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 ArribaRESUMEN
Doxorubicin (DOX) is an anthracycline antibiotic used as an antitumor treatment. However, its clinical application is limited due to severe side effects such as cardiotoxicity. In recent years, numerous studies have demonstrated that cellular aging has become a therapeutic target for DOX-induced cardiomyopathy. However, the underlying mechanism and specific molecular targets of DOX-induced cardiomyocyte aging remain unclear. Poly (ADP-ribose) polymerase (PARP) is a family of protein post-translational modification enzymes in eukaryotic cells, including 18 members. PARP-1, the most well-studied member of this family, has become a potential molecular target for the prevention and treatment of various cardiovascular diseases, such as DOX cardiomyopathy and heart failure. PARP-1 and PARP-2 share 69% homology in the catalytic regions. However, they do not entirely overlap in function. The role of PARP-2 in cardiovascular diseases, especially in DOX-induced cardiomyocyte aging, is less studied. In this study, we found for the first time that down-regulation of PARP-2 can inhibit DOX-induced cellular aging in cardiomyocytes. On the contrary, overexpression of PARP-2 can aggravate DOX-induced cardiomyocyte aging and injury. Further research showed that PARP-2 inhibited the expression and activity of SIRT1, which in turn was involved in the development of DOX-induced cardiomyocyte aging and injury. Our findings provide a preliminary experimental basis for establishing PARP-2 as a new target for preventing and treating DOX cardiomyopathy and related drug development.
Asunto(s)
Senescencia Celular , Doxorrubicina , Miocitos Cardíacos , Poli(ADP-Ribosa) Polimerasas , Sirtuina 1 , Doxorrubicina/efectos adversos , Doxorrubicina/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Sirtuina 1/metabolismo , Sirtuina 1/genética , Animales , Senescencia Celular/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Poli(ADP-Ribosa) Polimerasas/genética , Ratas , Cardiotoxicidad/patología , Cardiotoxicidad/metabolismo , Cardiotoxicidad/prevención & control , Cardiotoxicidad/etiología , Apoptosis/efectos de los fármacos , Ratas Sprague-Dawley , Antibióticos Antineoplásicos/toxicidad , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/farmacología , Cardiomiopatías/inducido químicamente , Cardiomiopatías/patología , Cardiomiopatías/metabolismo , Cardiomiopatías/genética , HumanosRESUMEN
Chemotherapeutic anthracyclines, like doxorubicin (DOX), are drugs endowed with cytostatic activity and are widely used in antitumor therapy. Their molecular mechanism of action involves the formation of a stable anthracycline-DNA complex, which prevents cell division and results in cell death. It is known that elevated DOX concentrations induce DNA chain loops and overlaps. Here, for the first time, tip-enhanced Raman scattering was used to identify and localize intercalated DOX in isolated double-stranded calf thymus DNA, and the correlated near-field spectroscopic and morphologic experiments locate the DOX molecules in the DNA and provide further information regarding specific DOX-nucleobase interactions. Thus, the study provides a tool specifically for identifying intercalation markers and generally analyzing drug-DNA interactions. The structure of such complexes down to the molecular level provides mechanistic information about cytotoxicity and the development of potential anticancer drugs.
