Photoclick surface modification of MOF-808 for galactose-mediated targeted chemotherapy.

Controllable surface modification of nanoparticulate drug delivery vectors is key to enhancing specific desirable properties such as colloidal stability, targeting, and stimuli-responsive cargo release. Metal-organic frameworks (MOFs) have been proposed as potential delivery devices, with surface modification achieved by various bioconjugate "click" reactions, including copper-catalysed and strain-promoted azide-alkyne cycloaddition. Herein, we show that photo-induced nitrile imine-mediated tetrazole-ene cycloaddition (NITEC) can be used to surface-modify tetrazole-appended Zr MOFs with maleimides, and vice versa, with the extent of this traceless surface functionalisation controlled by the length of photoirradiation.

Integrated Design of a Membrane-Lytic Peptide-Based Intravenous Nanotherapeutic Suppresses Triple-Negative Breast Cancer.

Membrane-lytic peptides offer broad synthetic flexibilities and design potential to the arsenal of anticancer therapeutics, which can be limited by cytotoxicity to noncancerous cells and induction of drug resistance via stress-induced mutagenesis. Despite continued research efforts on membrane-perforating peptides for antimicrobial applications, success in anticancer peptide therapeutics remains elusive given the muted distinction between cancerous and normal cell membranes and the challenge of peptide degradation and neutralization upon intravenous delivery. Using triple-negative breast cancer as a model, the authors report the development of a new class of anticancer peptides.

The Bulk Osteosarcoma and Osteosarcoma Stem Cell Activity of a Necroptosis-Inducing Nickel(II)-Phenanthroline Complex.

We report the anti-osteosarcoma and anti-osteosarcoma stem cell (OSC) properties of a nickel(II) complex, 1. Complex 1 displays similar potency towards bulk osteosarcoma cells and OSCs, in the micromolar range. Notably, 1 displays similar or better OSC potency than the clinically approved platinum(II) anticancer drugs cisplatin and carboplatin in two- and three-dimensional osteosarcoma cell cultures.

A tri-metallic palladium complex with breast cancer stem cell potency.

A multi-nuclear, triangular-shaped palladium(ii) complex is shown to equipotently kill bulk cancer cells and cancer stem cells (CSCs) in the micromolar range. The palladium(ii) complex evokes CSC apoptosis by entering CSC nuclei and damaging genomic DNA.

A reactive oxygen species-generating, cancer stem cell-potent manganese(ii) complex and its encapsulation into polymeric nanoparticles.

Intracellular redox modulation offers a viable approach to effectively remove cancer stem cells (CSCs), a subpopulation of tumour cells thought to be responsible for cancer recurrence and metastasis. Here we report the breast CSC potency of reactive oxygen species (ROS)-generating manganese(ii)- and copper(ii)-4,7-diphenyl-1,10-phenanthroline complexes bearing diclofenac, a nonsteriodial anti-inflammatory drug (NSAID), and . Notably, the manganese(ii) complex, , exhibits 9-fold, 31-fold, and 40-fold greater potency towards breast CSCs than , salinomycin (an established breast CSC-potent agent), and cisplatin (a clinically approved anticancer drug) respectively.

A Triangular Platinum(II) Multinuclear Complex with Cytotoxicity Towards Breast Cancer Stem Cells.

The preparation of multinuclear metal complexes offers a route to novel anticancer agents and delivery systems. The potency of a novel triangular multinuclear complex containing three platinum atoms, Pt-3, towards breast cancer stem cells (CSCs) is reported. The trinuclear platinum(II) complex, Pt-3 exhibits selective toxicity towards breast CSCs over bulk breast cancer cells and non-tumorigenic breast cells.

Modulating the Chemical and Biological Properties of Cancer Stem Cell-Potent Copper(II)-Nonsteroidal Anti-Inflammatory Drug Complexes.

Copper(II) complexes bearing nonsteroidal anti-inflammatory drugs (NSAIDs) are known to potently kill cancer stem cells (CSCs), a subpopulation of tumour cells with high metastatic and relapse fidelity. One of the major disadvantages associated to these copper(II) complexes is their instability in the presence of strong cellular reductants (such as ascorbic acid). Here we present a biologically stable copper(II)-NSAID complex containing a bathocuproinedisulfonic acid disodium ligand and two indomethacin moieties, Cu(bathocuproinedisulfonic acid disodium)(indomethacin), .

Biophysical analysis of cancer stem cell-potent copper(ii) coordination complexes.

Copper(ii) coordination complexes, 1 and 2, containing nonsteroidal anti-inflammatory drugs (NSAIDs) potently kill breast cancer stem cells (CSCs) and bulk breast cancer cells. Although detailed biological studies have been conducted to shed light on their mechanism of cytotoxicity, little is known about their molecular level mechanism of action. This biophysical study, aided by the preparation of a fluorophore-containing analogue, 3, reveals that the complexes operate by undergoing reduction to a copper(i) form and releasing the associated NSAIDs.

Diflunisal-adjoined cobalt(iii)-polypyridyl complexes as anti-cancer stem cell agents.

