RESUMEN

Introduction: RNA interference (RNAi) stands as a widely employed gene interference technology, with small interfering RNA (siRNA) emerging as a promising tool for cancer treatment. However, the inherent limitations of siRNA, such as easy degradation and low bioavailability, hamper its efficacy in cancer therapy. To address these challenges, this study focused on the development of a nanocarrier system (HLM-N@DOX/R) capable of delivering both siRNA and doxorubicin for the treatment of breast cancer. Methods: The study involved a comprehensive investigation into various characteristics of the nanocarrier, including shape, diameter, Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), encapsulation efficiency, and drug loading. Subsequently, in vitro and in vivo studies were conducted on cytotoxicity, cellular uptake, cellular immunofluorescence, lysosome escape, and mouse tumor models to evaluate the efficacy of the nanocarrier in reversing tumor multidrug resistance and anti-tumor effects. Results: The results showed that HLM-N@DOX/R had a high encapsulation efficiency and drug loading capacity, and exhibited pH/redox dual responsive drug release characteristics. In vitro and in vivo studies showed that HLM-N@DOX/R inhibited the expression of P-gp by 80%, inhibited MDR tumor growth by 71% and eliminated P protein mediated multidrug resistance. Conclusion: In summary, HLM-N holds tremendous potential as an effective and targeted co-delivery system for DOX and P-gp siRNA, offering a promising strategy for overcoming MDR in breast cancer.

Asunto(s)

Neoplasias de la Mama , Doxorrubicina , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Liposomas , ARN Interferente Pequeño , Animales , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/administración & dosificación , Femenino , Liposomas/química , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/química , ARN Interferente Pequeño/farmacocinética , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Células MCF-7 , Ratones Endogámicos BALB C , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Nanopartículas/química , Liberación de Fármacos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Intracellular cargo delivery is crucial for drug evaluation, nanomedicine development, and gene therapy, in which high efficiency while maintaining cell viability is needed for downstream analysis. Here, an acoustic-mediated precise drug delivering mechanism is proposed by directly modulating cell micro-oscillation mode and membrane permeability. Through phase shifting keying-based spatiotemporal acoustic tweezers, controllable oscillating cell arrays can be achieved in shaking potentials. At the same time, continually oscillating radiation force and fluid shear stress exerted on cells effectively disturbs cellular membrane mobility and enhances permeability, thereby facilitating nanodrug entrance. In experiments, cell oscillation is tunable in frequency (10-2 to 102 Hz), shaking direction, amplitude (0 to quarter acoustic wavelength), and speed. Doxorubicin is actively delivered across cellular membranes and accumulates in inner cells, with a concentration more than 8 times that of the control group. Moreover, there is no obvious compromise in cell activity during oscillation, exhibiting excellent biocompatibility. This "dancing acoustic waves" scheme introduces a new dimension of cell manipulation in both space and time domains and an effective drug delivering strategy, offering advantages of flexibility, gentleness, and high throughput. It may advance related fields like nanobiological research, drug and nanomedicine development, and medical treatment.

Asunto(s)

Acústica , Doxorrubicina , Sistemas de Liberación de Medicamentos , Doxorrubicina/farmacología , Doxorrubicina/química , Humanos , Supervivencia Celular/efectos de los fármacos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química

RESUMEN

Oral squamous cell carcinoma (OSCC) is highly heterogeneous and aggressive, but therapies based on single-targeted nanoparticles frequently address these tumors as a single illness. To achieve more efficient drug transport, it is crucial to develop nanodrug-carrying systems that simultaneously target two or more cancer biomarkers. In addition, combining chemotherapy with near-infrared (NIR) light-mediated thermotherapy allows the thermal ablation of local malignancies via photothermal therapy (PTT), and triggers drug release to improve chemosensitivity. Thus, a novel dual-targeted nano-loading system, DOX@GO-HA-HN-1 (GHHD), was created for synergistic chemotherapy and PTT by the co-modification of carboxylated graphene oxide (GO) with hyaluronic acid (HA) and HN-1 peptide and loading with the anticancer drug doxorubicin (DOX). Targeted delivery using GHHD was shown to be superior to single-targeted nanoparticle delivery. NIR radiation will encourage the absorption of GHHD by tumor cells and cause the site-specific release of DOX in conjunction with the acidic microenvironment of the tumor. In addition, chemo-photothermal combination therapy for cancer treatment was realized by causing cell apoptosis under the irradiation of 808-nm laser. In summary, the application of GHHD to chemotherapy combined with photothermal therapy for OSCC is shown to have important potential as a means of combatting the low accumulation of single chemotherapeutic agents in tumors and drug resistance generated by single therapeutic means, enhancing therapeutic efficacy.