Asunto(s)
ADN , Doxorrubicina , Espectrometría Raman , Doxorrubicina/farmacología , Doxorrubicina/química , ADN/química , Animales , Bovinos , Sustancias Intercalantes/química , Sustancias Intercalantes/farmacología , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/químicaRESUMEN
Among the various RNA modifications, adenosine-to-inosine RNA editing, catalyzed by adenosine deaminase acting on RNA (ADAR) family, ADAR1 and ADAR2, is the most common nucleotide conversion in mammalian cells. The pathological relevance of ADAR expression has been highlighted in recent human genetic studies. Low expression of the ADAR2 gene is correlated with a poor prognosis in breast cancer patients, but the underlying mechanism remains enigmatic. In this study, we constructed Adar2-knockdown (Adar2-KD) murine breast cancer 4T1 cells and observed their reduced susceptibility to chemotherapeutic drug doxorubicin. Downregulation of ADAR2 induced the expression of P-glycoprotein (P-gp), leading to a reduction in the intracellular accumulation of doxorubicin. The upregulation of P-gp occurred at the post-transcriptional level due to the decreased miR-195a-3p function. The search for the underlying cause of the induction of P-gp expression in Adar2-KD 4T1 cells led to the identification of circular RNA (circRNA) circHif1a as a sponge for miR-195a-3p. The enhanced expression of circHif1a inhibited miR-195a-3p function, resulting in the upregulation of P-gp expression. These results suggest that ADAR2 acts as a suppressor of circHif1a biogenesis and then allows miR-195a-3p to interfere with P-gp translation. Our findings may help to improve drug efficacy by clarifying the mechanism of chemoresistance in breast cancer.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Adenosina Desaminasa , Doxorrubicina , Regulación Neoplásica de la Expresión Génica , MicroARNs , Edición de ARN , ARN Circular , Animales , Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/genética , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Femenino , ARN Circular/genética , ARN Circular/metabolismo , Doxorrubicina/farmacología , Línea Celular Tumoral , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Resistencia a Antineoplásicos/genética , Antibióticos Antineoplásicos/farmacologíaRESUMEN
In this study, maleic anhydride-modified lignin (LG-M), a ROS-cleavable thioketal (TK) bond, and polyethylene glycol (PEG) were used to synthesize a lignin-based copolymer (LG-M(TK)-PEG). Doxorubicin (DOX) was attached to the ROS-cleavable bond in the LG-M(TK)-PEG for the preparation of the ROS-activatable DOX prodrug (LG-M(TK-DOX)-PEG). Nanoparticles (NPs) with a size of 125.7 ± 3.1 nm were prepared by using LG-M(TK-DOX)-PEG, and they exhibited enhanced uptake by cancer cells compared to free DOX. Notably, the presence of lignin in the nanoparticles could boost ROS production in breast cancer 4T1 cells while showing little effect on L929 normal cells. This selective effect facilitated the specific activation of the DOX prodrug in the tumor microenvironment, resulting in the superior tumor inhibitory effects and enhanced biosafety relative to free DOX. This work demonstrates the potential of the LG-M(TK-DOX)-PEG NPs as an efficient drug delivery system for cancer treatment.
Asunto(s)
Doxorrubicina , Liberación de Fármacos , Lignina , Nanopartículas , Estrés Oxidativo , Polietilenglicoles , Especies Reactivas de Oxígeno , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/administración & dosificación , Lignina/química , Nanopartículas/química , Especies Reactivas de Oxígeno/metabolismo , Animales , Estrés Oxidativo/efectos de los fármacos , Línea Celular Tumoral , Ratones , Polietilenglicoles/química , Profármacos/química , Profármacos/farmacología , Femenino , Humanos , Portadores de Fármacos/química , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/química , Anhídridos Maleicos/químicaRESUMEN
This study aimed to investigate the effect of in vivo pH-responsive doxorubicin (DOX) release and the targetability of pilot molecules in folic acid (FA)-modified micelles using a pharmacokinetic-pharmacodynamic (PK-PD) model. The time profiles of intratumoral DOX concentrations in Walker256 tumor-bearing rats were monitored using a microdialysis probe, followed by compartmental analysis, to evaluate intratumoral tissue pharmacokinetics. Maximal DOX was released from micelles 350 min after the administration of pH-responsive DOX-releasing micelles. However, FA modification of the micelles shortened the time to peak drug concentration to 150 min. Additionally, FA modification resulted in a 27-fold increase in the tumor inflow rate constant. Walker256 tumor-bearing rats were subsequently treated with DOX, pH-responsive DOX-releasing micelles, and pH-responsive DOX-releasing FA-modified micelles to monitor the tumor growth-time profiles. An intratumoral threshold concentration of DOX (55-64 ng/g tumor) was introduced into the drug efficacy compartment to construct a PD model, followed by PK-PD analysis of the tumor growth-time profiles. Similar results of threshold concentration and drug potency of DOX were obtained across all three formulations. Cell proliferation was delayed as the drug delivery ability of DOX was improved. The PK model, which was developed using the microdialysis method, revealed the intratumoral pH-responsive DOX distribution profiles. This facilitated the estimation of intratumoral PK parameters. The PD model with threshold concentrations contributed to the estimation of PD parameters in the three formulations, with consistent mechanisms observed. We believe that our PK-PD model can objectively assess the contributions of pH-responsive release ability and pilot molecule targetability to pharmacological effects.
