K are shown in Figure (a) and Figure S22­(a), respectively. The complexes display a strong absorption band in the region of 250–300 nm, which is assigned to spin-allowed ligand-centered or interligand ( 1 π–π*) transitions. , In addition, the weak and broad absorption bands (less intense) in the region of 350–500 nm are designated to the mixed singlet and triplet metal-to-ligand charge transfer (MLCT) or dπ­(Ir)−π*­(L) (spin allowed and spin forbidden). , The absorption spectra for the synthesized Ir­(III) complexes are analogous to most of the reported cyclometalated iridium­(III) complexes. , …”

Controlling the sensitivity and selectivity for the detection of nitro-based explosives by modulating the electronic substituents on the ligand of AIPE-active cyclometalated iridium(iii) complexes

“…With increasing size of aggregates, two phenomena occur whose effects on the emission intensity are opposite. 72,73 One of them leads to an enhancement of emission intensity due to the restricted intramolecular motion (RIM) and in the other case a decrease of the emission intensity with decreasing number of molecules present on the surface and an increase of the size of aggregates occur. 74 Thus, effectively, fewer number of molecules gets excited at the 90% water fraction, which is the predominant factor leading to the decrease in the emission intensity.…”