RESUMEN
The toxicity of drugs causes various adverse effects in patients. While antidotes that neutralize drug toxicity help reduce systemic damage during clinical therapy, these antidotes are generally accompanied by the loss of drug efficacy. Herein, the spatiotemporally targeted polycystine-based nanoantidotes were designed as a neutralizer of cisplatin (CDDP) to decrease its toxicity without affecting its anticancer efficacy. The nanoantidotes administered before CDDP selectively accumulated in the liver and kidney and then firmly bound to CDDP through the highly stable Pt-S bond during subsequent chemotherapy. This two-step administration strategy reduced the level of Pt in normal organs, shortened the half-life of CDDP in plasma, and increased the tolerance to CDDP. More importantly, the nanoantidotes maintained the anticancer efficacy of CDDP after reducing systemic toxicity, indicating its great potential in expanding the clinical application of CDDP.
Asunto(s)
Antineoplásicos , Cisplatino , Humanos , Antineoplásicos/farmacología , Antineoplásicos/metabolismo , Antídotos/metabolismo , Antídotos/farmacología , Riñón/metabolismo , Péptidos/farmacología , Péptidos/metabolismoRESUMEN
Understanding the biomolecular interactions in a specific organelle has been a long-standing challenge because it requires super-resolution imaging to resolve the spatial locations and dynamic interactions of multiple biomacromolecules. Two key difficulties are the scarcity of suitable probes for super-resolution nanoscopy and the complications that arise from the use of multiple probes. Herein, we report a quinolinium derivative probe that is selectively enriched in mitochondria and switches on in three different fluorescence modes in response to hydrogen peroxide (H2 O2 ), proteins, and nucleic acids, enabling the visualization of mitochondrial nucleoprotein dynamics. STED nanoscopy reveals that the proteins localize at mitochondrial cristae and largely fuse with nucleic acids to form nucleoproteins, whereas increasing H2 O2 level leads to disassociation of nucleic acid-protein complexes.
Asunto(s)
Colorantes Fluorescentes/química , Mitocondrias/metabolismo , Proteínas Nucleares/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Células Hep G2 , Humanos , Peróxido de Hidrógeno/metabolismo , Ácidos Nucleicos/metabolismoRESUMEN
The interplay between the tumor cells and their microenvironments is as inseparable as the relationship between "seeds" and "soil." The tumor microenvironments (TMEs) exacerbate malignancy by enriching malignant cell subclones, generating extracellular matrices, and recruiting immunosuppressive cells, thereby diminishing the efficacy of clinical therapies. Modulating TMEs has emerged as a promising strategy to enhance cancer therapy. However, the existing drugs used in clinical settings do not target the TMEs specifically, underscoring the urgent need for advanced strategies. Bioactive materials present unique opportunities for modulating TMEs. Poly(amino acid)s with precisely controllable structures and properties offer exceptional characteristics, such as diverse structural units, excellent biosafety, ease of modification, sensitive biological responsiveness, and unique secondary structures. These attributes hold significant potential for the modulation of TMEs and clinical applications further. Consequently, developing bioactive poly(amino acid)s capable of modulating the TMEs by elucidating structure-activity relationships and mechanisms is a promising approach for innovative clinical oncology therapy. This review summarizes the recent progress of our research team in developing bioactive poly(amino acid)s for multi-modal tumor therapy. First, a brief overview of poly(amino acid) synthesis and their advantages as nanocarriers is provided. Subsequently, the pioneering research of our research group on synthesizing the biologically responsive, dynamically allosteric, and immunologically effective poly(amino acid)s are highlighted. These poly(amino acid)s are designed to enhance tumor therapy by modulating the intracellular, extracellular matrix, and stromal cell microenvironments. Finally, the future development of poly(amino acid)s is discussed. This review will guide and inspire the construction of bioactive poly(amino acid)s with promising clinical applications in cancer therapy. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Biology-Inspired Nanomaterials > Peptide-Based Structures.
Asunto(s)
Aminoácidos , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/tratamiento farmacológico , Aminoácidos/química , Aminoácidos/uso terapéutico , Animales , Microambiente Tumoral/efectos de los fármacos , Ratones , Polímeros/química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Traditional hepatocellular carcinoma-chip models lack the cell structure and microenvironments necessary for high pathophysiological correlation, leading to low accuracy in predicting drug efficacy and high production costs. This study proposed a decellularized hepatocellular carcinoma-on-a-chip model to screen anti-tumor nanomedicine. In this model, human hepatocellular carcinoma (HepG2) and human normal liver cells (L02) were co-cultured on a three-dimensional (3D) decellularized extracellular matrix (dECM) in vitro to mimic the tumor microenvironments of human hepatocellular carcinoma in vivo. Additionally, a smart nanomedicine was developed by encapsulating doxorubicin (DOX) into the ferric oxide (Fe3O4)-incorporated liposome nanovesicle (NLV/Fe+DOX). NLV/Fe+DOX selectively killed 78.59% ± 6.78% of HepG2 cells through targeted delivery and synergistic chemo-chemodynamic-photothermal therapies, while the viability of surrounding L02 cells on the chip model retained high, at over 90.0%. The drug efficacy tested using this unique chip model correlated well with the results of cellular and animal experiments. In summary, our proposed hepatocellular carcinoma-chip model is a low-cost yet accurate drug-testing platform with significant potential for drug screening.