Asunto(s)
Doxorrubicina , Ácido Fólico , Micelas , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Animales , Ratas , Concentración de Iones de Hidrógeno , Ácido Fólico/química , Ácido Fólico/farmacocinética , Liberación de Fármacos , Proliferación Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Línea Celular Tumoral , Portadores de Fármacos/química , Femenino , Ratas Wistar , Humanos , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacologíaRESUMEN
One of the most significant reasons hindering the clinical translation of nanomedicines is the rapid clearance of intravenously injected nanoparticles by the mononuclear phagocyte system, particularly by Kupffer cells in the liver, leading to an inefficient delivery of nanomedicines for tumor treatment. The threshold theory suggests that the liver's capacity to clear nanoparticles is limited, and a single high dose of nanoparticles can reduce the hepatic clearance efficiency, allowing more nanomedicines to reach tumor tissues and enhance therapeutic efficacy. Building upon this theory, researchers have conducted numerous validation studies based on the same nanoparticle carrier systems. These studies involve the use of albumin nanoparticles to improve the therapeutic efficacy of albumin nanomedicines as well as polyethylene glycol (PEG)-modified liposomal nanoparticles to enhance the efficacy of PEGylated liposomal nanomedicines. However, there is no research indicating the feasibility of the threshold theory when blank nanoparticles and nanomedicine belong to different nanoparticle carrier systems currently. In this study, we prepared two different sizes of albumin nanoparticles by using bovine serum albumin. We used the marketed nanomedicine liposomal doxorubicin hydrochloride injection (trade name: LIBOD, manufacturer: Shanghai Fudan-zhangjiang Biopharmaceutical Co., Ltd.), as the representative nanomedicine. Through in vivo experiments, we found that using threshold doses of albumin nanoparticles still can reduce the clearance rate of LIBOD, prolong its time in vivo, increase the area under the plasma concentration-time curve (AUC), and also lead to an increased accumulation of the drug at the tumor site. Furthermore, evaluation of in vivo efficacy and safety further indicates that threshold doses of 100 nm albumin nanoparticles can enhance the antitumor effect of LIBOD without causing harm to the animals. During the study, we found that the particle size of albumin nanoparticles influenced the in vivo distribution of the nanomedicine at the same threshold dose. Compared with 200 nm albumin nanoparticles, 100 nm albumin nanoparticles more effectively reduce the clearance efficiency of LIBOD and enhance nanomedicine accumulation at the tumor site, warranting further investigation. This study utilized albumin nanoparticles to reduce hepatic clearance efficiency and enhance the delivery efficiency of nonalbumin nanocarrier liposomal nanomedicine, providing a new avenue to improve the efficacy and clinical translation of nanomedicines with different carrier systems.
Asunto(s)
Doxorrubicina , Nanopartículas , Polietilenglicoles , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/análogos & derivados , Animales , Nanopartículas/química , Polietilenglicoles/química , Ratones , Liposomas/química , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/administración & dosificación , Distribución Tisular , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Ratones Endogámicos BALB C , Hígado/efectos de los fármacos , Hígado/metabolismo , Tamaño de la Partícula , Nanomedicina/métodos , Humanos , Masculino , FemeninoRESUMEN
Doxorubicin (DOX) is one of the most commonly used anticancer drugs; however, its clinical application is greatly limited due to its toxicity and chemotherapy resistance. The delivery of DOX by liposomes (Lipos) can improve the blood circulation time in vivo and reduce toxic side effects, but the drug's accumulation in the tumor is often insufficient for effective treatment. In this study, we present a calcium cross-linked liposome gel for the encapsulation of DOX, demonstrating its superior long-term release capabilities compared to conventional Lipos. By leveraging this enhanced long-term release, we can enhance drug accumulation within tumors, ultimately leading to improved antitumor efficacy. Lipos were prepared using the thin-film dispersion method in this study. We utilized the ion-responsiveness of glutathione-gelatin (GSH-GG) to form the gel outside the Lipos and named the nanoparticles coated with GSH-GG on the outside of Lipos as Lipos@GSH-GG. The average size of Lipos@GSH-GG was around 342.9 nm, with a negative charge of -25.6 mV. The in vitro experiments revealed that Lipos@GSH-GG exhibited excellent biocompatibility and slower drug release compared to conventional Lipos. Further analysis of cellular uptake and cytotoxicity demonstrated that Lipos@GSH-GG loading DOX (DOX&Lipos@GSH-GG) exhibited superior long-term release effects and lower toxic side effects compared to Lipos loading DOX (DOX&Lipos). Additionally, the findings regarding the long-term release effect in vivo and the tumor accumulation within tumor-bearing mice of Lipos@GSH-GG suggested that, compared to Lipos, it demonstrated superior long-term release capabilities and achieved greater drug accumulation within tumors. In vivo antitumor efficacy experiments showed that DOX&Lipos@GSH-GG demonstrated superior antitumor efficacy to DOX&Lipos. Our study highlights Lipos@GSH-GG as a promising nanocarrier with the potential to enhance efficacy and safety by means of long-term release effects and may offer an alternative approach for effective antitumor therapy in the future.
