RESUMEN
Liver cancer is the third leading cause of cancer deaths globally. The use of Hydroxycamptothecin (HCPT) as a first-line chemotherapeutic agent for liver, lung, and gastric cancers is often hampered by its low activity, limited targeting, and poor water solubility. This results in a low accumulation of HCPT in tumor cells, as well as the inability to maintain continuous treatment. Consequently, there is an urgent need to develop an accessory method that can enhance the therapeutic efficacy of HCPT while exhibiting good biocompatibility and targeted delivery ability. To address this critical issue, an enzyme-triggered supramolecular nanocarrier, refer as SCD/LCC SNCs, has been successfully developed, leveraging the aggregation of the negatively charged sulfate-modified ß-CDs and positively charged lauroylcholine chloride (LCC). This nanocarrier demonstrates acetylcholinesterase (LCC) triggered decomposition behavior, making it a promising drug carrier for HCPT. The cellular assays conducted have demonstrated that HCPT loaded into these SCD/LCC SNCs exhibit reduced cytotoxicity towards normal cells while maintaining robust tumor inhibitory activity and inducing apoptosis. Therefore, this study offers a promising strategy for the effective use of HCPT in the treatment of liver cancer.
Asunto(s)
Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Camptotecina/farmacología , Camptotecina/química , Camptotecina/análogos & derivados , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Apoptosis/efectos de los fármacos , Portadores de Fármacos/química , Antineoplásicos/farmacología , Antineoplásicos/química , Sistemas de Liberación de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Nanopartículas/química , Supervivencia Celular/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Células Hep G2RESUMEN
BACKGROUND: Camptothecin (CPT) is one of the frequently used small chemotherapy drugs for treating hepatocellular carcinoma (HCC), but its clinical application is limited due to severe toxicities and acquired resistance. Combined chemo-gene therapy has been reported to be an effective strategy for counteracting drug resistance while sensitizing cancer cells to cytotoxic agents. Thus, we hypothesized that combining CPT with miR-145 could synergistically suppress tumor proliferation and enhance anti-tumor activity. METHODS: Lactobionic acid (LA) modified lipid nanoparticles (LNPs) were developed to co-deliver CPT and miR-145 into asialoglycoprotein receptors-expressing HCC in vitro and in vivo. We evaluated the synergetic antitumor effect of miR-145 and CPT using CCK8, Western blotting, apoptosis and wound scratch assay in vitro, and the mechanisms underlying the synergetic antitumor effects were further investigated. Tumor inhibitory efficacy, safety evaluation and MRI-visible ability were assessed using diethylnitrosamine (DEN) + CCl4-induced HCC mouse model. RESULTS: The LA modification improved the targeting delivery of cargos to HCC cells and tissues. The LA-CMGL-mediated co-delivery of miR-145 and CPT is more effective on tumor inhibitory than LA-CPT-L or LA-miR-145-L treatment alone, both in vitro and in vivo, with almost no side effects during the treatment period. Mechanistically, miR-145 likely induces apoptosis by targeting SUMO-specific peptidase 1 (SENP1)-mediated hexokinase (HK2) SUMOylation and glycolysis pathways and, in turn, sensitizing the cancer cells to CPT. In vitro and in vivo tests confirmed that the loaded Gd-DOTA served as an effective T1-weighted contrast agent for noninvasive tumor detection as well as real-time monitoring of drug delivery and biodistribution. CONCLUSIONS: The LA-CMGL-mediated co-delivery of miR-145 and CPT displays a synergistic therapy against HCC. The novel MRI-visible, actively targeted chemo-gene co-delivery system for HCC therapy provides a scientific basis and a useful idea for the development of HCC treatment strategies in the future.