RESUMEN
A ratiometric fluorescent probe with a large emission shift was developed for the accurate measurement of hydrogen peroxide (H2O2) in sophisticated pyroptosis signaling pathways. The results reported here demonstrate that H2O2, as a principal member of ROS, is a critical upstream signaling molecule in regulating pyroptosis.
Asunto(s)
Colorantes Fluorescentes/metabolismo , Peróxido de Hidrógeno/metabolismo , Piroptosis , Transducción de Señal , Línea Celular , Supervivencia Celular , HumanosRESUMEN
Recent advancements in super-resolution nanoscopy allowed the study of mitochondrial biology at nanoscale and boosted the understanding its correlated cellular processes those were previously poorly understood. Nevertheless, studying mitochondrial ultrastructure remains a challenge due to the lack of probes that could target specific mitochondrial substances (e.g. cristae or mtDNA) and survive under harsh super-resolution optical conditions. Herein, in this work, we have rationally constructed a pyridine-BODIPY (Py-BODIPY) derivative that could target mitochondrial membrane in living cells without interfering its physiological microenvironments. Furthermore, we found Py-BODIPY is a membrane potential independent probe, hence it is not limit to live-cell staining but also showed a strong internalization into pre-fixed and stimulus disrupted sample. Importantly, its cristae specificity and superb photostability allow the observation of mitochondrial dynamic nano-structures with an unprecedented resolution, allow demonstrating how mitochondrial 3D ultrastructure evolved under oxidative phosphorylation condition.
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Técnicas Biosensibles , Dinámicas Mitocondriales , Compuestos de Boro , Humanos , Fosforilación Oxidativa , PiridinasRESUMEN
We report on new types of chitosan-based nanogels via an ortho ester-based linkage, used as drug carriers for efficient chemotherapy. First, we synthesized a novel diacrylamide containing ortho ester (OEAM) as an acid-labile cross-linker. Subsequently, methacrylated succinyl-chitosan (MASCS) was prepared and polymerized with OEAM at different molar ratios to give a series of pH-triggered MASCS nanogels. Doxorubicin (DOX) as a model anticancer drug was loaded into MASCS nanogels with a loading content of 16.5%. As expected, with the incorporation of ortho ester linkages, these nanogels showed pH-triggered degradation and drug release at acidic pH values. In vitro cellular uptake shows that the DOX-loaded nanogels could be preferentially internalized by two-dimensional (2D) cells and three-dimensional (3D) multicellular spheroids (MCs), resulting in higher inhibition of the proliferation of tumor cells. In vivo biodistribution and anti-tumor effect were determined in H22 tumor-bearing mice, and the results demonstrate that the acid-labile MASCS nanogels can significantly prolong the blood circulation time of DOX and improve the accumulation in tumor areas, leading to higher therapeutic efficacy. STATEMENT OF SIGNIFICANCE: We designed new pH-triggered chitosan nanogels via an ortho ester-based cross-linker for efficient drug-loading and chemotherapy. These drug-loaded nanogels exhibit excellent pH-triggered drug release behavior due to the degradation of ortho ester linkages in mildly acidic environments. In vitro and in vivo results demonstrate that the nanogels could be efficiently internalized by 2D cells and 3D-MCs, improve drug concentration in solid tumors, and lead to higher therapeutic efficacy. To the best of our knowledge, this is the first report on using an ortho ester-based cross-linker to prepare pH-triggered chitosan nanogels as tumor carriers, which may provide a potential route for improved safety and to increase the therapeutic efficacy of anticancer therapy.