Asunto(s)
Calcio , Doxorrubicina , Liberación de Fármacos , Glutatión , Liposomas , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Animales , Ratones , Liposomas/química , Humanos , Calcio/química , Calcio/metabolismo , Glutatión/química , Femenino , Geles/química , Gelatina/química , Ratones Desnudos , Nanopartículas/química , Ratones Endogámicos BALB C , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Reactivos de Enlaces Cruzados/química , Sistemas de Liberación de Medicamentos/métodosRESUMEN
Nanoparticle-based drug carriers that can respond to oxidative stress in tumor tissue have attracted attention for site-specific drug release. Taking advantage of the characteristic microenvironment in tumors, one of the attractive directions in drug delivery research is to design drug carriers that release drugs upon oxidation. A strategy to incorporate oxidation-sensitive thioether motifs such as thiomorpholine acrylamide (TMAM) to drug carriers has been often used to achieve oxidation-induced dissociation, thereby targeted drug release. However, those delivery systems often suffer from a slow dissociation rate due to the intrinsic hydrophobicity of the thioether structures. In this study, we aimed to enhance the dissociation rate of TMAM-based micelles upon oxidation. The random copolymers of N-isopropylacrylamide and TMAM (P(NIPAM/TMAM)) were designed as an oxidation-sensitive segment that showed a fast response to oxidative stress. We first synthesized P(NIPAM/TMAM) copolymers with different NIPAM:TMAM molar ratios. Those copolymers exhibited low critical solution temperatures (LCSTs) below 32 °C, which shifted to higher temperatures after oxidation. The changes in LCSTs depend on the NIPAM:TMAM molar ratios. At the NIPAM:TMAM molar ratio of 82:18, the LCSTs before and after oxidation were 17 and 54 °C, respectively. We then prepared micelles from the diblock copolymers of poly(N-acryloyl morpholine) (PAM) and P(NIPAM/TMAM). The micelles showed an accelerated dissociation rate upon oxidation compared to the micelles without NIPAM units. Furthermore, the doxorubicin (Dox)-loaded micelles showed enhanced relative toxicity in human colorectal cancer (HT29) cells over human umbilical vein endothelial cells (HUVECs). Our novel strategy to design an oxidation-sensitive micellar core comprising a P(NIPAM/TMAM) segment can be used as a chemotherapeutic delivery system that responds to an oxidative tumor microenvironment in an appropriate time scale.
Asunto(s)
Antibióticos Antineoplásicos , Micelas , Humanos , Antibióticos Antineoplásicos/farmacología , Células Endoteliales/metabolismo , Polímeros/química , Doxorrubicina/farmacología , Doxorrubicina/química , Portadores de Fármacos/química , Estrés Oxidativo , SulfurosRESUMEN
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/químicaRESUMEN
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, â¼20-50 nm major size fraction) encapsulated in a poly(oligo(ethylene glycol) methyl ether methacrylate) nanogel (POEGMA, â¼150 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/químicaRESUMEN
We developed a supramolecular system for codelivery of doxorubicin (Dox) and p53 gene based on a ß-CD-containing star-shaped cationic polymer. First, a star-shaped cationic polymer consisting of a ß-CD core and 3 arms of oligoethylenimine (OEI), named CD-OEI, was used to form a supramolecular inclusion complex with hydrophobic Dox. The CD-OEI/Dox complex was subsequently used to condense plasmid DNA via electrostatic interactions to form CD-OEI/Dox/DNA polyplex nanoparticles with positive surface charges that enhanced the cellular uptake of both Dox and DNA. This supramolecular drug and gene codelivery system showed high gene transfection efficiency and effective protein expression in cancer cells. The codelivery of Dox and DNA encoding the p53 gene resulted in reduced cell viability and enhanced antitumor effects at low Dox concentrations. With its enhanced cellular uptake and anticancer efficacy, the system holds promise as a delivery carrier for potential combination cancer therapies.
