Ferroptosis Inducing Co(III) Polypyridine Sulfasalazine Complex for Therapeutically Enhanced Anticancer Therapy.

Despite significant improvements in the treatment of cancerous tumors in the last decades, cancer remains one of the deadliest diseases worldwide. To overcome the shortcomings of currently applied chemotherapeutic treatments, much research efforts have been devoted towards the development of ferroptosis inducing anticancer agents. Ferroptosis is a newly described form of regulated, non-apoptotic cell death that is associated with high potential inside the clinics. Herein, the chemical synthesis and biological evaluation of a Co(III) polypyridine sulfasalazine as a ferroptosis inducer is reported. Upon entering the cancerous cells, the metal complex primarily accumulated in the mitochondria, triggering the production of hydroxy radicals and lipid peroxides, ultimately causing cell death by ferroptosis. The compound demonstrated to eradicate various monolayer cancer cells as well as colon carcinoma multicellular tumor spheroids. To the best of our knowledge this study reports on the first example of a Co(III) complex that is capable of inducing ferroptosis.

Cobalt(III) prodrug-based nanomedicine for inducing immunogenic cell death and enhancing chemo-immunotherapy.

Despite impressive advances in immune checkpoint blockade therapy, its efficacy as a standalone treatment remains limited. The influence of chemotherapeutic agents on tumor immunotherapy has progressively come to light in recent years, positioning them as promising contenders in the realm of combination therapy options for tumor immunotherapy. Herein, we present the rational design, synthesis, and biological evaluation of the first example of a Co(III) prodrug (Co2) capable of eliciting a localized cytotoxic effect while simultaneously inducing a systemic immune response via type II immunogenic cell death (ICD). To enhance its pharmacological properties, a glutathione-sensitive polymer was synthesized, and Co2 was encapsulated into polymeric nanoparticles (NP-Co2) to improve efficacy. Furthermore, NP-Co2 activates the GRP78/p-PERK/p-eIF2α/CHOP pathway, thereby inducing ICD in cancer cells. This facilitates the transformation of "cold tumors" into "hot tumors" and augments the effectiveness of the PD-1 monoclonal antibody (αPD-1). In essence, this nanomedicine, utilizing Co(III) prodrugs to induce ICD, provides a promising strategy to enhance chemotherapy and αPD-1 antibody-mediated cancer immunotherapy.

Encapsulation of Cu(II) Terpyridine Complexes into Polymeric Nanoparticles for Enhanced Anticancer Therapy.

Cancer is one of the deadliest diseases worldwide. One of the most commonly applied therapeutic techniques to combat this disease is chemotherapy. Despite its success, the majority of clinically applied chemotherapeutic agents are associated with strong side effects and drug resistance. To overcome this limitation, much research efforts are devoted toward the development of new anticancer agents. Among the most promising class of compounds, Cu(II) complexes have emerged. Despite their strong cytotoxic effect, these agents are typically associated with low water solubility, low stability, and poor tumor selectivity. To overcome these limitations, herein, we report on the encapsulation of a promising Cu(II) terpyridine complex with the Pluronic F-127/Poloxamer-407 polymeric carrier into nanoparticles. Besides overcoming the pharmacological drawbacks, the nanoparticles were able to eradicate human breast adenocarcinoma monolayer cells as well as challenging multicellular tumor spheroids at nanomolar concentrations.

Endowing Pt(IV) with Perfluorocarbon Chains and Human Serum Albumin Encapsulation for Highly Effective Antitumor Chemoimmunotherapy.

Tumor metastases and reoccurrence are considered the leading causes of cancer-associated deaths. As an emerging therapeutic method, increasing research efforts have been devoted to immunogenic cell death (ICD)-inducing compounds to solve the challenge. The clinically approved chemotherapeutic Pt complexes are not or are only poorly able to trigger ICD. Herein, the axial functionalization of the Pt(II) complex cisplatin with perfluorocarbon chains into ICD-inducing Pt(IV) prodrugs is reported. Strikingly, while the Pt(II) complex as well as the perfluorocarbon ligands did not induce ICD, the Pt(IV) prodrug demonstrated unexpectantly the induction of ICD through accumulation in the endoplasmic reticulum and generation of reactive oxygen species in this organelle. To enhance the pharmacological properties, the compound was encapsulated with human serum albumin into nanoparticles. While selectively accumulating in the tumorous tissue, the nanoparticles demonstrated a strong tumor growth inhibitory effect against osteosarcoma inside a mouse model. In vivo tumor vaccine analysis also demonstrated the ability of Pt(IV) to be an ideal ICD inducer. Overall, this study reports on axially perfluorocarbon chain-modified Pt(IV) complexes for ICD induction and chemoimmunotherapy in osteosarcoma.

Facile one-pot synthesis of Ir(III) Bodipy polymeric gemini nanoparticles for tumor selective NIR photoactivated anticancer therapy.