Asunto(s)
Camptotecina , Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Nanopartículas , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Animales , Ratones , MicroARNs/genética , MicroARNs/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Humanos , Nanopartículas/química , Camptotecina/farmacología , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/uso terapéutico , Imagen por Resonancia Magnética/métodos , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Lípidos/química , LiposomasRESUMEN
Colorectal cancer (CRC) remains one of the most prevalent malignant tumors of the digestive system, yet the availability of safe and effective chemotherapeutic agents for clinical use remains limited. Camptothecin (CPT) and its derivatives, though approved for cancer treatment, have encountered significant challenges in clinical application due to their low bioavailability and high systemic toxicity. Strategic modification at the 7-position of CPT enables the development of novel CPT derivatives with high activity. In the present study, a series of compounds incorporating aminoureas, amino thioureas, and acylamino thioureas as substituents at the 7-position were screened. These compounds were subsequently evaluated for their cytotoxicity against the human gastric cancer (GC) cell line AGS and the CRC cell line HCT116. Two derivatives, XSJ05 (IC50 = 0.006 ± 0.003 µM) and XSJ07 (IC50 = 0.013 ± 0.003 µM), exhibited remarkably effective anti-CRC activity, being better than TPT. In addition, they have a better safety profile. In vitro mechanistic studies revealed that XSJ05 and XSJ07 exerted their inhibitory effects on CRC cell proliferation by suppressing the activity of topoisomerase I (Topo I). This suppression triggers DNA double-strand breaks, leads to DNA damage and subsequently causes CRC cells to arrest in the G2/M phase. Ultimately, the cells undergo apoptosis. Collectively, these findings indicate that XSJ05 and XSJ07 possess superior activity coupled with favorable safety profiles, suggesting their potential as lead compounds for the development of CRC therapeutics.
Asunto(s)
Antineoplásicos , Apoptosis , Camptotecina , Proliferación Celular , Neoplasias Colorrectales , ADN-Topoisomerasas de Tipo I , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Topoisomerasa I , Humanos , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/síntesis química , Camptotecina/farmacología , Camptotecina/química , Camptotecina/síntesis química , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , ADN-Topoisomerasas de Tipo I/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Estructura Molecular , Apoptosis/efectos de los fármacos , Tiourea/farmacología , Tiourea/química , Tiourea/síntesis química , Línea Celular TumoralRESUMEN
DNA-protein crosslinks (DPCs) are toxic lesions that inhibit DNA related processes. Post-translational modifications (PTMs), including SUMOylation and ubiquitylation, play a central role in DPC resolution, but whether other PTMs are also involved remains elusive. Here, we identify a DPC repair pathway orchestrated by poly-ADP-ribosylation (PARylation). Using Xenopus egg extracts, we show that DPCs on single-stranded DNA gaps can be targeted for degradation via a replication-independent mechanism. During this process, DPCs are initially PARylated by PARP1 and subsequently ubiquitylated and degraded by the proteasome. Notably, PARP1-mediated DPC resolution is required for resolving topoisomerase 1-DNA cleavage complexes (TOP1ccs) induced by camptothecin. Using the Flp-nick system, we further reveal that in the absence of PARP1 activity, the TOP1cc-like lesion persists and induces replisome disassembly when encountered by a DNA replication fork. In summary, our work uncovers a PARP1-mediated DPC repair pathway that may underlie the synergistic toxicity between TOP1 poisons and PARP inhibitors.
Asunto(s)
Reparación del ADN , Replicación del ADN , ADN-Topoisomerasas de Tipo I , Poli(ADP-Ribosa) Polimerasa-1 , Poli ADP Ribosilación , Animales , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/genética , ADN-Topoisomerasas de Tipo I/metabolismo , Xenopus laevis , Ubiquitinación , Humanos , ADN/metabolismo , Daño del ADN , Camptotecina/farmacología , Procesamiento Proteico-Postraduccional , ADN de Cadena Simple/metabolismo , Proteínas de Xenopus/metabolismoRESUMEN
Recently, the sortilin receptor (SORT1) was found to be preferentially over-expressed on the surface of many cancer cells, which makes SORT1 a novel anticancer target. The SORT1 binding proprietary peptide TH19P01 could achieve the SORT1-mediated cancer cell binding and subsequent internalization. Inspired by the peptide-drug conjugate (PDC) strategy, the TH19P01-camptothecin (CPT) conjugates were designed, efficiently synthesized, and evaluated for their anticancer potential in this study. The water solubility, in vitro anticancer activity, time-kill kinetics, cellular uptake, anti-migration activity, and hemolysis effects were systematically estimated. Besides, in order to monitor the release of CPT from conjugates in real-time, the CPT/Dnp-based "turn on" hybrid peptide was designed, which indicted that CPT could be sustainably released from the hybrid peptide in both human serum and cancer cellular environments. Strikingly, compared with free CPT, the water solubility, cellular uptake, and selectivity towards cancer cells of hybrid peptide LYJ-2 have all been significantly enhanced. Moreover, unlike free CPT or TH19P01, LYJ-2 exhibited selective anti-proliferative and anti-migration effects against SORT1-positive MDA-MB-231 cells. Collectively, this study not only established efficient strategies to improve the solubility and anticancer potential of chemotherapeutic agent CPT, but also provided important references for the future development of TH19P01 based PDCs targeting SORT1.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular , Antineoplásicos , Camptotecina , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Camptotecina/farmacología , Camptotecina/química , Camptotecina/síntesis química , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Péptidos/química , Péptidos/farmacología , Péptidos/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Movimiento Celular/efectos de los fármacosRESUMEN
