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Vincristine (VCR), an effective antitumor drug, has been utilized in several polytherapy regimens for acute lymphoblastic leukemia, neuroblastoma and rhabdomyosarcoma. However, clinical evidence shows that the metabolism of VCR varies greatly among patients. The traditional based body surface area (BSA) administration method is prone to insufficient exposure to VCR or severe VCR-induced peripheral neurotoxicity (VIPN). Therefore, reliable strategies are urgently needed to improve efficacy and reduce VIPN. Due to the unpredictable pharmacokinetic changes of VCR, therapeutic drug monitoring (TDM) may help to ensure its efficacy and to manage VIPN. At present, there is a lot of supporting evidence for the suitability of applying TDM to VCR therapy. Based on the consensus guidelines drafted by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), this review aimed to summarize various available data to evaluate the potential utility of VCR TDM for cancer patients. Of note, valuable evidence has accumulated on pharmacokinetics variability, pharmacodynamics, drug exposure-clinical response relationship, biomarkers for VIPN prediction, and assays for VCR monitoring. However, there are still many relevant clinical pharmacological questions that cannot yet be answered merely based on insufficient evidence. Currently, we cannot recommend a therapeutic exposure range and cannot yet provide a dose-adaptation strategy for clinicians and patients. In areas where the evidence is not yet sufficient, more research is needed in the future. The precision medicine of VCR cannot rely on TDM alone and needs to consider the clinical, environmental, genetic background and patient-specific factors as a whole.
Assuntos
Neuroblastoma , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Adulto , Vincristina/efeitos adversos , Monitoramento de Medicamentos , Medicina de PrecisãoRESUMO
The antitumor efficiency and clinical translation of traditional nanomedicines is mainly restricted by low drug loading, complex preparation technology, and potential toxicity caused by the overused carrier materials. In recent decades, small-molecule prodrug nanoassemblies (SMP-NAs), which are formed by the self-assembly of prodrugs themselves, have been widely investigated with distinct advantages of ultrahigh drug-loading and negligible excipients-trigged adverse reaction. Benefited from the simple preparation process, SMP-NAs are widely used for chemotherapy, phototherapy, immunotherapy, and tumor diagnosis. In addition, combination therapy based on the accurate co-delivery behavior of SMP-NAs can effectively address the challenges of tumor heterogeneity and multidrug resistance. Recent trends in SMP-NAs are outlined, and the corresponding self-assembly mechanisms are discussed in detail. Besides, the smart stimuli-responsive SMP-NAs and the combination therapy based on SMP-NAs are summarized, with special emphasis on the structure-function relationships. Finally, the outlooks and potential challenges of SMP-NAs in cancer therapy are highlighted.
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Antineoplásicos , Nanopartículas , Pró-Fármacos , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , NanomedicinaRESUMO
The efficacy of DNA-damaging agents, such as the topoisomerase I inhibitor SN38, is often compromised by the robust DNA repair mechanisms in tumor cells, notably homologous recombination (HR) repair. Addressing this challenge, we introduce a novel nano-strategy utilizing binary tumor-killing mechanisms to enhance the therapeutic impact of DNA damage and mitochondrial dysfunction in cancer treatment. Our approach employs a synergistic drug pair comprising SN38 and the BET inhibitor JQ-1. We synthesized two prodrugs by conjugating linoleic acid (LA) to SN38 and JQ-1 via a cinnamaldehyde thioacetal (CT) bond, facilitating co-delivery. These prodrugs co-assemble into a nanostructure, referred to as SJNP, in an optimal synergistic ratio. SJNP was validated for its efficacy at both the cellular and tissue levels, where it primarily disrupts the transcription factor protein BRD4. This disruption leads to downregulation of BRCA1 and RAD51, impairing the HR process and exacerbating DNA damage. Additionally, SJNP releases cinnamaldehyde (CA) upon CT linkage cleavage, elevating intracellular ROS levels in a self-amplifying manner and inducing ROS-mediated mitochondrial dysfunction. Our results indicate that SJNP effectively targets murine triple-negative breast cancer (TNBC) with minimal adverse toxicity, showcasing its potential as a formidable opponent in the fight against cancer.