Over the last decades, a variety of metal complexes have been developed as chemotherapeutic agents. Despite the promising therapeutic prospects, the vast majority of these compounds suffer from low solubility, poor pharmacological properties, and most importantly poor tumor accumulation. To circumvent these limitations, herein, the incorporation of cytotoxic Ir(III) complexes and a variety of photosensitizers into polymeric gemini nanoparticles that selectively accumulate in the tumorous tissue and could be activated by near-infrared (NIR) light to exert an anticancer effect is reported. Upon exposure to light, the photosensitizer is able to generate singlet oxygen, triggering the rapid dissociation of the nanostructure and the activation of the Ir prodrug, thereby initiating a cascade of mitochondrial targeting and damage that ultimately leads to cell apoptosis. While selectively accumulating into tumorous tissue, the nanoparticles achieve almost complete eradication of the cisplatin-resistant cervical carcinoma tumor in vivo upon exposure to NIR irradiation.

Highly cytotoxic Cu(II) terpyridine complexes as chemotherapeutic agents.

Cancer is considered as the biggest medicinal challenge worldwide. During a typical treatment, the tumorous tissue is removed in a surgical procedure and the patient further treated by chemotherapy. One of the most frequently applied drugs are platinum complexes. Despite their clinical success, these compounds are associated with severe side effects and low therapeutic efficiency. To overcome these limitations, herein, the synthesis and biological evaluation of Cu(II) terpyridine complexes as chemotherapeutic drug candidates is suggested. The compounds were found to be highly cytotoxic in the nanomolar range against various cancer cell lines. Mechanistic insights revealed that the compounds primarily accumulated in the cytoplasm and generated reactive oxygen species in this organelle, triggering cell death by apoptosis. Based on their high therapeutic effect, these metal complexes could serve as a starting point for further drug development.

Dinuclear Rhenium(I) Tricarbonyl Complexes as Anticancer Drug Candidates.

Cancer is one of the deadliest diseases worldwide. Chemotherapy remains one of the most dominant forms for anticancer treatment. Despite their clinical success, the used chemotherapeutic agents are associated with severe side effect and pharmacological limitations. To overcome these drawbacks there is a need for the development of new types of chemotherapeutic agents. Herein, the chemical synthesis and biological evaluation of dinuclear rhenium(I) complexes as potential chemotherapeutic drug candidates are proposed. The metal complexes were found to be internalized by an energy dependent endocytosis pathway, primary accumulating in the mitochondria. The rhenium(I) complexes demonstrated to induce cell death against a variety of cancer cells in the micromolar range through apoptosis. The lead compound showed to eradicate a pancreatic carcinoma multicellular tumor spheroid at micromolar concentrations.

Reduction of Platinum(IV) Prodrug Hemoglobin Nanoparticles with Deeply Penetrating Ultrasound Radiation for Tumor-Targeted Therapeutically Enhanced Anticancer Therapy.

The development of PtIV prodrugs that are reduced into the therapeutically active PtII species within the tumor microenvironment has received much research interest. In order to provide spatial and temporal control over the treatment, there is a high demand for the development of compounds that could be selectively activated upon irradiation. Despite recent progress, the majority of PtIV complexes are excited with ultraviolet or blue light, limiting the use of such compounds to superficial application. To overcome this limitation, herein, the first example of PtIV prodrug nanoparticles that could be reduced with deeply penetrating ultrasound radiation is reported, enabling the treatment of deep-seated or large tumors. The nanoparticles were found to selectively accumulate inside a mouse colon carcinoma tumor upon intravenous injection and were able to eradicate the tumor upon exposure to ultrasound radiation.

Immunogenic Cell Death Inducing Metal Complexes for Cancer Therapy.

Cancer is one of the deadliest diseases worldwide. Recent statistics have shown that metastases and tumor relapse are the leading causes of cancer-associated deaths. While traditional treatments are able to efficiently remove the primary tumor, secondary tumors remain poorly accessible. Capitalizing on this there is an urgent need for novel treatment modalities. Among the most promising approaches, increasing research interest has been devoted to immunogenic cell death inducing agents that are able to trigger localized cell death of the cancer cells as well as induce an immune response inside the whole organism. Preliminary studies have shown that immunogenic cell death inducing compounds could be able to overcome metastatic and relapsing tumors. Herein, the application of metal complexes as immunogenic cell death inducing compounds is systematically reviewed.

Inhibitors of lipogenic enzymes as a potential therapy against cancer.

Cancer cells rely on several metabolic pathways such as lipid metabolism to meet the increase in energy demand, cell division, and growth and successfully adapt to challenging environments. Fatty acid synthesis is therefore commonly enhanced in many cancer cell lines. Thus, relevant efforts are being made by the scientific community to inhibit the enzymes involved in lipid metabolism to disrupt cancer cell proliferation. We review the rapidly expanding body of inhibitors that target lipid metabolism, their side effects, and current status in clinical trials as potential therapeutic approaches against cancer. We focus on their molecular, biochemical and structural properties, selectivity and effectiveness and discuss their potential role as antitumor drugs.