Asunto(s)
Doxorrubicina , Nanopartículas , Electricidad Estática , Proteína p53 Supresora de Tumor , Humanos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/administración & dosificación , beta-Ciclodextrinas/química , Supervivencia Celular/efectos de los fármacos , ADN/química , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/administración & dosificación , Portadores de Fármacos/química , Técnicas de Transferencia de Gen , Nanopartículas/química , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The permeability and responsiveness of polymer membranes are absolutely relevant in the design of polymersomes for cargo delivery. Accordingly, we herein correlate the structural features, permeability, and responsiveness of doxorubicin-loaded (DOX-loaded) nonresponsive and stimuli-responsive polymersomes with their in vitro and in vivo antitumor performance. Polymer vesicles were produced using amphiphilic block copolymers containing a hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) segment linked to poly[N-(4-isopropylphenylacetamide)ethyl methacrylate] (PPPhA, nonresponsive block), poly[4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)benzyl methacrylate] [PbAPE, reactive oxygen species (ROS)-responsive block], or poly[2-(diisopropylamino)ethyl methacrylate] (PDPA, pH-responsive block). The PDPA-based polymersomes demonstrated outstanding biological performance with antitumor activity notably enhanced compared to their counterparts. We attribute this behavior to a fast-triggered DOX release in acidic tumor environments as induced by pH-responsive polymersome disassembly at pH < 6.8. Possibly, an insufficient ROS concentration in the selected tumor model attenuates the rate of ROS-responsive vesicle degradation, whereas the nonresponsive nature of the PPPhA block remarkably impacts the performance of such potential nanomedicines.
Asunto(s)
Doxorrubicina , Doxorrubicina/farmacología , Doxorrubicina/química , Humanos , Animales , Ratones , Permeabilidad de la Membrana Celular/efectos de los fármacos , Polímeros/química , Polímeros/farmacología , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Portadores de Fármacos/química , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Acrilamidas/química , Acrilamidas/farmacología , Concentración de Iones de HidrógenoRESUMEN
Doxorubicin (Dox) is an anti-tumor drug with a broad spectrum, whereas the cardiotoxicity limits its further application. In clinical settings, liposome delivery vehicles are used to reduce Dox cardiotoxicity. Here, we substitute extracellular vesicles (EVs) for liposomes and deeply investigate the mechanism for EV-encapsulated Dox delivery. The results demonstrate that EVs dramatically increase import efficiency and anti-tumor effects of Dox in vitro and in vivo, and the efficiency increase benefits from its unique entry pattern. Dox-loading EVs repeat a "kiss-and-run" motion before EVs internalization. Once EVs touch the cell membrane, Dox disassociates from EVs and directly enters the cytoplasm, leading to higher and faster Dox import than single Dox. This unique entry pattern makes the adhesion between EVs and cell membrane rather than the total amount of EV internalization the key factor for regulating the Dox import. Furthermore, we recognize ICAM1 as the molecule mediating the adhesion between EVs and cell membranes. Interestingly, EV-encapsulated Dox can induce ICAM1 expression by irritating IFN-γ and TNF-α secretion in TME, thereby increasing tumor targeting of Dox-loading EVs. Altogether, EVs and EV-encapsulated Dox synergize via ICAM1, which collectively enhances the curative effects for tumor treatment.