Asunto(s)
Quitosano , Doxorrubicina , Nanopartículas , Neoplasias Experimentales/tratamiento farmacológico , Animales , Quitosano/química , Quitosano/farmacocinética , Quitosano/farmacología , Reactivos de Enlaces Cruzados/química , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Células Hep G2 , Humanos , Hidrogeles/química , Hidrogeles/farmacología , Concentración de Iones de Hidrógeno , Ratones , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A new type of pH-triggered hyaluronic acid nanogel system (HA-NGs) was successfully developed for tumor-targeted delivery of drugs. HA-NGs were obtained by copolymerization between methacrylate HA and a new cross-linker containing ortho ester groups in an aqueous solution. The therapeutic drug (DOX) was loaded into the HA-NGs (DOX@HA-NGs) and exhibited appropriate loading of about 17.3% with a size of around 200nm. Such new pH-triggered HA-NGs are found to be highly desirable for targeted cancer therapy because it could significantly minimize the amount of premature drug release in neutral pH, and also provide a sufficient amount of drug to effectively kill the cancer cells caused by the degradation of ortho ester groups at acid pH values. Results from the cellular uptake and cytotoxicity of DOX@HA-NGs performed in two-dimensional (2D) cell culture demonstrated that DOX@HA-NGs exhibit excellent tumor homing and higher cytotoxicity. Importantly, the penetration and inhibition against three-dimensional (3D) tumor spheroids demonstrated that DOX@HA-NGs could fully penetrate into HepG2 tumor spheroids, thus leading to higher inhibition. So, such new tumor-targeting DOX@HA-NGs prepared via ortho ester linkages will exhibit excellent stability in a neutral environment, pH-triggered drug release, as well as enhanced penetration and destruction against 3D tumor spheroids, thereby making targeted cancer therapy possible.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Preparaciones de Acción Retardada/química , Doxorrubicina/administración & dosificación , Geles/química , Ácido Hialurónico/química , Nanoestructuras/química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Esterificación , Humanos , Concentración de Iones de Hidrógeno , Neoplasias/tratamiento farmacológico , Esferoides Celulares , Células Tumorales CultivadasRESUMEN
This work describes an acid-degradable and tumor-targeted nanogels prepared by the copolymerization between lactobionic acid-modified methacrylated carboxymethyl chitosan and acid-labile methacrylated orthoester-based monomers. The size distribution and micromorphology of the prepared nanogels were observed by dynamic light scattering, transmission electron microscopy and scanning electron microscopy. The stability of nanogels in various environments was then investigated. Doxorubicin as a model drug was successfully encapsulated into nanogels. In vitro cellular uptake and MTT results indicate that the tumor-targeting and pH-sensitive nanogels display higher cellular internalization and cytotoxicity than non-target nanogels and free DOX. The improved penetration and growth inhibition against 3-D multicellular spheroids further demonstrate that the dual-functional nanogels may be a potential nano-carrier for drug delivery in cancer therapy.
Asunto(s)
Polietilenglicoles/química , Polietileneimina/química , Quitosano , Doxorrubicina , Humanos , Nanogeles , NeoplasiasRESUMEN
To promote drug accumulation and cell-killing ability at tumor tissue, we have prepared a stepwise targeted drug delivery system that can remain stealthy and long-circulating in the blood vessels, improve drug retention at extracellular stimuli, enhance cellular uptake through special targeting ligands, and then achieve rapid drug release to improve toxicity to tumor cells at intracellular stimuli. Herein, galactose-grafted, ultra-pH-sensitive drug carriers (POEAd-g-LA-DOX micelles), which could respond to both extracellular and intracellular pH, and combine with galactose-receptors in cell membrane, were constructed by a facile method, therefore achieving: (i) remaining stable at pH 7.4; (ii) responding to tumoral extracellular pH following gradually larger nanoparticles (NPs); (iii) conjugating receptors in the cell membrane of liver cancer through surface galactose-ligands of micelles; (iv) being sensitive to tumoral intracellular pH following further swelling for rapid drug release. In vitro cytotoxicity and cellular uptake measurement showed that POEAd-g-LA20-DOX micelle was more easily internalized and more toxic effect on tumor cells than free DOX. Moreover, in vivo biodistribution and tumor inhibition examinations demonstrated that POEAd-g-LA20-DOX formulation had more superior efficacy to significantly enhance drug accumulation in tumor, and then restrain tumor growth while decreasing drug concentration in heart. STATEMENT OF SIGNIFICANCE: Chemotherapeutic efficacy is limited by poor tumor selectivity, which also causes severe toxicity in normal tissues and organs, although many targeted drug delivery systems have been developed by passive targeting strategies or active targeting strategies with specific targeting ligands in recent years. Herein, galactose-grafted, ultra-pH-sensitive, ortho ester-based drug carriers, which can respond to both extracellular and intracellular pH, and target to galactose-receptors in cell membrane, have been successfully constructed by facile method, therefore achieving stepwise targeting to microenvironment of liver cancer and then enhancing drug accumulation and tumor inhibition. The strategy of designing dual-stimuli-responsive copolymers can be potentially useful, and extrapolated to synthesizing other categories of highly labile drug carriers in a range of biomedical applications.