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Acroleína , Camptotecina , Sistemas de Liberação de Medicamentos , Nanopartículas , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Nanopartículas/administração & dosagem , Nanopartículas/química , Animais , Humanos , Feminino , Linhagem Celular Tumoral , Acroleína/análogos & derivados , Acroleína/administração & dosagem , Acroleína/química , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Camptotecina/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Ácido Linoleico/química , Ácido Linoleico/administração & dosagem , Triazóis/administração & dosagem , Triazóis/farmacologia , Triazóis/química , Dano ao DNA/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Camundongos Nus , Camundongos , Proteínas de Ciclo Celular/metabolismo , Fatores de Transcrição/metabolismo , Inibidores da Topoisomerase I/administração & dosagem , Proteínas que Contêm Bromodomínio , AzepinasRESUMO
Owing to the unique DNA damaging cytotoxicity, platinum (Pt)-based chemotherapy has long been the first-line choice for clinical oncology. Unfortunately, Pt drugs are restricted by the severe dose-dependent toxicity and drug resistance. Correspondingly, Pt(IV) prodrugs are developed with the aim to improve the antitumor performance of Pt drugs. However, as "free" molecules, Pt(IV) prodrugs are still subject to unsatisfactory in vivo destiny and antitumor efficacy. Recently, Pt(IV) prodrug nanotherapeutics, inheriting both the merits of Pt(IV) prodrugs and nanotherapeutics, have emerged and demonstrated the promise to address the underexploited dilemma of Pt-based cancer therapy. Herein, we summarize the latest fronts of emerging Pt(IV) prodrug nanotherapeutics. First, the basic outlines of Pt(IV) prodrug nanotherapeutics are overviewed. Afterwards, how versatile Pt(IV) prodrug nanotherapeutics overcome the multiple biological barriers of antitumor drug delivery is introduced in detail. Moreover, advanced combination therapies based on multimodal Pt(IV) prodrug nanotherapeutics are discussed with special emphasis on the synergistic mechanisms. Finally, prospects and challenges of Pt(IV) prodrug nanotherapeutics for future clinical translation are spotlighted.
Assuntos
Neoplasias , Pró-Fármacos , Humanos , Pró-Fármacos/uso terapêutico , Neoplasias/tratamento farmacológico , Terapia Combinada , Sistemas de Liberação de Medicamentos , Oncologia , Platina/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: Heparanase is the only confirmed endoglycosidase that cleaves heparan sulfate (HS), a ubiquitous glycosaminoglycan with various essential roles in multiple pathological processes. Thus, the development of heparanase inhibitors has become an attractive strategy for drug discovery, especially in tumour therapy, in which HS mimetics are the most promising compounds. The various biological effects of heparanase also suggest a role for HS mimetics in many non-cancer indications, such as type 1 diabetes. However, the potential benefits of HS mimetics in obesity-related type 2 diabetes have not been elucidated. EXPERIMENTAL APPROACH: In this study, we investigated muparfostat (PI-88), a developed HS mimetic currently enrolled in Phase III clinical trials, in obese mouse models and in vitro cultured murine hepatocytes. KEY RESULTS: Daily administration of muparfostat for 4 weeks caused hyperlipidaemia and aggravated hepatic steatosis in obese mice models, but not in lean animals. In cultured hepatocytes, muparfostat did not alter lipid accumulation. Acute tests suggested that muparfostat binds to lipoprotein lipase in competition with HS on vascular endothelial cell surfaces, thereby reducing the degradation of circulating triglycerides by lipoprotein lipase and subsequent uptake of fatty acids into vascular endothelial cells and causing hyperlipidaemia. This hyperlipidaemia aggravates hepatic steatosis and causes liver injury in muparfostat-treated obese mice. CONCLUSIONS AND IMPLICATIONS: The binding activity of HS mimetics to lipoprotein lipase should be investigated as an additional pharmacological effect during heparanase inhibitor drug discovery. This study also provides novel evidence for an increased risk of drug-induced liver injury in obese individuals.