Asunto(s)

Carcinoma de Células Escamosas , Doxorrubicina , Sistemas de Liberación de Medicamentos , Grafito , Rayos Infrarrojos , Neoplasias de la Boca , Doxorrubicina/farmacología , Doxorrubicina/química , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Neoplasias de la Boca/terapia , Grafito/química , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Concentración de Iones de Hidrógeno , Portadores de Fármacos/química , Nanopartículas/química , Liberación de Fármacos , Animales , Apoptosis/efectos de los fármacos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/administración & dosificación , Proliferación Celular/efectos de los fármacos , Terapia Fototérmica , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Ácido Hialurónico/química , Supervivencia Celular/efectos de los fármacos , Ratones , Tamaño de la Partícula , Propiedades de Superficie

RESUMEN

Breast cancer is a common malignant tumor in women. Ferroptosis, a programmed cell death pathway, is closely associated with breast cancer and its resistance. The transferrin receptor (TFRC) is a key factor in ferroptosis, playing a crucial role in intracellular iron accumulation and the occurrence of ferroptosis. This study investigates the influence and significance of TFRC and its upstream transcription factor hypoxia-inducible factor-1α (HIF1α) on the efficacy of neoadjuvant therapy in breast cancer. The differential gene obtained from clinical samples through genetic sequencing is TFRC. Bioinformatics analysis revealed that TFRC expression in breast cancer was significantly greater in breast cancer tissues than in normal tissues, but significantly downregulated in Adriamycin (ADR)-resistant tissues. Iron-responsive element-binding protein 2 (IREB2) interacts with TFRC and participates in ferroptosis. HIF1α, an upstream transcription factor, positively regulates TFRC. Experimental results indicated higher levels of ferroptosis markers in breast cancer tissue than in normal tissue. In the TAC neoadjuvant regimen-sensitive group, iron ion (Fe2+) and malondialdehyde (MDA) levels were greater than those in the resistant group (all p < .05). Expression levels of TFRC, IREB2, FTH1, and HIF1α were higher in breast cancer tissue compared to normal tissue. Additionally, the expression of the TFRC protein in the TAC neoadjuvant regimen-sensitive group was significantly higher than that in the resistant group (all p < .05), while the difference in the level of expression of IREB2 and FTH1 between the sensitive and resistant groups was not significant (p > .05). The dual-luciferase assay revealed that HIF1α acts as an upstream transcription factor of TFRC (p < .05). Overexpression of HIF1α in ADR-resistant breast cancer cells increased TFRC, Fe2+, and MDA content. After ADR treatment, the cell survival rate decreased significantly, and ferroptosis could be reversed by the combined application of Fer-1 (all p < .05). In conclusion, ferroptosis and chemotherapy resistance are correlated in breast cancer. TFRC is a key regulatory factor influenced by HIF1α and is associated with chemotherapy resistance. Upregulating HIF1α in resistant cells may reverse resistance by activating ferroptosis through TFRC overexpression.

Asunto(s)

Neoplasias de la Mama , Doxorrubicina , Resistencia a Antineoplásicos , Ferroptosis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Receptores de Transferrina , Femenino , Humanos , Persona de Mediana Edad , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Quimioterapia Adyuvante/métodos , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Ferroptosis/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Células MCF-7 , Receptores de Transferrina/metabolismo , Receptores de Transferrina/genética , Regulación hacia Arriba

RESUMEN

We have studied the endocytic mechanisms that determine subcellular localization for three carrier-free chemotherapeutic-photothermal (chemo-PTT) combination ionic nanomedicines (INMs) composed of doxorubicin (DOX) and an near-infrared (NIR) dye (ICG, IR820, or IR783). This study aims to understand the cellular basis for previously published enhanced toxicity results of these combination nanomedicines toward MCF-7 breast cancer cells. The active transport mechanism of INMs, unlike free DOX, which is known to employ passive transport, was validated by conducting temperature-dependent cellular uptake of the drug in MCF-7 cells using confocal microscopy. The internalization pathway of these INMs was further probed in the presence and absence of different endocytosis inhibitors. Detailed examination of the mode of entry of the carrier-free INMs in MCF-7 cells revealed that they are primarily internalized through clathrin-mediated endocytosis. In addition, time-dependent subcellular localization studies were also investigated. Examination of time-dependent confocal images indicated that the INMs targeted multiple organelles, in contrast to free DOX that primarily targets the nucleus. Collectively, the high cellular endocytic uptake in cancerous cells (EPR effect) and the multimode targeting ability demonstrated the main reason for the low half-maxima inhibitory concentration (IC50) value (the high cytotoxicity) of these carrier-free INMs as compared to their respective parent chemo and PTT drugs.