Background: A successful immune response against tumors depends on various cellular processes. Hence, there is an urgent need to construct a proficient nanoplatform for immunotherapy that can concurrently regulate the activities of various cells participating in the immune process. We have developed zeolitic imidazolate framework-8 (ZIF-8) formula, with good pH sensitivity, which is conducive to the release of drugs in the tumor site (acidic environment) and significantly improves immunotherapy. This is achieved through the coordinated action of different therapeutic agents, such as the photothermal agent polydopamine (PDA), the chemodrug camptothecin (CPT), and the immunomodulator 1-methyl-D-tryptophan (1-MT). Materials and Methods: In this study, we evaluated the antitumor effect of PDA/(CPT + 1-MT) @ZIF-8 (PCMZ) nanoparticles (NPs) in vitro and in vivo and investigated the molecular mechanism of PCMZ NPs in tumor suppression via photothermal-chemo-immunotherapy. Results: MTT and Annexin V-FITC/PI double staining apoptosis test showed that PCMZ NPs could induce apoptosis of 4T1 cell, and PCMZ NPs could cause 4T1 cell necrosis under 808 nm laser irradiation. The objective is to establish a unilateral breast cancer model in mice and investigate the effect of PCMZ NPs on tumor growth and tumor suppression in tumor bearing mice. The results showed that PCMZ NPs showed good heating effect in vivo and effectively inhibited tumor growth under 808 nm laser irradiation. In addition, PCMZ NPs could induce the immunogenic death of tumor cells, promote the maturation of DCs, inhibit IDO pathway, and finally differentiate T cells into cytotoxic T cells and helper T cells, so as to effectively activate the anti-tumor immune response. Conclusion: The PCMZ NPs, possessing good photothermal conversion capabilities due to join of PDA, effectively overcome two main challenges in immunotherapy: insufficient stimulation of the immune response and evasion of the immune system. This provides a robust platform against invasive cancer and recurrent tumors.
Asunto(s)
Camptotecina , Inmunoterapia , Indoles , Ratones Endogámicos BALB C , Polímeros , Triptófano , Zeolitas , Animales , Indoles/química , Indoles/farmacología , Zeolitas/química , Zeolitas/farmacología , Inmunoterapia/métodos , Triptófano/química , Triptófano/farmacología , Triptófano/análogos & derivados , Ratones , Concentración de Iones de Hidrógeno , Línea Celular Tumoral , Femenino , Polímeros/química , Polímeros/farmacología , Camptotecina/química , Camptotecina/farmacología , Nanopartículas/química , Apoptosis/efectos de los fármacos , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Humanos , Terapia Fototérmica/métodos , Imidazoles/química , Imidazoles/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Terapia CombinadaRESUMEN
BACKGROUND: Accurate estimation of cell viability is crucial in various applications such as cytotoxicity testing and routine cell culture on both industrial and laboratory scales. For this, the real-time monitoring of cell status would be beneficial. Conventional cell-based assays for cell viability have limitations in sensitivity and time-effectiveness. Analysis of cell-free DNA (cfDNA) in (culture) media is a good alternative as cfDNA release are a well-known phenomenon during cell death. RESULTS: We demonstrate a direct digital PCR (dPCR) method to estimate cell viability by analyzing cfDNA in media during induced cell death. After validating the duplex dPCR method for short and long amplicons of the SMAD4 and RPP30 loci, we determined that a media volume of 2 µL is feasible to measure the target DNA copy number with minimal negative effects on amplification. dPCR inhibition was evident with a higher media volume per reaction targeting long amplicons. Next, we applied our dPCR method using media cfDNA and other conventional methods to the monitoring of camptothecin (CPT)-induced cell death. Copy numbers increased significantly after 4 h of CPT treatment, showing a fold change of approximately 4-6 compared to the controls. Cell-based assays such as the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and annexin V/7-AAD assay also indicated increased cell death at 4 h, but the trypan blue exclusion assay did not. SIGNIFICANCE: The developed media cfDNA direct dPCR method allows for efficient measurements of the degree of cell viability. Unlike other conventional cell-based assays, our method has advantages of no loss of cultured cells and the ability to implement online analysis. Accurate and sensitive media cfDNA analysis using dPCR can be adopted in various applications such as determining cytotoxicity levels in large-scale bioreactors or screening for effective anticancer drugs.