Assuntos
Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Animais , Camundongos , Células Endoteliais/metabolismo , Heparitina Sulfato , Lipase Lipoproteica/metabolismo , Camundongos ObesosRESUMO
Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.
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Electroactive aniline tetramer-spider silk composite fibers with high conductivity and mechanical strength were developed using a dip coating method. The fabricated spider silk composite fibers retain the high mechanical strength (0.92 GPa) and unique reversible relaxation-contraction behavior of spider dragline silks. The aniline tetramer modified on the silk surface imparted electroactive properties to the composite fibers. The color of aniline tetramer/spider silk composite fibers could be controlled by applying different pH values and voltages. Furthermore, the composite fiber's resistivity could reach 186 Ω m which can conduct electrical current to light LEDs. This study could provide a valuable guideline for developing highly-conductive electrochromic spider silks for use in E-textiles.
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The unique characteristics of the tumor microenvironment (TME) could be exploited to develop antitumor nanomedicine strategies. However, in many cases, the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity. Given the amplified characteristics of TME regulated by vascular disrupting agents (VDAs), nanomedicines may achieve unexpected improved efficacy. Herein, we fabricate platelet membrane-fusogenic liposomes (PML/DP&PPa), namely "platesomes", which actively load the hypoxia-activated pro-prodrug DMG-PR104A (DP) and physically encapsulate the photosensitizer pyropheophorbide a (PPa). Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate (CA4P), PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P. First, CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention (EPR) effect, and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa. Besides, CA4P-induced vascular occlusion inhibits oxygen supply, followed by photodynamic therapy-caused acute tumor hypoxia. This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis. Thus, such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation, and provides a preferable solution to high-efficiency cancer therapy.
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Indolizine derivatives have been reported for the treatment of numerous diseases. However, few studies were carried out for non-small cell lung cancer (NSCLC). We synthesized series of indolizine compounds. The results of MTT assay showed compound 8 (C8) markedly inhibited the proliferation of A549 cells, however, C8 (15, 30 µg/mL) had little cytotoxicity in other cell lines (SH-SY5Y, HepG2, and BEAS-2B cells), Hoechst staining and JC-1 staining showed that C8 induced changes in the nucleus morphology, increased the loss in mitochondrial membrane potential in A549 cells. The results of flow cytometry manifested that cell cycle of the cells was arrested in the G2 / M phase by C8, ROS levels and the proportion of apoptosis of cells increased. We performed western blotting analysis to detect the expression levels of apoptosis and cycle-related proteins. These results validated that the apoptosis of cells was triggered by endoplasmic reticulum stress (ERS) and the PI3K/Akt-mediated mitochondrial pathway collaboratively. Besides, the utilization of PI3K/Akt inhibitors and p53 inhibitors further proves the above argument and C8-induced cycle arrest of A549 cells is majorly regulated by p53. C8 induced the accumulation of ROS contents involved in mitochondrial damage. The proliferation of A549 cells was inhibited after treatment with the compound, which induced apoptosis and cycle arrest of cells. It is suggested that C8(dithiolation indolizine) is a potential candidate compound against non-small cell lung cancer.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Indolizinas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Antineoplásicos/síntese química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Hep G2 , Humanos , Indolizinas/síntese química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismoRESUMO
Prodrug nanoassemblies have emerged as a promising platform for the delivery of anticancer drugs. PEGylation is a "gold standard" to improve colloidal stability and pharmacokinetics of nanomedicines. However, the clinical application of PEG materials is challenged by in vivo oxidative degradation and immunogenicity. Rational design of advanced biomaterials for the surface modification of nanomedicines is the hot spot of research. Here, a zwitterionic sulfobetaine surfactant is constructed as a novel surface modifier to coassemble with 10-hydroxycamptothecin-linoleic acid conjugate, with the classical PEGylated material as control. Interestingly, both the type and ratio of surfactants have profound impacts on the molecular mechanisms of the assembly of prodrugs, thereby affecting the pharmaceutical properties. Compared with PEGylated spherical prodrug nanoassemblies, zwitterion-modified prodrug nanoassemblies have distinct rod shape and superhydrophilic surface, and exhibit potent antitumor activity due to the combination of multiple advantages in terms of colloidal stability, cellular uptake, and pharmacokinetics. The findings illustrate the crucial role of zwitterionic surfactants as the surface modifier in the determination of in vivo fate of the prodrug nanoassemblies, and pave the way for the development of advanced nanomedicines.