We report a novel series of cobalt(iii)-polypridyl complexes, 4-6, that can selectively release diflunisal, a nonsteroidal anti-inflammatory drug, under reducing conditions. Remarkably, the 1,10-phenanthroline-bearing complex 5 displays selective potency towards hard-to-kill cancer stem cells (CSCs) (IC50 = 2.1 ± 0.

Polypyridyl Zinc(II)-Indomethacin Complexes with Potent Anti-Breast Cancer Stem Cell Activity.

Cancer stem cells (CSCs) are thought of as a clinically pertinent subpopulation of tumors, partly responsible for cancer relapse and metastasis. Research programs aimed at discovering anti-CSC agents have largely focused on biologics and purely organic molecules. Recently, we showed that a family of redox-active copper(II) complexes with phenanthroline-based ligands and nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, are capable of potently and selectively killing breast CSCs.

Highly Charged, Cytotoxic, Cyclometalated Iridium(III) Complexes as Cancer Stem Cell Mitochondriotropics.

The cancer stem cell (CSC) toxicity and mechanism of action of a series of iridium(III) complexes bearing polypridyl and charged 1-methyl-2-(2-pyridyl)pyridinium ligands, 1-4 is reported. The most effective complex (containing 1,10-phenanthroline), 3, kills CSCs and bulk cancer cells with equal potency (in the micromolar range), indicating that it could potentially remove heterogenous tumour populations with a single dose. Encouragingly, 3 also inhibits mammopshere formation to a similar extent as salinomycin, a well-established anti-CSC agent.

Synthesis, characterization, and cytotoxic properties of mono- and di-nuclear cobalt(ii)-polypyridyl complexes.

We report the synthesis and characterisation of mono- and di-nuclear cobalt(ii) complexes (1-3) containing L1, a polypyridyl ligand with pyrazole moieties. DNA binding studies suggest that the mono-nuclear complex, 1, binds to DNA via the grooves prior to inducing oxidative DNA cleavage whereas the larger di-nuclear complexes, 2 and 3, bind to DNA via the grooves and through intercalation prior to inducing oxidative DNA cleavage. The cobalt(ii) complexes display micromolar potency towards U2OS (bone osteosarcoma), HepG2 (liver hepatocellular carcinoma), and GM05757 (normal human fibroblast) cells, comparable to clinically used platinum agents, cisplatin and carboplatin.

A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells.

The breast cancer stem cell (CSC) and bulk breast cancer cell potency of a series of metallopeptides containing dichloro(1,10-phenanthroline)copper(II) and various organelle-targeting peptide sequences is reported. The mitochondria-targeting metallopeptide 1 exploits the higher mitochondrial load in breast CSCs over the corresponding non-CSCs and the vulnerability of breast CSCs to mitochondrial damage to potently and selectively kill breast CSCs. Strikingly, 1 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC-potent agent.

Cancer Stem Cell and Bulk Cancer Cell Active Copper(II) Complexes with Vanillin Schiff Base Derivatives and Naproxen.

Four copper(II) complexes, 1-4 containing regioisomeric vanillin Schiff base derivatives and the nonsteroidal anti-inflammatory drug (NSAID), naproxen, were synthesised and characterised. All complexes effectively cleave DNA in cell-free systems, with 4 displaying the highest nuclease activity. DNA binding studies suggest that 4 binds to DNA via the grooves prior to inducing oxidative DNA cleavage.

Induction of Necroptosis in Cancer Stem Cells using a Nickel(II)-Dithiocarbamate Phenanthroline Complex.

The cytotoxic properties of a series of nickel(II)-dithiocarbamate phenanthroline complexes is reported. The complexes 1-6 kill bulk cancer cells and cancer stem cells (CSCs) with micromolar potency. Two of the complexes, 2 and 6, kill twice as many breast cancer stem cell (CSC)-enriched HMLER-shEcad cells as compared to breast CSC-depleted HMLER cells.

The breast cancer stem cell potency of copper(ii) complexes bearing nonsteroidal anti-inflammatory drugs and their encapsulation using polymeric nanoparticles.

We report the cancer stem cell (CSC) potency of a novel series of copper(ii)-phenanthroline complexes bearing nonsteriodial anti-inflammatory drugs: naproxen, tolfenamic acid, and indomethacin (2a-3c). Two of the complexes, 2a and 3c, kill breast CSC-enriched HMLER-shEcad cells (grown in both monolayer and three-dimensional cell cultures) to a significantly better extent than salinomycin, a well-established CSC toxin. The most potent complex in the series, 3c induces its cytotoxic effect by generating intracellular reactive oxygen species (ROS) and inhibiting cyclooxgenase-2 (COX-2) activity.

The Potent Inhibitory Effect of a Naproxen-Appended Cobalt(III)-Cyclam Complex on Cancer Stem Cells.

We report the potency against cancer stem cells (CSCs) of a new cobalt(III)-cyclam complex (1) that bears the nonsteroidal anti-inflammatory drug, naproxen. The complex displays selective potency for breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells. Additionally, it inhibited the formation of three-dimensional tumour-like mammospheres, and reduced their viability to a greater extent than clinically used breast cancer drugs (vinorelbine, cisplatin and paclitaxel).