Asunto(s)
Antibióticos Antineoplásicos , Doxorrubicina , Vesículas Extracelulares , Molécula 1 de Adhesión Intercelular , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Animales , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/efectos de los fármacos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Ratones Endogámicos BALB C , Ratones , Femenino , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Adhesión Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Ratones Desnudos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
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 fármacosRESUMEN
PURPOSE: To develop a noninvasive therapeutic approach able to alter the biophysical organization and physiology of the extracellular matrix (ECM) in breast cancer. MATERIALS AND METHODS: In a 4T1 murine model of breast cancer, histoplasty treatment with a proprietary 700-kHz multielement therapy transducer using a coaxially aligned ultrasound (US) imaging probe was used to target the center of an ex vivo tumor and deliver subablative acoustic energy. Tumor collagen morphology was qualitatively evaluated before and after histoplasty with second harmonic generation. Separately, mice bearing bilateral 4T1 tumors (n = 4; total tumors = 8) were intravenously injected with liposomal doxorubicin. The right flank tumor was histoplasty-treated, and tumors were fluorescently imaged to detect doxorubicin uptake after histoplasty treatment. Next, 4T1 tumor-bearing mice were randomized into 2 treatment groups (sham vs histoplasty, n = 3 per group). Forty-eight hours after sham/histoplasty treatment, tumors were harvested and analyzed using flow cytometry. RESULTS: Histoplasty significantly increased (P = .002) liposomal doxorubicin diffusion into 4T1 tumors compared with untreated tumors (2.12- vs 1.66-fold increase over control). Flow cytometry on histoplasty-treated tumors (n = 3) demonstrated a significant increase in tumor macrophage frequency (42% of CD45 vs 33%; P = .022) and a significant decrease in myeloid-derived suppressive cell frequency (7.1% of CD45 vs 10.3%; P = .044). Histoplasty-treated tumors demonstrated increased CD8+ (5.1% of CD45 vs 3.1%; P = .117) and CD4+ (14.1% of CD45 vs 11.8%; P = .075) T-cell frequency. CONCLUSIONS: Histoplasty is a nonablative focused US approach to noninvasively modify the tumor ECM, increase chemotherapeutic uptake, and alter the tumor immune microenvironment.
Asunto(s)
Doxorrubicina , Ratones Endogámicos BALB C , Microambiente Tumoral , Animales , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Femenino , Línea Celular Tumoral , Ratones , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/administración & dosificación , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Neoplasias Mamarias Experimentales/cirugía , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias de la Mama/patología , Transductores , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Polietilenglicoles/química , Modelos Animales de Enfermedad , Antígenos Comunes de LeucocitoRESUMEN
Doxorubicin (DOX) is widely used in cancer treatment but the dose-related toxicity of DOX on organs including the liver limit its use. Therefore, there is great interest in combining DOX with natural compounds with antioxidant properties to reduce toxicity and increase drug efficacy. Esculetin is a natural coumarin derivative with biological properties encompassing anti-inflammatory and antioxidant activities. In light of these properties, this study was meticulously crafted to investigate the potential of esculetin in preventing doxorubicin (DOX)-induced hepatotoxicity in Sprague-Dawley rats. The rats were divided into a total of six groups: control group, DOX group (administered DOX at a cumulative dose of 5 mg/kg intraperitoneally every other day for 2 weeks), E50 group (administered 50 mg/kg of esculetin intraperitoneally every day), E100 group (administered 100 mg/kg of esculetin intraperitoneally every day) and combined groups (DOX + E50 and DOX + E100) in which esculetin was administered together with DOX. The treatments, both with DOX alone and in combination with E50, manifested a reduction in catalase (CAT mRNA) levels in comparison to the control group. Notably, the enzymatic activities of superoxide dismutase (SOD), CAT, and glutathione peroxidase (GPx) witnessed significant decreases in the liver of rats treated with DOX. Moreover, DOX treatment induced a statistically significant elevation in malondialdehyde (MDA) levels, coupled with a concurrent decrease in glutathione (GSH) levels. Additionally, molecular docking studies were conducted. However, further studies are needed to confirm the hepatoprotective properties of esculetin and to precisely elucidate its mechanisms of action.
Asunto(s)
Antioxidantes , Doxorrubicina , Umbeliferonas , Ratas , Animales , Antioxidantes/farmacología , Ratas Sprague-Dawley , Simulación del Acoplamiento Molecular , Doxorrubicina/toxicidad , Estrés Oxidativo , Glutatión/metabolismo , Hígado/metabolismo , Antibióticos Antineoplásicos/farmacologíaRESUMEN
Streptomyces peucetius ATCC 27952 is known to produce a variety of secondary metabolites, including two important antitumor anthracyclines: daunorubicin and doxorubicin. Identification of peucemycin and 25-hydroxy peucemycin (peucemycin A), as well as their biosynthetic pathway, has expanded its biosynthetic potential. In this study, we isolated a new peucemycin derivative and identified it as 19-hydroxy peucemycin (peucemycin B). Its antibacterial activity was lower than those of peucemycin and peucemycin A. On the other hand, this newly identified peucemycin derivative had higher anticancer activity than the other two compounds for MKN45, NCI-H1650, and MDA-MB-231 cancer cell lines with IC50 values of 76.97 µM, 99.68 µM, and 135.2 µM, respectively. Peucemycin biosynthetic gene cluster revealed the presence of a SARP regulator named PeuR whose role was unknown. The presence of the TTA codon in the peuR and the absence of global regulator BldA in S. peucetius reduced its ability to regulate the peucemycin biosynthetic gene cluster. Hence, different mutants harboring these genes were prepared. S. peucetius bldA25 harboring bldA produced 1.75 times and 1.77 times more peucemycin A (11.8 mg/L) and peucemycin B (21.2 mg/L), respectively, than the wild type. On the other hand, S. peucetius R25 harboring peuR produced 1.86 and 1.79 times more peucemycin A (12.5 mg/L) and peucemycin B (21.5 mg/L), respectively, than the wild type. Finally, strain S. peucetius bldAR25 carrying bldA and peuR produced roughly 3.52 and 2.63 times more peucemycin A (23.8 mg/L) and peucemycin B (31.5 mg/L), respectively, than the wild type. KEY POINTS: ⢠This study identifies a new peucemycin derivative, 19-hydroxy peucemycin (peucemycin B). ⢠The SARP regulator (PeuR) acts as a positive regulator of the peucemycin biosynthetic gene cluster. ⢠The overexpression of peuR and heterologous expression of bldA increase the production of peucemycin derivatives.