Asunto(s)

Doxorrubicina , Endocitosis , Nanomedicina , Doxorrubicina/farmacología , Doxorrubicina/química , Humanos , Endocitosis/efectos de los fármacos , Células MCF-7 , Tamaño de la Partícula , Orgánulos/metabolismo , Orgánulos/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Ensayo de Materiales , Ensayos de Selección de Medicamentos Antitumorales , Supervivencia Celular/efectos de los fármacos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Iones/química

RESUMEN

Subcutaneous (SC) administration of chemotherapeutics combined with near-infrared (NIR) light activation can effectively target skin tumors by triggering localized drug release and enhancing cytotoxic effects. In this study, we developed NIR-responsive indocyanine green (ICG) and the chemotherapeutic agent doxorubicin (Dox) loaded into gelatin nanoparticles (NPs) for SC delivery in a skin tumor-bearing mouse model. Histological examination (hematoxylin and eosin staining) confirmed the successful delivery and swelling behavior of the Dox/ICG-loaded gelatin NPs at the SC site. In vitro and in vivo experiments demonstrated that NIR activation of the Dox/ICG-loaded gelatin NPs generated significant photothermal heat (48 and 46 °C), leading to targeted drug release and a substantial reduction in skin tumor size (from 15 to 3 mm3). Our findings suggest that this dual-modality approach of SC chemotherapeutic administration and NIR-triggered photothermal therapy can concentrate cytotoxic drugs at the tumor site, offering a promising strategy for improving skin cancer treatment.

Asunto(s)

Doxorrubicina , Gelatina , Verde de Indocianina , Rayos Infrarrojos , Ensayo de Materiales , Nanopartículas , Neoplasias Cutáneas , Gelatina/química , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Animales , Nanopartículas/química , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Ratones , Verde de Indocianina/química , Verde de Indocianina/administración & dosificación , Verde de Indocianina/farmacología , Tamaño de la Partícula , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Supervivencia Celular/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Humanos , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/administración & dosificación , Proliferación Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Ratones Endogámicos BALB C , Línea Celular Tumoral , Terapia Fototérmica , Liberación de Fármacos , Portadores de Fármacos/química , Inyecciones Subcutáneas

RESUMEN

The fabrications of hollow microcapsules (MCs) with new architecture and ability to incorporate different nanomaterials have received great interest for targeted cancer therapy. Recently, CuS based nanomaterials have been demonstrated to possess the ability to mimic Fenton-like activity in tumor environment and inducing cancer cell apoptosis by generating highly reactive oxygen species (ROS). In this study, we have developed poly(allylamine) hydrochloride (PAH)/dextran sulfate (DS) polyelectrolyte MCs capable of carrying doxorubicin (DOX) for targeted cancer therapy and ultrasound imaging. The electron microscopy investigations showed the formation of polymeric MCs of 3 µm in size with incorporated CuS NRs in their interior structure. The surface modification of MCs with folic acid (FA), and encapsulation of model hydrophilic molecules in MCs was studied by UV-Visible (UV-Vis) spectroscopy, Fourier transform infra-red (FTIR) spectroscopy and confocal laser scanning microscopy. The encapsulation efficiency of DOX was found to be 56 % and the release was found to be linear at pH 5.5 and 7.4 in the absence of ultrasound exposure. The ultrasound exposure resulted in sudden rupture of MCs at 1 MHz and 1 W/cm2 and caused burst release of DOX at both pH conditions. The FA decorated PAH/DS/CuS NR MCs exhibited improved anti-cancer activity against MDA-MB-231 cancer cells due to the synergistic effects of ultrasound mediated burst release of chemotherapeutic drug (DOX), glutathione-stimulated ROS and targeted cancer therapy. Further, the capsules showed better echogenicity than that of control PAH/DS MCs when imaged under medical ultrasound-scanning system. Hence, the MCs demonstrated in this study have huge potential for targeted cancer theranostics by offering an option to image the cancer cells during the treatment period.

Asunto(s)

Cápsulas , Cobre , Doxorrubicina , Liberación de Fármacos , Nanotubos , Humanos , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Doxorrubicina/química , Nanotubos/química , Línea Celular Tumoral , Cobre/química , Polielectrolitos/química , Supervivencia Celular/efectos de los fármacos , Ultrasonografía/métodos , Sulfato de Dextran , Poliaminas/química , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Especies Reactivas de Oxígeno/metabolismo , Ácido Fólico/química , Portadores de Fármacos/química

RESUMEN

Colorectal cancer (CRC) is one of the most common and challenging malignancy that needs some effective and safer chemotherapeutic agents for the treatment. In this study, anticancer agent epirubicin (Epi) was loaded in polymeric polyethylene glycol-polylactic acid-nanoparticles (mPEG-PLA-NPs) coated with a marine anti-cancer non-toxic polysaccharide fucoidan (FC), to achieve a synergistic activity against CRC. The characterization of the NPs revealed that they were spherical, monodispersed, stable, with a negative zeta potential, and exhibited good biocompatibility and controlled release. In vitro anti-cancer activity of the NPs on HCT116 cell line was found to be promising, and corroborated well with in vivo studies involving BALB/C mice injected with C26 murine cancer cells. The outcome of MTT assay demonstrated that IC50 value of free Epi was 3.72 µM, and that of non-coated and coated Epi nano-formulations was 33.67 and 10.19 µM, respectively. Higher tumor regression, better survival and reduced off-side cardiotoxicity were observed when this novel NPs formulation was used to treat tumor-bearing mice. Free FC and Epi treated mice showed 37.73 % and 61.49 % regression in tumor size, whereas there was 79.76 % and 90.34 % tumor regression in mice treated with non-coated Epi NPs and coated Epi NPs, respectively. Therefore, mPEG-PLA-FC-Epi-NPs hold a potential to be used as an effective chemotherapeutic formulation against CRC, since it exhibited better efficacy and lower toxicity.

