RESUMO
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.
RESUMO
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.
Assuntos
Antineoplásicos , Apoptose , Complexos de Coordenação , Rênio , Rênio/química , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacosRESUMO
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.
RESUMO
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.
Assuntos
Antineoplásicos , Apoptose , Complexos de Coordenação , Cobre , Ensaios de Seleção de Medicamentos Antitumorais , Piridinas , Espécies Reativas de Oxigênio , Humanos , Piridinas/química , Piridinas/farmacologia , Cobre/química , Cobre/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Due to cell mutation and self-adaptation, the application of clinical drugs with early epidermal growth factor receptor (EGFR)-targeted inhibitors is severely limited. To overcome this limitation, herein, the synthesis and in-depth biological evaluation of an erlotinib-platinum(II) complex as an EGFR-targeted anticancer agent is reported. The metal complex is able to self-assemble inside an aqueous solution and readily form nanostructures with strong photophysical properties. While being poorly toxic toward healthy cells and upon treatment in the dark, the compound was able to induce a cytotoxic effect in the very low micromolar range upon irradiation against EGFR overexpressing (drug resistant) human lung cancer cells as well as multicellular tumor spheroids. Mechanistic insights revealed that the compound was able to selectively degrade the EGFR using the lysosomal degradation pathway upon generation of singlet oxygen at the EGFR. We are confident that this work will open new avenues for the treatment of EGFR-overexpressing tumors.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Fotoquimioterapia , Humanos , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Platina/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/patologia , Receptores ErbB/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular TumoralRESUMO
Nanomaterials have attractive physicochemical properties. A variety of nanomaterials such as inorganic, lipid, polymers, and protein nanoparticles have been widely developed for nanomedicine via chemical conjugation or physical encapsulation of bioactive molecules. Superior to traditional drugs, nanomedicines offer high biocompatibility, good water solubility, long blood circulation times, and tumor-targeting properties. Capitalizing on this, several nanoformulations have already been clinically approved and many others are currently being studied in clinical trials. Despite their undoubtful success, the molecular mechanism of action of the vast majority of nanomedicines remains poorly understood. To tackle this limitation, herein, this review critically discusses the strategy of applying multiomics analysis to study the mechanism of action of nanomedicines, named nanomedomics, including advantages, applications, and future directions. A comprehensive understanding of the molecular mechanism could provide valuable insight and therefore foster the development and clinical translation of nanomedicines.
Assuntos
Nanomedicina , Humanos , Animais , Nanoestruturas/química , GenômicaRESUMO
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.
Assuntos
Antineoplásicos , Compostos de Boro , Raios Infravermelhos , Irídio , Nanopartículas , Polímeros , Nanopartículas/química , Humanos , Animais , Compostos de Boro/química , Compostos de Boro/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Irídio/química , Polímeros/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Feminino , Camundongos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Fotoquimioterapia/métodos , Células HeLa , Camundongos NusRESUMO
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.
Assuntos
Antineoplásicos , Fluorocarbonos , Imunoterapia , Albumina Sérica Humana , Fluorocarbonos/química , Fluorocarbonos/farmacologia , Humanos , Animais , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Albumina Sérica Humana/química , Cisplatino/farmacologia , Cisplatino/química , Linhagem Celular Tumoral , Nanopartículas/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Proliferação de Células/efeitos dos fármacos , Platina/química , Platina/farmacologia , Camundongos Endogâmicos BALB C , Morte Celular Imunogênica/efeitos dos fármacosRESUMO
Cancer cells have a strategically optimized metabolism and tumor microenvironment for rapid proliferation and growth. Increasing research efforts have been focused on developing therapeutic agents that specifically target the metabolism of cancer cells. In this work, we prepared 1-methyl-4-phenylpyridinium-functionalized Ir(iii) complexes that selectively localize in the mitochondria and generate singlet oxygen and superoxide anion radicals upon two-photon irradiation. The generation of this oxidative stress leads to the disruption of the mitochondrial respiratory chain and therefore the disturbance of mitochondrial oxidative phosphorylation and glycolysis metabolisms, triggering cell death by combining immunogenic cell death and ferritinophagy. To the best of our knowledge, this latter is reported for the first time in the context of photodynamic therapy (PDT). To provide cancer selectivity, the best compound of this work was encapsulated within exosomes to form tumor-targeted nanoparticles. Treatment of the primary tumor of mice with two-photon irradiation (720 nm) 24 h after injection of the nanoparticles in the tail vein stops the primary tumor progression and almost completely inhibits the growth of distant tumors that were not irradiated. Our compound is a promising photosensitizer that efficiently disrupts the mitochondrial respiratory chain and induces ferritinophagy-mediated long-term immunotherapy.
RESUMO
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.