Asunto(s)
Daunorrubicina , Doxorrubicina , Streptomyces , Antraciclinas/metabolismo , Antibióticos Antineoplásicos/farmacologíaRESUMEN
Hemangioma of infancy is the most common vascular tumor during infancy and childhood. Despite the proven efficacy of propranolol treatment, certain patients still encounter resistance or face recurrence. The need for frequent daily medication also poses challenges to patient adherence. Bleomycin (BLM) has demonstrated effectiveness against vascular anomalies, yet its use is limited by dose-related complications. Addressing this, this study proposes a novel approach for treating hemangiomas using BLM-loaded hyaluronic acid (HA)-based microneedle (MN) patches. BLM is encapsulated during the synthesis of polylactic acid (PLA) microspheres (MPs). The successful preparation of PLA MPs and MN patches is confirmed through scanning electron microscopy (SEM) images. The HA microneedles dissolve rapidly upon skin insertion, releasing BLM@PLA MPs. These MPs gradually degrade within 28 days, providing a sustained release of BLM. Comprehensive safety assessments, including cell viability, hemolysis ratio, and intradermal reactions in rabbits, validate the safety of MN patches. The BLM@PLA-MNs exhibit an effective inhibitory efficiency against hemangioma formation in a murine hemangioma model. Of significant importance, RNA-seq analysis reveals that BLM@PLA-MNs exert their inhibitory effect on hemangiomas by regulating the P53 pathway. In summary, BLM@PLA-MNs emerge as a promising clinical candidate for the effective treatment of hemangiomas.
Asunto(s)
Bleomicina , Preparaciones de Acción Retardada , Sistemas de Liberación de Medicamentos , Hemangioma , Ácido Hialurónico , Agujas , Poliésteres , Bleomicina/farmacología , Animales , Ratones , Conejos , Hemangioma/tratamiento farmacológico , Ácido Hialurónico/química , Preparaciones de Acción Retardada/química , Sistemas de Liberación de Medicamentos/métodos , Poliésteres/química , Humanos , Microesferas , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Liberación de FármacosRESUMEN
In different types of cancer treatments, cancer-specific T cells are required for effective anticancer immunity, which has a central role in cancer immunotherapy. However, due to the multiple inhibitions of CD8+ T cells by tumor-related immune cells, CD8+ T-cell mediated antitumor immunotherapy has not achieved breakthrough progress in the treatment of solid tumors. Receptors for sialic acid (SA) are highly expressed in tumor-associated immune cells, so SA-modified nanoparticles are a drug delivery nanoplatform using tumor-associated immune cells as vehicles. To relieve the multiple inhibitions of CD8+ T cells by tumor-associated immune cells, we prepared SA-modified doxorubicin liposomes (SL-DOX, Scheme 1A). In our study, free SA decreased the toxicity of SL-DOX to tumor-associated immune cells. Compared with common liposomes, SL-DOX could inhibit tumor growth more effectively. It is worth noting that SL-DOX could not only kill tumor-related neutrophils and monocytes to relieve the multiple inhibitions of CD8+ T cells but also induce immunogenic death of tumor cells to promote the infiltration and differentiation of CD8+ T cells (Scheme 1B). Therefore, SL-DOX has potential value for the clinical therapeutic effect of CD8+ T cells mediating anti-tumor immunotherapy.