Asunto(s)

Neoplasias Colorrectales , Epirrubicina , Ratones Endogámicos BALB C , Nanopartículas , Poliésteres , Polietilenglicoles , Polisacáridos , Animales , Epirrubicina/administración & dosificación , Epirrubicina/química , Epirrubicina/farmacología , Polisacáridos/química , Polisacáridos/administración & dosificación , Polisacáridos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Humanos , Nanopartículas/química , Polietilenglicoles/química , Polietilenglicoles/administración & dosificación , Células HCT116 , Poliésteres/química , Ratones , Liberación de Fármacos , Portadores de Fármacos/química , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Masculino

RESUMEN

Lung cancer is among most prevalent cancers in the world, in which non-small cell lung cancer (NSCLC) accounts for more than 85 % of all subtypes of lung cancers. NSCLC is often diagnosed at an advanced stage with a high mortality rate. Despite the demonstrated efficacy of chemotherapy in the treatment of NSCLC, the main drawback of current therapy is the lack of an effective drug-targeted delivery system, which may result in undesirable side effects during the clinical treatment. In this study, we construct a "dual-targeting" anti-cancer drug delivery platform by combining superparamagnetic iron oxide nanoparticles (SPIONs) with exosomes derived from NSCLC cells. We successfully promoted the targeted delivery of anti-drug doxorubicin (DOX) at the cellular levels by combining the homing targeted ability of exosomes with the magnetic targeted ability of SPIONs. Moreover, non-small cell lung cancer cell (NCI-h1299) tumor models were established. It was found that exosome-SPIONs (Exo-SPIONs) loaded with DOX exhibited optimal tumor tissue delivery and tumor suppression in the presence of an external magnetic field, and reduced the toxicity of the DOX to normal tissues. The constructed "dual-targeting" anti-cancer drug delivery platform holds promise for targeted chemotherapy for NSCLC.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Doxorrubicina , Sistemas de Liberación de Medicamentos , Exosomas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Exosomas/química , Exosomas/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/administración & dosificación , Animales , Línea Celular Tumoral , Ratones , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/administración & dosificación , Proliferación Celular/efectos de los fármacos , Nanopartículas Magnéticas de Óxido de Hierro/química , Supervivencia Celular/efectos de los fármacos , Ratones Desnudos , Nanopartículas de Magnetita/química , Antineoplásicos/farmacología , Antineoplásicos/química , Ratones Endogámicos BALB C , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

Breast cancer (BC) is the leading commonly diagnosed cancer in the world, with complex mechanisms underlying its development. There is an urgent need to enlighten key genes as potential therapeutic targets crucial to advancing BC treatment. This study sought to investigate the influence of doxorubicin (DOX) on identified key genes consistent across numerous BC datasets obtained through bioinformatic analysis. To date, a meta-analysis of publicly available coding datasets for expression profiling by array from the Gene Expression Omnibus (GEO) has been carried out. Differentially Expressed Genes (DEGs) identified using GEO2R revealed a total of 23 common DEGs, including nine upregulated genes and 14 downregulated genes among the datasets of three platforms (GPL570, GPL6244, and GPL17586), and the commonly upregulated DEGs, showed significant enrichment in the cell cycle in KEGG analysis. The top nine genes, NUSAP1, CENPF, TPX2, PRC1, ANLN, BUB1B, AURKA, CCNB2, and CDK-1, with higher degree values and MCODE scores in the cytoscape program, were regarded as hub genes. The hub genes were activated in disease states commonly across all the subclasses of BC and correlated with the unfavorable overall survival of BC patients, as verified by the GEPIA and UALCAN databases. qRT-PCR confirmed that DOX treatment resulted in reduced expression of these genes in BC cell lines, which reinforces the evidence that DOX remains an effective drug for BC and suggests that developing modified formulations of doxorubicin to reduce toxicity and resistance, could enhance its efficacy as an effective therapeutic option for BC.