Asunto(s)
Supervivencia Celular , Ácidos Nucleicos Libres de Células , Reacción en Cadena de la Polimerasa , Supervivencia Celular/efectos de los fármacos , Humanos , Reacción en Cadena de la Polimerasa/métodos , Camptotecina/farmacología , Medios de Cultivo/químicaRESUMEN
BACKGROUND: Anti-HER2 therapies, including the HER2 antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have led to improved survival outcomes in patients with HER2-overexpressing (HER2+) metastatic breast cancer. However, intrinsic or acquired resistance to anti-HER2-based therapies remains a clinical challenge in these patients, as there is no standard of care following disease progression. The purpose of this study was to elucidate the mechanisms of resistance to T-DM1 and T-DXd in HER2+ BC patients and preclinical models and identify targets whose inhibition enhances the antitumor activity of T-DXd in HER2-directed ADC-resistant HER2+ breast cancer in vitro and in vivo. METHODS: Targeted DNA and whole transcriptome sequencing were performed in breast cancer patient tissue samples to investigate genetic aberrations that arose after anti-HER2 therapy. We generated T-DM1 and T-DXd-resistant HER2+ breast cancer cell lines. To elucidate their resistance mechanisms and to identify potential synergistic kinase targets for enhancing the efficacy of T-DXd, we used fluorescence in situ hybridization, droplet digital PCR, Western blotting, whole-genome sequencing, cDNA microarray, and synthetic lethal kinome RNA interference screening. In addition, cell viability, colony formation, and xenograft assays were used to determine the synergistic antitumor effect of T-DXd combinations. RESULTS: We found reduced HER2 expression in patients and amplified DNA repair-related genes in patients after anti-HER2 therapy. Reduced ERBB2 gene amplification in HER2-directed ADC-resistant HER2+ breast cancer cell lines was through DNA damage and epigenetic mechanisms. In HER2-directed ADC-resistant HER2+ breast cancer cell lines, our non-biased RNA interference screening identified the DNA repair pathway as a potential target within the canonical pathways to enhance the efficacy of T-DXd. We validated that the combination of T-DXd with ataxia telangiectasia and Rad3-related inhibitor, elimusertib, led to significant breast cancer cell death in vitro (P < 0.01) and in vivo (P < 0.01) compared to single agents. CONCLUSIONS: The DNA repair pathways contribute to HER2-directed ADC resistance. Our data justify exploring the combination treatment of T-DXd with DNA repair-targeting drugs to treat HER2-directed ADC-resistant HER2+ breast cancer in clinical trials.
Asunto(s)
Neoplasias de la Mama , Reparación del ADN , Resistencia a Antineoplásicos , Inmunoconjugados , Receptor ErbB-2 , Trastuzumab , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Animales , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Ratones , Receptor ErbB-2/metabolismo , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Camptotecina/análogos & derivados , Camptotecina/farmacología , Camptotecina/uso terapéutico , Sinergismo FarmacológicoRESUMEN
Introduction: In recent years, the development of drug-eluting embolization beads that can be imaged has become a hot research topic in regard to meeting clinical needs. In our previous study, we successfully developed nano-assembled microspheres (NAMs) for multimodal imaging purposes. NAMs can not only be visualized under CT/MR/Raman imaging but can also load clinically required doses of doxorubicin. It is important to systematically compare the pharmacokinetics of NAMs with those of commercially available DC Beads and CalliSpheres to evaluate the clinical application potential of NAMs. Methods: In our study, we compared NAMs with two types of drug-eluting beads (DEBs) in terms of irinotecan, drug-loading capacity, release profiles, microsphere diameter variation, and morphological characteristics. Results: Our results indicate that NAMs had an irinotecan loading capacity similar to those of DC Beads and CalliSpheres but exhibited better sustained release in vitro. Conclusion: NAMs have great potential for application in transcatheter arterial chemoembolization for the treatment of colorectal cancer liver metastases.