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Antineoplásicos , Nanopartículas , Pró-Fármacos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Nanomedicina , Pró-Fármacos/farmacologiaRESUMO
Photodynamic therapy (PDT) leads to tumor hypoxia which could be utilized for the activation of hypoxia-activated prodrugs (HAPs). However, conventional photosensitizer-loaded nanoformulations suffer from an aggregation-caused quenching (ACQ) effect, which limits the efficiency of PDT and synergistic therapy. Herein, prodrug-nanoparticles (NPs) are prepared by the self-assembly of heterodimeric prodrugs composed of pyropheophorbide a (PPa), hypoxia-activated prodrug PR104A, and a thioether or thioketal linkage. In addition, a novel dual-modality drug release pattern is proposed on the basis of the structural states of prodrug-NPs. Under light irradiation, PR104A is released via photoinduced electron transfer (PET) due to the aggregation state of prodrugs. With the disassembly of prodrug-NPs, the ACQ effect is relieved, and PPa produces singlet oxygen which further promotes the reactive oxygen species (ROS)-sensitive release of PR104A. Such prodrug-NPs turn the disadvantage of the ACQ effect to facilitate drug release, demonstrating high-efficiency synergy in combination with PDT and hypoxia-activated therapy.
Assuntos
Hipóxia Celular/fisiologia , Liberação Controlada de Fármacos/fisiologia , Nanopartículas/química , Fotoquimioterapia/métodos , Pró-Fármacos/química , Animais , Humanos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de OxigênioRESUMO
Indolizine derivatives are a class of compounds with excellent biological activity. In this study, a series of indolizine derivatives, compound 1 (C1), compound 2 (C2), compound 3 (C3), and compound 4 (C4), were synthesized. 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) assay was used to evaluate their cytotoxicity against HepG2 (p53-wild), A549, and HeLa cell lines. HepG2 cells apoptosis induced by C3 was determined using Hoechst staining and acridine orange/ethidium bromide staining. Cells' apoptotic ratio was measured by Annexin V-FITC/PI double staining. Changes in mitochondrial membrane potential and intracellular reactive oxygen species (ROS) in HepG2 cells after C3 treatment were determined. Immunofluorescence staining and Western blot analysis were carried out to detect p53 levels and analyze the apoptosis-associated proteins, respectively. Moreover, the cytotoxic activity of C3 was examined in two other hepatocellular carcinoma (HCC) cell lines with different p53 status including Huh-7 cells (p53-mutant) and Hep3B cells (p53-null). The results indicated that C3 showed stronger inhibition towards HepG2 cells than other cell lines. Fluorescent staining and flow cytometry analysis confirmed that C3 induced apoptosis of HepG2 cells. C3 could also increase intracellular ROS and cause a decrease in the mitochondrial membrane potential. C3 promoted p53 activation and increased p53 accumulation in nuclei. The expression of p53 and Bax was increased with the down-regulation of Bcl-2, which promoted the release of cytochrome c and caspase-3 activation. Collectively, the study demonstrated that C3 caused HepG2 cell apoptosis via the mitochondria p53 pathway. These results inspired us to further develop indolizine derivatives as potential potent inhibitors against liver cancer.