Asunto(s)

Neoplasias de la Mama , Doxorrubicina , Regulación Neoplásica de la Expresión Génica , Humanos , Doxorrubicina/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Antibióticos Antineoplásicos/farmacología , Perfilación de la Expresión Génica , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Biología Computacional/métodos

RESUMEN

The objective of this study was to explore the effects and mechanisms of the combination of isobavachalcone (IBC) and doxorubicin (DOX) on the progression of anaplastic thyroid cancer (ATC). Cell viability of 8505C and CAL62 cells was observed by CCK-8 assay. Kits were used to detect the presence of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and cellular iron. Protein expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was detected using western blot, and CD31 was detected through immunofluorescence. Tumor xenograft models of 8505C cells were constructed to observe the effect of IBC and DOX on ATC growth in vivo. The co-administration of IBC and DOX exhibited a synergistic effect of suppressing the growth of 8505C and CAL62 cells. The concurrent use of IBC and DOX resulted in elevated iron, ROS, and MDA levels, while reducing GSH levels and protein expression of SLC7A11 and GPX4. However, the Fer-1 ferroptosis inhibitor effectively counteracted this effect. In vitro and in vivo, the inhibitory effect on ATC cell proliferation and tumor growth was significantly enhanced by the combination of IBC and DOX. The combination of IBC and DOX can inhibit the growth of ATC by activating ferroptosis, and might prove to be a potent chemotherapy protocol for addressing ATC.

Asunto(s)

Chalconas , Doxorrubicina , Sinergismo Farmacológico , Ferroptosis , Especies Reactivas de Oxígeno , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Ferroptosis/efectos de los fármacos , Doxorrubicina/farmacología , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/metabolismo , Animales , Humanos , Chalconas/farmacología , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Progresión de la Enfermedad , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Supervivencia Celular/efectos de los fármacos , Glutatión/metabolismo , Glutatión/efectos de los fármacos , Antibióticos Antineoplásicos/farmacología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo

RESUMEN

Background: At present, the few photothermal/chemotherapy studies about retinoblastoma that have been reported are mainly restricted to ectopic models involving subcutaneous implantation. However, eyeball is unique physiological structure, the blood-retina barrier (BRB) hinders the absorption of drug molecules through the systemic route. Moreover, the abundant blood circulation in the fundus accelerates drug metabolism. To uphold the required drug concentration, patients must undergo frequent chemotherapy sessions. Purpose: To address these challenges above, we need to develop a secure and effective drug delivery system (FA-PEG-PDA-DOX) for the fundus. Methods: We offered superior therapeutic efficacy with minimal or no side effects and successfully established orthotopic mouse models. We evaluated cellular uptake performance and targeting efficiency of FA-PEG-PDA-DOX nanosystem and assessed its synergistic antitumor effects in vitro and vivo. Biodistribution assessments were performed to determine the retention time and targeting efficiency of the NPs in vivo. Additionally, safety assessments were conducted. Results: Cell endocytosis rates of the FA-PEG-PDA-DOX+Laser group became 5.23 times that of the DOX group and 2.28 times that of FA-PEG-PDA-DOX group without irradiation. The fluorescence signal of FA-PEG-PDA-DOX persisted for more than 120 hours at the tumor site. The number of tumor cells (17.2%) in the proliferative cycle decreased by 61.6% in the photothermal-chemotherapy group, in contrast to that of the saline control group (78.8%). FA-PEG-PDA-DOX nanoparticles(NPs) exhibited favorable biosafety and high biocompatibility. Conclusion: The dual functional targeted nanosystem, with the effects of DOX and mild-temperature elevation by irradiation, resulted in precise chemo/photothermal therapy in nude mice model.

Asunto(s)

Doxorrubicina , Indoles , Terapia Fototérmica , Polímeros , Retinoblastoma , Animales , Retinoblastoma/terapia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Ratones , Terapia Fototérmica/métodos , Humanos , Indoles/química , Indoles/farmacocinética , Indoles/farmacología , Línea Celular Tumoral , Polímeros/química , Distribución Tisular , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Ratones Desnudos , Nanopartículas/química , Sistemas de Liberación de Medicamentos/métodos , Neoplasias de la Retina/terapia , Neoplasias de la Retina/tratamiento farmacológico , Ratones Endogámicos BALB C , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/administración & dosificación , Modelos Animales de Enfermedad , Ensayos Antitumor por Modelo de Xenoinjerto , Sistema de Administración de Fármacos con Nanopartículas/química , Sistema de Administración de Fármacos con Nanopartículas/farmacocinética

RESUMEN

The GPS-Nanoconveyor (MA-NV@DOX-Cas13a) is a targeted nanoplatform designed for the imaging and gene/chemotherapy synergistic treatment of melanoma. It utilizes rolling circle amplification (RCA) products as a scaffold to construct a DNA "Nanoconveyor" (NV), which incorporates a multivalent aptamer (MA) as a "GPS", encapsulates doxorubicin (DOX) in the transporter, and equips it with CRISPR/Cas13a ribonucleoproteins (Cas13a RNP). Carrying MA enhances the ability to recognize the overexpressed receptor nucleolin on B16 cells, enabling targeted imaging and precise delivery of MA-NV@DOX-Cas13a through receptor-mediated endocytosis. The activation of signal transducer and activator of transcription 3 (STAT3) in cancer cells triggers cis-cleavage of CRISPR/Cas13a, initiating its trans-cleavage function. Additionally, deoxyribonuclease I (DNase I) degrades MA-NV, releasing DOX for intracellular imaging and as a chemotherapeutic agent. Experiments demonstrate the superior capabilities of this versatile nanoplatform for cellular imaging and co-treatment while highlighting the advantages of these nanodrug delivery systems in mitigating DOX side effects.