Asunto(s)
Irinotecán , Microesferas , Imagen Multimodal , Irinotecán/administración & dosificación , Irinotecán/farmacología , Humanos , Imagen Multimodal/métodos , Portadores de Fármacos/química , Liberación de Fármacos , Quimioembolización Terapéutica/métodos , Sistemas de Liberación de Medicamentos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/diagnóstico por imagen , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/farmacologíaRESUMEN
An anticancer nanodrug with few side effects that does not require the use of a nanocarrier, polyethylene glycol, or other additives has been developed. We have fabricated nano-prodrugs (NPDs) composed only of homodimeric prodrugs of the anticancer agent SN-38, which contains a disulfide bond. The prodrugs are stable against hydrolysis but selectively release SN-38 when the disulfide bond is cleaved by glutathione, which is present in high concentrations in cancer cells. The best-performing NPDs showed good dispersion stability in nanoparticle form, and animal experiments revealed that they possess much higher antitumor activity than irinotecan, a clinically applied prodrug of SN-38. This performance was achieved by improving tumor accumulation due to the size effect and targeted drug release mechanism. The present study provides an insight into the development of non-invasive NPDs with high pharmacological activity, and also offers new possibilities for designing prodrug molecules that can release drugs in response to various kinds of triggers.
Asunto(s)
Camptotecina , Irinotecán , Profármacos , Profármacos/química , Profármacos/farmacología , Animales , Irinotecán/química , Irinotecán/farmacología , Humanos , Ratones , Camptotecina/química , Camptotecina/farmacología , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Línea Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Nanopartículas/química , Liberación de Fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Ratones Endogámicos BALB C , Ratones DesnudosRESUMEN
[Gd(OH)]2+[(SN-38)0.5(FdUMP)0.5]2- inorganic-organic hybrid nanoparticles (IOH-NPs) with a chemotherapeutic cocktail of ethyl-10-hydroxycamptothecin (SN-38, active form of irinotecan) and 5-fluoro-2'-deoxyuridine-5'-phosphate (FdUMP, active form of 5'-fluoruracil), 40 nm in size, are prepared in water. The IOH-NPs contain a total drug load of 63 wt% with 33 wt% of SN-38 and 30 wt% of FdUMP. Cell-based assays show efficient cellular uptake and promising anti-tumour activity on two pancreatic cancer cell lines of murine origin (KPC, Panc02). Beside the high-load drug cocktail, especially the option to use SN-38, which - although 100- to 1000-times more potent than irinotecan - is usually unsuitable for systemic administration due to poor solubility, low stability, and high toxicity upon non-selective delivery. The [Gd(OH)]2+[(SN-38)0.5(FdUMP)0.5]2- IOH-NPs are a new concept to deliver a drug cocktail with SN-38 and FdUMP directly to the tumour, shielded in a nanoparticle, to reduce side effects.
Asunto(s)
Camptotecina , Irinotecán , Nanopartículas , Irinotecán/química , Irinotecán/farmacología , Camptotecina/química , Camptotecina/farmacología , Camptotecina/análogos & derivados , Ratones , Línea Celular Tumoral , Animales , Nanopartículas/química , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Portadores de Fármacos/química , Floxuridina/química , Floxuridina/farmacologíaRESUMEN
In this study, thermo-sensitive poly(N-isopropyl acrylamide) (PNP) was polymerized with pH-sensitive poly(acrylic acid) (PAA) to prepare a PAA-b-PNP block copolymer. Above its cloud point, the block copolymer self-assembled into nanoparticles (NPs), encapsulating the anticancer drug camptothecin (CPT) in situ. Chitosan (CS) and fucoidan (Fu) further modified these NPs, forming Fu-CPT-NPs to enhance biocompatibility, drug encapsulation efficiency (EE), and loading content (LC), crucially facilitating P-selectin targeting of lung cancer cells through a drug delivery system. The EE and LC reached 82 % and 3.5 %, respectively. According to transmission electron microscope observation, these Fu-CPT-NPs had uniform spherical shapes with an average diameter of ca. 250 nm. They could maintain their stability in a pH range of 5.0-6.8. In vitro experimental results revealed that the Fu-CPT-NPs exhibited good biocompatibility and had anticancer activity after encapsulating CPT. It could deliver CPT to cancer cells by targeting P-selectin, effectively increasing cell uptake and inducing cell apoptosis. Animal study results showed that the Fu-CPT-NPs inhibited lung tumor growth by increasing tumor cell apoptosis without causing significant tissue damage related to generating reactive oxygen species in lung cancer cells. This system can effectively improve drug-delivery efficiency and treatment effects and has great potential for treating lung cancer.
