Corrole Nanoparticles for Chemotherapy of Castration-Resistant Prostate Cancer and as Sonodynamic Agents for Pancreatic Cancer Treatment.

A nanoparticle-based system, composed of the gallium(III) complex of a minimally substituted corrole that is coated by transferrin as a targeting vehicle (3-Ga NPs), has been used for pre-clinical evaluation of its efficacy against human metastatic castration-resistant prostate cancer (mCRPC) tumor xenografts. All mice (N = 9) responded to a dose of 10 mg/kg, with a remarkable tumor growth inhibition of 400% following 2 weeks of treatment; Ames and hERG tests excluded potential concerns regarding mutagenicity and cardiotoxicity, respectively. Also demonstrated is the potential application of these 3-Ga NPs as sonodynamic agents for the preclinical treatment of pancreatic cancer. 10 mg/kg 3-Ga NPs combined with exposure to ultrasound waves (2 min of 1 MHz 0.1 w/cm2 twice a week) induced up to 77% tumor shrinkage. Consistently, tumor/tissue distribution and serum levels of 3-Ga NPs in mice revealed high tumor specificity, favorable pharmacokinetics, fast absorption, slower redistribution, and very slow drug clearance.

A Synthetic SOD/Catalase Mimic Compound for the Treatment of ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. To date, the etiology of the disease is still unclear, with evidence of reactive oxygen species, mitochondrial dysfunction, iron homeostasis perturbation, protein misfolding and protein aggregation as key players in the pathology of the disease. Twenty percent of familial ALS and two percent of sporadic ALS instances are due to a mutation in Cu/Zn superoxide dismutase (SOD1). Sporadic and familial ALS affects the same neurons with similar pathology; therefore, the underlying hypothesis is that therapies effective in mutant SOD1 models could be translated to sporadic ALS. Corrole metal complexes have lately been identified as strong and potent catalytic antioxidants with beneficial effects in oxidative stress-related diseases such as Parkinson's disease, Alzheimer's disease, atherosclerosis, diabetes and its complications. One of the most promising candidates is the iron complex of an amphiphilic corrole, 1-Fe. In this study we used the SOD1 G93R mutant zebrafish ALS model to assess whether 1-Fe, as a potent catalytic antioxidant, displays any therapeutic merits in vivo. Our results show that 1-Fe caused a substantial increase in mutant zebrafish locomotor activity (up to 30%), bringing the locomotive abilities of the mutant treated group close to that of the wild type untreated group (50% more than the mutated untreated group). Furthermore, 1-Fe did not affect WT larvae locomotor activity, suggesting that 1-Fe enhances locomotor ability by targeting mechanisms underlying SOD1 ALS specifically. These results may pave the way for future development of 1-Fe as a viable treatment for ALS.

Protein-coated corrole nanoparticles for the treatment of prostate cancer cells.

Development of novel therapeutic strategies to eradicate malignant tumors is of paramount importance in cancer research. In a recent study, we have introduced a facile protocol for the preparation of corrole-protein nanoparticles (NPs). These NPs consist of a corrole-core coated with protein. We now report that a novel lipophilic corrole, (2)Ga, delivered as human serum albumin (HSA)-coated NPs, displayed antineoplastic activity towards human prostate cancer DU-145 cells. Cryo-TEM analysis of these NPs revealed an average diameter of 50.2 ± 8.1 nm with a spherical architecture exhibiting low polydispersity. In vitro cellular uptake of (2)Ga/albumin NPs was attributable to rapid internalization of the corrole through ligand binding-dependent extracellular release and intercalation of the corrole cargo into the lipid bilayer of the plasma membrane. This finding is in contrast with a previously reported study on corrole-protein NPs that displayed cellular uptake via endocytosis. Investigation of the non-light-induced mechanism of action of (2)Ga suggested the induction of necrosis through plasma membrane destabilization, impairment of calcium homeostasis, lysosomal stress and rupture, as well as formation of reactive oxygen species (ROS). (2)Ga also exhibited potent light-induced cytotoxicity through ROS generation. These findings demonstrate a rapid cellular uptake of (2)Ga/protein NPs along with targeted induction of tumor cell necrosis.

Corroles and corrole/transferrin nanoconjugates as candidates for sonodynamic therapy.

We report the utility of water-soluble corroles and also protein-coated nanoparticles (NPs) of lipophilic corroles as potent candidates for sonodynamic therapy (SDT), through the detection and quantification of the singlet oxygen that is produced by the ultrasonic irradiation of their aqueous solutions. Preliminary results on a cancer cell line provide evidence for the true utility of the NPs for SDT.

Structures and Spectroscopic Properties of Metallocorrole Nanoparticles.

In aqueous media, hydrophobic metallocorroles form nanoparticles that are potential theranostic anticancer agents. We have analyzed the electronic and Raman spectra of Al(III), Ga(III), and Au(III) corrole nanoparticles (and made comparisons with DFT-validated assignments of the IR spectra of corresponding monomers) in order to estimate the strengths of corrole-corrole electronic couplings in these assemblies. We find that these spectra are virtually unchanged upon aggregation, confirming that the intermolecular interactions in these nanoparticles are very weak.

Cell-Penetrating Protein/Corrole Nanoparticles.

Recent work has highlighted the potential of metallocorroles as versatile platforms for the development of drugs and imaging agents, since the bioavailability, physicochemical properties and therapeutic activity can be dramatically altered by metal ion substitution and/or functional group replacement. Significant advances in cancer treatment and imaging have been reported based on work with a water-soluble bis-sulfonated gallium corrole in both cellular and rodent-based models. We now show that cytotoxicities increase in the order Ga < Fe < Al < Mn < Sb < Au for bis-sulfonated corroles; and, importantly, that they correlate with metallocorrole affinities for very low density lipoprotein (VLDL), the main carrier of lipophilic drugs. As chemotherapeutic potential is predicted to be enhanced by increased lipophilicity, we have developed a novel method for the preparation of cell-penetrating lipophilic metallocorrole/serum-protein nanoparticles (NPs). Cryo-TEM revealed an average core metallocorrole particle size of 32 nm, with protein tendrils extending from the core (conjugate size is ~100 nm). Optical imaging of DU-145 prostate cancer cells treated with corrole NPs (≤100 nM) revealed fast cellular uptake, very slow release, and distribution into the endoplasmic reticulum (ER) and lysosomes. The physical properties of corrole NPs prepared in combination with transferrin and albumin were alike, but the former were internalized to a greater extent by the transferrin-receptor-rich DU-145 cells. Our method of preparation of corrole/protein NPs may be generalizable to many bioactive hydrophobic molecules to enhance their bioavailability and target affinity.

One-Pot Synthesis of Contracted and Expanded Porphyrins with meso-CF3 Groups.

Corrole and sapphyrin with the smallest meso-substituents reported so far were prepared in a one-pot synthesis that relies on a non-aldehydic precursor for introducing CF3 groups. The substantial amounts of products obtained by this facile pathway allowed for the full characterization of 5,10,15-tris(trifluoromethyl)corrole, the access to a variety of stable chelates thereof and investigations that disclose the unique structural and chemical properties induced by the CF3 substituents. The novel 5,10,15,20-tetra(trifluoromethyl)sapphyrin undergoes only single protonation, which according to its crystal structure is stabilized by favorable non-bonding F/H interaction between the meso-CF3 and the inverted pyrrolic NH.

One-Pot Conversion of Fluorophores to Phosphorophores.

Facile, one-pot conversion of free base 5,10,15-tris(pentafluorophenyl)corrole, (H3)tpfc, into the coinage metal complexes of 2,3,17,18-tetraiodo-5,10,15-tris(pentafluorophenyl)corrole, (I4-tpfc)M (M = Cu, Ag, Au), is reported. The iodination/metalation procedures provide much higher yields and larger selectivity than both conceivable stepwise syntheses. Photophysical analysis shows that the gold(III) complex (I4-tpfc)Au displays phosphorescence at room temperature and a substantial quantum yield for singlet oxygen formation.

Neurorescue by a ROS Decomposition Catalyst.

The effect of the bis-sulfonated iron(III) corrole (1-Fe), a potent decomposition catalyst of reactive oxygen species, on rescuing SN4741 cells that were damaged by 6-hydroxydopamine (6-OHDA) was investigated as an in vitro model system for studying cell death of dopaminergic neurons in the substantia nigra. Important findings that accompanied the ability to rescue dopaminergic neurons were increased expression of phenotypic dopaminergic proteins, such as tyrosine hydroxylase (TH) and dopamine transporter (DAT), which were significantly depleted upon 6-OHDA-mediated damage. 1-Fe also elevated expression levels of aldehyde dehydrogenase 1 (ALDH-1), previously disclosed as a cardinal protein in the pathogenesis of Parkinson's disease. Since these findings suggested that 1-Fe affects quite a wide range of intracellular mechanisms, vital intracellular pathways that involve neuroplasticity, growth, differentiation and survival of neurons, were examined. Phosphatidylinositol 3-kinase (PI3K) and protein kinase c (PKC) were found to be involved, as pharmacological inhibitors of these kinases abolished the neurorescue effect of 1-Fe. 1-Fe also elevated the expression of antiapoptotic protein Bcl-2, which is essential for proper mitochondrial function and cellular survival. The overall conclusion is that 1-Fe is capable of rescuing already damaged neuronal cells by a variety of mechanisms that are beyond its antioxidant activity.