Asunto(s)

Sistemas CRISPR-Cas , Doxorrubicina , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/administración & dosificación , Animales , Ratones , Humanos , Aptámeros de Nucleótidos/química , Técnicas de Amplificación de Ácido Nucleico/métodos , Línea Celular Tumoral , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/química

RESUMEN

BACKGROUND/AIM: Doxorubicin is first-line therapy for soft-tissue sarcoma, but patients can develop resistance which is usually fatal. As a novel therapeutic strategy, the present study aimed to determine the synergy of recombinant methioninase (rMETase) and doxorubicin against HT1080 fibrosarcoma cells compared to Hs27 normal fibroblasts, and rMETase efficacy against doxorubicin-resistant HT1080 cells in vitro. MATERIALS AND METHODS: The 50% inhibitory concentrations (IC50) of doxorubicin and rMETase, as well as their combination efficacy, against HT1080 human fibrosarcoma cells, Hs27 normal human fibroblasts and doxorubicin-resistant HT1080 (DR-HT1080) cells were determined. Dual-color HT1080 cells which expressed red fluorescent protein (RFP) in the cytoplasm and green fluorescent protein (GFP) in the nuclei were used to visualize nuclear fragmentation during treatment. Nuclear fragmentation was observed with an IX71 fluorescence microscope. RESULTS: The IC50 for doxorubicin was 3.3 µM for HT1080 cells, 12.4 µM for DR-HT1080 cells, and 7.25 µM for Hs27 cells. The IC50 for rMETase was 0.75 U/ml for HT1080 cells, 0.42 U/ml for DR-HT1080 cells, and 0.93 U/ml for Hs27 cells. The combination of rMETase and doxorubicin was synergistic against fibrosarcoma cells but not against normal fibroblasts. The combination of doxorubicin plus rMETase also caused more fragmented nuclei than either treatment alone in HT1080 cells. rMETase alone was highly effective against the DR-HT1080 cells as well as the parental HT1080 cells. CONCLUSION: The present results indicate the future clinical potential of rMETase in combination with doxorubicin for fibrosarcoma, including doxorubicin-resistant fibrosarcoma.

Asunto(s)

Liasas de Carbono-Azufre , Doxorrubicina , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Fibrosarcoma , Proteínas Recombinantes , Humanos , Doxorrubicina/farmacología , Fibrosarcoma/tratamiento farmacológico , Fibrosarcoma/patología , Fibrosarcoma/metabolismo , Liasas de Carbono-Azufre/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Línea Celular Tumoral , Proteínas Recombinantes/farmacología , Antibióticos Antineoplásicos/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo

RESUMEN

Chemoresistance is a common and thorny problem in the treatment of osteosarcoma (OS), which obstructs the response of relapse or metastasis of OS to chemotherapy and leads to the unfavorable prognosis of OS patients. Cyclin L1 (CCNL1) is a non-canonical cyclin that plays an important role in the regulation of tumor cell proliferation and lymph node metastasis. In this work, we explored the impact of CCNL1 expression levels on proliferation, migration, and Adriamycin (ADM) resistance in OS and related mechanisms. We found that CCNL1 expression levels were significantly associated with clinical prognosis of patients with OS and CCNL1 could promote OS proliferation and migration. In addition, we also revealed that cellular CCNL1 was significantly increased in ADM-resistant OS cells and promoted ADM resistance. The PI3K/AKT-mTOR pathway is involved in CCNL1-mediated ADM resistance in OS. In summary, CCNL1 is involved in the progression of ADM resistance and OS through the PI3K/AKT-mTOR pathway, which will provide a new clue to the mechanism of ADM resistance and a potential target for the treatment of ADM-resistant OS.

Asunto(s)

Neoplasias Óseas , Doxorrubicina , Resistencia a Antineoplásicos , Osteosarcoma , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/metabolismo , Osteosarcoma/patología , Osteosarcoma/genética , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Resistencia a Antineoplásicos/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Neoplasias Óseas/genética , Proliferación Celular/efectos de los fármacos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Movimiento Celular/efectos de los fármacos , Progresión de la Enfermedad , Masculino , Femenino , Regulación Neoplásica de la Expresión Génica , Pronóstico

RESUMEN

Adriamycin (ADR) is widely used against breast cancer, but subsequent resistance always occurs. YAP, a downstream protein of angiomotin (AMOT), importantly contributes to ADR resistance, whereas the mechanism is largely unknown. MCF-7 cells and MDA-MB-231 cells were used to establish ADR-resistant cell. Then, mRNA and protein expressions of AMOT and YAP expressions were determined. After AMOT transfection alone or in combination with YAP, the sensitivity of the cells to ADR were evaluated in vitro by examining cell proliferation, apoptosis, and cell cycle, as well as in vivo by examining tumor growth. Additionally, the expressions of proteins in YAP pathway were determined in AMOT-overexpressing cells. In the ADR-resistant cells, the expression of AMOT was decreased while YAP was increased, respectively, and the nucleus localization of YAP was increased at the same time. After AMOT overexpression, these were inhibited, whereas the cell sensitivity to ADR was enhanced. However, the AMOT-induced changes were significantly suppressed by YAP knockdown. The consistent results in vivo showed that AMOT enhanced the inhibition of ADR on tumor growth, and inhibited YAP signaling, evidenced by decreased levels of YAP, CycD1, and p-ERK. Our data revealed that decreased AMOT contributed to ADR resistance in breast cancer cells, which was importantly negatively mediated YAP. These observations provide a potential therapy against breast cancer with ADR resistance.