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Camptotecina , Quitosano , Neoplasias Pulmonares , Nanopartículas , Polisacáridos , Quitosano/química , Polisacáridos/química , Polisacáridos/farmacología , Humanos , Camptotecina/farmacología , Camptotecina/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Nanopartículas/química , Animales , Ratones , Apoptosis/efectos de los fármacos , Portadores de Fármacos/química , Células A549 , Línea Celular Tumoral , Resinas Acrílicas/química , Liberación de Fármacos , Concentración de Iones de Hidrógeno , Selectina-P/metabolismo , Polímeros/químicaRESUMEN
Camptothecin (CPT) is a monoterpenoid indole alkaloid with a wide spectrum of anticancer activity. However, its application is hindered by poor solubility, lack of targeting specificity, and severe side effects. Structural derivatization of CPT and the development of suitable drug delivery systems are potential strategies for addressing these issues. In this study, we discovered that the protein Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) from Homo sapiens catalyzes CPT to yield 9-hydroxycamptothecin (9-HCPT), which exhibits increased water solubility and cytotoxicity. We then created a RNA-protein complex based drug delivery system with enzyme and pH responsiveness and improved the targeting and stability of the nanomedicine through protein module assembly. The subcellular localization of nanoparticles can be visualized using fluorescent RNA probes. Our results not only identified the protein CYP1A1 responsible for the structural derivatization of CPT to synthesize 9-HCPT but also offered potential strategies for enhancing the utilization of silk-based drug delivery systems in tumor therapy.
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Camptotecina , Citocromo P-450 CYP1A1 , Sistemas de Liberación de Medicamentos , Camptotecina/química , Camptotecina/farmacología , Camptotecina/análogos & derivados , Humanos , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A1/genética , ARN/química , Nanopartículas/química , Solubilidad , Línea Celular TumoralRESUMEN
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) targeting HER2-positive malignancies across various tumor types. Through its unique composition, T-DXd achieves selective payload delivery, inducing cell death and halting tumor progression. Clinical trials initially investigated T-DXd's efficacy in HER2-positive advanced or metastatic breast, gastric, lung, and colorectal cancers; however, recent results from the DESTINY-PanTumor02 trial further underscore T-DXd's versatility, prompting T-DXd's US FDA approval for HER2-positive (immunohistochemistry [IHC] 3+) solid tumors. Moreover, in addition to T-DXd's efficacy against brain metastasis, T-DXd is showing promising results in HER2-low and HER2-ultra-low metastatic breast cancer, indicating a broader population of patients who may benefit.
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Biomarcadores de Tumor , Inmunoconjugados , Receptor ErbB-2 , Trastuzumab , Humanos , Trastuzumab/uso terapéutico , Trastuzumab/farmacología , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Receptor ErbB-2/metabolismo , Biomarcadores de Tumor/metabolismo , Camptotecina/análogos & derivados , Camptotecina/farmacología , Camptotecina/uso terapéutico , Neoplasias/tratamiento farmacológicoRESUMEN
INTRODUCTION: Antibody-drug conjugates (ADCs) represent a revolutionary approach in the systemic treatment for both solid and hematologic tumors. Constituted by an antibody, a cytotoxic payload, and a linker, ADCs aim to selectively deliver cytotoxic agents to tumors while sparing normal tissues. Various ADCs have been tested and approved for multiple solid tumors so far, but if there is one that had a major impact on clinical practice, this is Trastuzumab-deruxtecan (T-DXd). Notably, T-DXd was approved for HER2-positive and HER2-low metastatic breast cancer (MBC), HER2-positive gastric cancer (GC), HER2-mutant non-small cell lung cancer (NSCLC) and HER2 3+ solid tumors. Moreover, it received Breakthrough Therapy Designation for HER2-positive colorectal cancer (CRC). AREAS COVERED: We review preclinical and clinical data of T-DXd, focusing on early-phase ongoing trials exploring combination therapies to enhance the activity of T-DXd in HER2-expressing solid tumors. EXPERT OPINION: The clinical use of T-DXd still raises questions about selection of patients, treatment duration, prioritization over other approved ADCs, and management of resistance. Concerns regarding the toxicity of T-DXd remain, particularly with combinations involving potentially toxic drugs. Advancements in biomarker identification and combination therapies offer promising avenues to enhance efficacy and overcome resistance to T-DXd, ultimately improving outcomes for patients with cancer.
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Camptotecina , Desarrollo de Medicamentos , Inmunoconjugados , Receptor ErbB-2 , Trastuzumab , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Receptor ErbB-2/metabolismo , Trastuzumab/farmacología , Trastuzumab/administración & dosificación , Animales , Camptotecina/farmacología , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversosRESUMEN
Cerium oxide (CeO2-x) performs well in photothermal and catalytic properties due to its abundance of oxygen vacancies. Based on this, we designed a thermosensitive therapeutic nanoplatform to achieve continuous circular drug release in tumor. It can solve the limitation caused by insufficient substrate in the process of tumor treatment. Briefly, CeO2-x and camptothecin (CPT) were wrapped in an agarose hydrogel, which could be melted by the photothermal effect of CeO2-x. At the same time, the local temperature increase provided photothermal treatment, which could induce the apoptosis of tumor cell. After that, CPT was released to damage the DNA in tumor cells to realize chemical treatment. In addition, CPT could active nicotinamide adenine dinucleotide oxidase to react with O2 to increase the intracellular H2O2. After that, the exposed CeO2-x could catalyze H2O2 to generate cytotoxic reactive oxygen species for chemodynamic therapy. More importantly, CeO2-x could catalyze H2O2 to produce O2, which could combine with the catalytic action of CPT to construct a substrate self-cycling nanoenzyme system. Overall, this self-cycling nanoplatform released hypoxia in the tumor microenvironment and built a multimode tumor treatment, which achieved an ideal antitumor affect.
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Materiales Biocompatibles , Cerio , Ensayo de Materiales , Cerio/química , Cerio/farmacología , Humanos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Tamaño de la Partícula , Animales , Ratones , Camptotecina/química , Camptotecina/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/metabolismo , TemperaturaRESUMEN
It is crucial to use simple methods to prepare stable polymeric micelles with multiple functions for cancer treatment. Herein, via a "bottom-up" strategy, we reported the fabrication of ß-CD-(PEOSMA-PCPTMA-PPEGMA)21 (ßPECP) unimolecular micelles that could simultaneously treat tumors and bacteria with chemotherapy and photodynamic therapy (PDT). The unimolecular micelles consisted of a 21-arm ß-cyclodextrin (ß-CD) core as a macromolecular initiator, photosensitizer eosin Y (EOS-Y) monomer EOSMA, anticancer drug camptothecin (CPT) monomer, and a hydrophilic shell PEGMA. Camptothecin monomer (CPTMA) could achieve controlled release of the CPT due to the presence of responsively broken disulfide bonds. PEGMA enhanced the biocompatibility of micelles as a hydrophilic shell. Two ßPECP with different lengths were synthesized by modulating reaction conditions and the proportion of monomers, which both were self-assembled to unimolecular micelles in water. ßPECP unimolecular micelles with higher EOS-Y/CPT content exhibited more excellent 1O2 production, in vitro drug release efficiency, higher cytotoxicity, and superior antibacterial activity. Also, we carried out simulations of the self-assembly and CPT release process of micelles, which agreed with the experiments. This nanosystem, which combines antimicrobial and antitumor functions, provides new ideas for bacteria-mediated tumor clinical chemoresistance.
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Antineoplásicos , Micelas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Profármacos/química , Profármacos/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Animales , Ratones , beta-Ciclodextrinas/química , Camptotecina/química , Camptotecina/farmacologíaRESUMEN
On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥â 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Mutación , Receptor ErbB-2 , Trastuzumab , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptor ErbB-2/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Femenino , Trastuzumab/uso terapéutico , Trastuzumab/farmacología , Masculino , Persona de Mediana Edad , Estados Unidos , United States Food and Drug Administration , Aprobación de Drogas , Anciano , Inmunoconjugados/uso terapéutico , Inmunoconjugados/farmacología , Inmunoconjugados/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/farmacología , Camptotecina/efectos adversos , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacologíaRESUMEN
OBJECTIVE: Colorectal cancer, one of the most frequently diagnosed cancers worldwide, has a high mortality rate. Thus, our research aims to examine the preventive effects of diosmin (DIO) alone and in conjunction with the anti-cancer drug irinotecan (camptothecin-11, CPT-11), on 1,2-dimethylhydrazine (DMH)-induced colon cancer (CC) in male Wistar rats. MATERIALS AND METHODS: Fifty adult male Wistar rats were categorized into five groups. Group I (Normal) received saline 0.9 orally % as a vehicle once a week for 14 weeks. Group II (DMH) received DMH (20 mg/kg/week) orally dissolved in 0.9% saline for 14 weeks and 1% carboxymethylcellulose (CMC) every other day for the final 10 weeks. Group III (DMH+DIO) received DMH orally for 14 weeks and DIO (10 mg/kg, suspended in 1% CMC) every other day for the final 10 weeks. Group IV (DMH+CPT-11) received DMH orally for 14 weeks and intraperitoneal injection of CPT-11 (3 mg/kg) twice a week for the final 10 weeks. Group V (DMH+DIO+CPT-11) orally received DMH for 14 weeks and both DIO and CPT-11. RESULTS: All treated groups showed a significant reduction (p<0.05) in their elevated serum malondialdehyde levels and significant amelioration (p<0.05) of their lowered activities of colon glutathione-S-transferase (GST) and glutathione reductase (GR) as well as serum glutathione level (GSH). In addition, simultaneous treatment with DIO and CPT-11 led to a significant decrease (p<0.05) in the elevated serum levels of carcinoembryonic antigen (CEA) in rats administered with DMH, as well as a reduction in the colon expression levels of the inflammatory mediator (NF-κB), cell proliferator protein (Ki-67), and proapoptotic protein (p53). CONCLUSIONS: These findings suggest DIO, CPT-11, and their combination have anticarcinogenic effects against DMH-induced CC by suppressing oxidative stress, simulating the antioxidant defense system, attenuating the inflammatory effects, and reducing cell proliferation.
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1,2-Dimetilhidrazina , Neoplasias del Colon , Diosmina , Irinotecán , Ratas Wistar , Animales , Masculino , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias del Colon/prevención & control , Neoplasias del Colon/metabolismo , Ratas , Diosmina/farmacología , Diosmina/administración & dosificación , Irinotecán/farmacología , Irinotecán/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/farmacología , Estrés Oxidativo/efectos de los fármacosRESUMEN
Suppression of fungal camptothecin (CPT) biosynthesis with the preservation and successive subculturing is the challenge that impedes fungi from the industrial application, so, screening for a novel fungal isolate with a conceivable stable producing potency of CPT was the main objective of this work. Catharanthus roseus with diverse contents of bioactive metabolites could have a plethora of novel endophytes with unique metabolic properties. Among the endophytes of C. roseus, Alternaria brassicicola EFBL-NV OR131587.1 was the highest CPT producer (96.5 µg/L). The structural identity of the putative CPT was verified by HPLC, FTIR, HNMR and LC-MS/MS, with a molecular mass 349 m/z, and molecular fragmentation patterns that typically identical to the authentic one. The purified A. brassicicola CPT has a strong antiproliferative activity towards UO-31 (0.75 µM) and MCF7 (3.2 µM), with selectivity index 30.8, and 7.1, respectively, in addition to resilient activity to inhibit Topo II (IC50 value 0.26 nM) than Topo 1 (IC50 value 3.2 nM). The purified CPT combat the wound healing of UO-31 cells by ~ 52%, stops their matrix formation, cell migration and metastasis. The purified CPT arrest the cellular division of the UO-31 at the S-phase, and inducing their cellular apoptosis by ~ 20.4 folds, compared to the control cells. Upon bioprocessing with the surface response methodology, the CPT yield by A. brassicicola was improved by ~ 3.3 folds, compared to control. The metabolic potency of synthesis of CPT by A. brassicicola was attenuated with the fungal storage and subculturing, losing ~ 50% of their CPT productivity by the 6th month of storage and 6th generation. Practically, the CPT productivity of the attenuated A. brassicicola was restored by addition of 1% surface sterilized leaves of C. roseus, ensuring the eliciting of cryptic gene cluster of A. brassicicola CPT via the plant microbiome-A. brassicicola interactions. So, for the first time, a novel endophytic isolate A. brassicicola, from C. roseus, was explored to have a relatively stable CPT biosynthetic machinery, with an affordable feasibility to restore their CPT productivity using C. roseus microbiome, in addition to the unique affinity of the extracted CPT to inhibit Topoisomerase I and II.