Asunto(s)

Angiomotinas , Apoptosis , Neoplasias de la Mama , Proliferación Celular , Doxorrubicina , Resistencia a Antineoplásicos , Ratones Desnudos , Proteínas Señalizadoras YAP , Humanos , Doxorrubicina/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Células MCF-7 , Proteínas Señalizadoras YAP/metabolismo , Animales , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Ratones Endogámicos BALB C , Antibióticos Antineoplásicos/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas de Microfilamentos/metabolismo , Proteínas de Microfilamentos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ciclo Celular/efectos de los fármacos

RESUMEN

An intelligent nanodrug delivery system (Cu/ZIF-8@GOx-DOX@HA, hereafter CZGDH) consisting of Cu-doped zeolite imidazolate framework-8 (Cu/ZIF-8, hereafter CZ), glucose oxidase (GOx), doxorubicin (DOX), and hyaluronic acid (HA) was established for targeted drug delivery and synergistic therapy of tumors. The CZGDH specifically entered tumor cells through the targeting effect of HA and exhibited acidity-triggered biodegradation for subsequent release of GOx, DOX, and Cu2+ in the tumor microenvironment (TME). The GOx oxidized the glucose (Glu) in tumor cells to produce H2O2 and gluconic acid for starvation therapy (ST). The DOX entered the intratumoral cell nucleus for chemotherapy (CT). The released Cu2+ consumed the overexpressed glutathione (GSH) in tumor cells to produce Cu+. The generated Cu+ and H2O2 triggered the Fenton-like reaction to generate toxic hydroxyl radicals (·OH), which disrupted the redox balance of tumor cells and effectively killed tumor cells for chemodynamic therapy (CDT). Therefore, synergistic multimodal tumor treatment via TME-activated cascade reaction was achieved. The nanodrug delivery system has a high drug loading rate (48.3 wt%), and the three-mode synergistic therapy has a strong killing effect on tumor cells (67.45%).

Asunto(s)

Cobre , Doxorrubicina , Glucosa Oxidasa , Ácido Hialurónico , Estructuras Metalorgánicas , Microambiente Tumoral , Zeolitas , Cobre/química , Doxorrubicina/farmacología , Doxorrubicina/química , Microambiente Tumoral/efectos de los fármacos , Glucosa Oxidasa/química , Glucosa Oxidasa/metabolismo , Humanos , Zeolitas/química , Animales , Estructuras Metalorgánicas/química , Ácido Hialurónico/química , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/metabolismo , Línea Celular Tumoral , Ratones , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Neoplasias/tratamiento farmacológico , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Imidazoles

RESUMEN

Stimulating the release of small nanoparticles (NPs) from a larger NP via the application of an exogenous stimulus offers the potential to address the different size requirements for circulation versus penetration that hinder chemotherapeutic drug delivery. Herein, we report a size-switching nanoassembly-based drug delivery system comprised of ultrasmall starch nanoparticles (SNPs, ∼20-50 nm major size fraction) encapsulated in a poly(oligo(ethylene glycol) methyl ether methacrylate) nanogel (POEGMA, ∼150 nm major size fraction) cross-linked via supramolecular PEG/α-cyclodextrin (α-CD) interactions. Upon heating the nanogel using a non-invasive, high-intensity focused ultrasound (HIFU) trigger, the thermoresponsive POEGMA-CD nanoassemblies are locally de-cross-linked, inducing in situ release of the highly penetrative drug-loaded SNPs. HIFU triggering increased the release of nanoassembly-loaded DOX from 17 to 37% after 3 h, a result correlated with significantly more effective tumor killing relative to nanoassemblies in the absence of HIFU or drug alone. Furthermore, 1.5× more total fluorescence was observed inside a tumor spheroid when nanoassemblies prepared with fluorophore-labeled SNPs were triggered with HIFU relative to the absence of HIFU. We anticipate this strategy holds promise for delivering tunable doses of chemotherapeutic drugs both at and within a tumor site using a non-invasive triggering approach.

Asunto(s)

Doxorrubicina , Polietilenglicoles , Humanos , Polietilenglicoles/química , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Nanogeles/química , Nanopartículas/química , alfa-Ciclodextrinas/química , Sistemas de Liberación de Medicamentos/métodos , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Animales , Portadores de Fármacos/química , Línea Celular Tumoral , Polietileneimina/química

RESUMEN

Combination therapy using chemo-photothermal therapy (chemo-PTT) shows great efficacy toward tumor ablation in preclinical studies. Besides, lipopolymersomes as a hybrid nanocarriers, integrate advantages of liposomes and polymersomes in a single platform in order to provide tremendous biocompatibility, biodegradability, noteworthy loading efficacy for both hydrophobic and hydrophilic drugs with adjustable drug release and high stability. In this study, a multipurpose lipopolymersome was fabricated for guided chemotherapy-PTT and NIR-imaging of melanoma. A lipopolymerosomal hybrid nanovesicle consisting of equal molar ratio of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) diblock copolymer (molar ratio 1:1) was fabricated. The nanoparticulate system was prepared through film rehydration technique for encapsulation of doxorubicin (DOX) and indocyanine green (ICG) to form DOX-ICG-LP platform. At the next stage, AS1411 DNA aptamer was conjugated to the surface of lipopolymersome (Apt-DOX-ICG-LP) for selective delivery. The sizes of DOX-ICG-LP and Apt-DOX-ICG-LP were obtained through DLS analysis (61.0 ± 6 and 74 ± 5, respectively). Near Infrared-responsive release pattern of the prepared lipopolymersome was verified in vitro. The formulated platform showed efficient photothermal conversion, and superior stability with acceptable encapsulation efficiency. Consistent with the in vitro studies, NIR-responsive lipopolymersome exhibited significantly higher cellular toxicity for Chemo-PTT versus single anti-cancer treatment. Moreover, superlative tumor shrinkage with favorable survival profile were attained in B16F10 tumor-bearing mice received Apt-DOX-ICG-LP and irradiated with 808 nm laser compared to those treated with either DOX-ICG-LP or Apt-DOX-ICG-LP without laser irradiation. The diagnostic capability of Apt-DOX-ICG-LP was addressed using in vivo NIR imaging, 6 and 24 h post-intravenous administration. The results indicated desirable feature of an established targeted theranostic capability of Apt-DOX-ICG-LP for both diagnostics and dual chemo-PTT of melanoma.

Asunto(s)

Doxorrubicina , Verde de Indocianina , Terapia Fototérmica , Polietilenglicoles , Nanomedicina Teranóstica , Animales , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Verde de Indocianina/administración & dosificación , Ratones , Polietilenglicoles/química , Terapia Fototérmica/métodos , Línea Celular Tumoral , Nanomedicina Teranóstica/métodos , Portadores de Fármacos/química , Liberación de Fármacos , Nanopartículas/química , Compuestos de Amonio Cuaternario/química , Humanos , Liposomas , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/terapia , Melanoma/tratamiento farmacológico , Melanoma/terapia , Polímeros/química , Poliésteres/química , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Ratones Endogámicos C57BL , Fototerapia/métodos , Ácidos Grasos Monoinsaturados

RESUMEN

A novel and efficient cancer therapy was developed using a smart hydrogel containing multifunctional bimetallic organic frameworks and anticancer drugs. The injectable self-healing hydrogel with pH-responsiveness was constructed through borate ester and imine bonds among dopamine-grafted sodium alginate (SADA), hydroxypropyl chitosan (HPCS) and 2-formylphenylboronic acid (2-FPBA). The Au nanoparticles-decorated Ti/Fe bimetallic organic framework tetragonal nanosheets (Au/TF-MOF TNS) were synthesized and incorporated into the hydrogel with the anticancer drugs doxorubicin (DOX). Upon intratumoral injection of nanocomposite hydrogel, the acidic tumor microenvironment triggered the cleavage of borate ester and imine bonds, causing the hydrogel to break down and accelerating the release of both Au/TF-MOF TNS and DOX. These Au/TF-MOF TNS functioned as nanozymes, producing hydroxyl radicals (·OH) for chemodynamic therapy (CDT), generating oxygen (O2) to support sonodynamic therapy (SDT), and depleting glucose for starvation therapy (ST). Additionally, the Au/TF-MOF TNS served as sonosensitizers, capable of converting O2 into singlet oxygen (1O2) upon ultrasound irradiation to achieve SDT. Therefore, this nanocomposite hydrogel system enabled synergistic sonodynamic-chemodynamic-starvation-chemo therapy (SDT-CDT-ST-CT) of cancer, presenting a promising platform for advanced cancer therapy strategies.

Asunto(s)

Doxorrubicina , Oro , Hidrogeles , Nanopartículas del Metal , Estructuras Metalorgánicas , Oro/química , Hidrogeles/química , Hidrogeles/farmacología , Concentración de Iones de Hidrógeno , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Nanopartículas del Metal/química , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/administración & dosificación , Humanos , Animales , Ratones , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Tamaño de la Partícula , Propiedades de Superficie , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/administración & dosificación , Alginatos/química , Liberación de Fármacos , Supervivencia Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos