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1.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802613

RESUMEN

This study demonstrates the rational fabrication of a magnetic composite nanofiber mesh that can achieve mutual synergy of hyperthermia, chemotherapy, and thermo-molecularly targeted therapy for highly potent therapeutic effects. The nanofiber is composed of biodegradable poly(ε-caprolactone) with doxorubicin, magnetic nanoparticles, and 17-allylamino-17-demethoxygeldanamycin. The nanofiber exhibits distinct hyperthermia, owing to the presence of magnetic nanoparticles upon exposure of the mesh to an alternating magnetic field, which causes heat-induced cell killing as well as enhanced chemotherapeutic efficiency of doxorubicin. The effectiveness of hyperthermia is further enhanced through the inhibition of heat shock protein activity after hyperthermia by releasing the inhibitor 17-allylamino-17-demethoxygeldanamycin. These findings represent a smart nanofiber system for potent cancer therapy and may provide a new approach for the development of localized medication delivery.


Asunto(s)
Benzoquinonas/farmacología , Preparaciones de Acción Retardada/farmacología , Doxorrubicina/farmacología , Lactamas Macrocíclicas/farmacología , Nanofibras/química , Neoplasias/tratamiento farmacológico , Benzoquinonas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/química , Doxorrubicina/química , Liberación de Fármacos , Sinergismo Farmacológico , Compuestos Férricos/química , Humanos , Lactamas Macrocíclicas/química , Células MCF-7 , Magnetismo/métodos , Nanopartículas de Magnetita/química
2.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804239

RESUMEN

Cancer is one of the deadliest diseases in human history with extremely poor prognosis. Although many traditional therapeutic modalities-such as surgery, chemotherapy, and radiation therapy-have proved to be successful in inhibiting the growth of tumor cells, their side effects may vastly limited the actual benefits and patient acceptance. In this context, a nanomedicine approach for cancer therapy using functionalized nanomaterial has been gaining ground recently. Considering the ability to carry various anticancer drugs and to act as a photothermal agent, the use of carbon-based nanomaterials for cancer therapy has advanced rapidly. Within those nanomaterials, reduced graphene oxide (rGO), a graphene family 2D carbon nanomaterial, emerged as a good candidate for cancer photothermal therapy due to its excellent photothermal conversion in the near infrared range, large specific surface area for drug loading, as well as functional groups for functionalization with molecules such as photosensitizers, siRNA, ligands, etc. By unique design, multifunctional nanosystems could be designed based on rGO, which are endowed with promising temperature/pH-dependent drug/gene delivery abilities for multimodal cancer therapy. This could be further augmented by additional advantages offered by functionalized rGO, such as high biocompatibility, targeted delivery, and enhanced photothermal effects. Herewith, we first provide an overview of the most effective reducing agents for rGO synthesis via chemical reduction. This was followed by in-depth review of application of functionalized rGO in different cancer treatment modalities such as chemotherapy, photothermal therapy and/or photodynamic therapy, gene therapy, chemotherapy/phototherapy, and photothermal/immunotherapy.


Asunto(s)
Grafito/uso terapéutico , Nanomedicina/tendencias , Nanoestructuras/uso terapéutico , Neoplasias/terapia , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Portadores de Fármacos/química , Portadores de Fármacos/uso terapéutico , Grafito/química , Humanos , Nanoestructuras/química , Neoplasias/patología , Fotoquimioterapia/métodos , Fototerapia/métodos
3.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33801927

RESUMEN

BACKGROUND: Nuclear protein-1 (NUPR1, also known as p8/Com-1) is a transcription factor involved in the regulation of cellular stress responses, including serum starvation and drug stimulation. METHODS: We investigated the mechanism of NUPR1 nuclear translocation involving karyopherin ß1 (KPNB1), using a single-molecule binding assay and confocal microscopy. The cellular effects associated with NUPR1-KPNB1 inhibition were investigated by gene expression profiling and cell cycle analysis. RESULTS: The single-molecule binding assay revealed that KPNB1 bound to NUPR1 with a binding affinity of 0.75 nM and that this binding was blocked by the aminothiazole ATZ-502. Following doxorubicin-only treatment, NUPR1 was translocated to the nucleus in more than 90% and NUPR1 translocation was blocked by the ATZ-502 combination treatment in MDA-MB-231 with no change in NUPR1 expression, providing strong evidence that NUPR1 nuclear translocation was directly inhibited by the ATZ-502 treatment. Inhibition of KPNB1 and NUPR1 binding was associated with a synergistic anticancer effect (up to 19.6-fold) in various cancer cell lines. NUPR1-related genes were also downregulated following the doxorubicin-ATZ-502 combination treatment. CONCLUSION: Our current findings clearly demonstrate that NUPR1 translocation into the nucleus requires karyopherin ß1 binding. Inhibition of the KPNB1 and NUPR1 interaction may constitute a new cancer therapeutic approach that can increase the drug efficacy while reducing the side effects.


Asunto(s)
Acrilamidas/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Benzotiazoles/farmacología , Doxorrubicina/farmacología , Proteínas de Neoplasias/metabolismo , beta Carioferinas/metabolismo , Acrilamidas/química , Transporte Activo de Núcleo Celular/efectos de los fármacos , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Benzotiazoles/química , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Sinergismo Farmacológico , Humanos , Células MCF-7 , Microscopía Confocal , Estructura Molecular , Unión Proteica/efectos de los fármacos
4.
Int J Nanomedicine ; 16: 1943-1960, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727808

RESUMEN

Introduction: The overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) is usually associated with aggressive and infiltrating breast cancer (BC) phenotype, and metastases. Functionalized silica-based nanocarriers (SiNPs) can be labeled for in vivo imaging applications and loaded with chemotherapy drugs, making possible the simultaneous noninvasive diagnosis and treatment (theranostic) for HER2-positive BC. Methods: Firstly, FITC-filled SiNPs, were engineered with two different amounts of Hc-TZ (trastuzumab half-chain) per single nanoparticle (1:2 and 1:8, SiNPs to Hc-TZ ratio), which was 99mTc-radiolabeled at histidine residues for ex vivo and in vivo biodistribution evaluations. Secondly, nanoparticles were loaded with DOX and their in vitro and ex vivo/in vivo delivery was assessed, in comparison with liposomal Doxorubicin (Caelyx). Finally, the treatment efficacy of DOX-SiNPs-TZ (1:8 Hc-TZ) was evaluated in vivo by PET and supported by MS-based proteomics profiling of tumors. Results: SiNPs-TZ (1:8 Hc-TZ) tumor uptake was significantly greater than that of SiNPs-TZ (1:2 Hc-TZ) at 6 hours post-injection (p.i.) in ex vivo biodistribution experiment. At 24 h p.i., radioactivity values remained steady. Fluorescence microscopy, confirmed the presence of radiolabeled SiNPs-TZ (1:8 Hc-TZ) within tumor even at later times. SiNPs-TZ (1:8 Hc-TZ) nanoparticles loaded with Doxorubicin (DOX-SiNPs-TZ) showed a similar DOX delivery capability than Caelyx (at 6 h p.i.), in in vitro and ex vivo assays. Nevertheless, at the end of treatment, tumor volume was significantly reduced by DOX-SiNPs-TZ (1:8 Hc-TZ), compared to Caelyx and DOX-SiNPs treatment. Proteomics study identified 88 high stringent differentially expressed proteins comparing the three treatment groups with controls. Conclusion: These findings demonstrated a promising detection specificity and treatment efficacy for our system (SiNPs-TZ, 1:8 Hc-TZ), encouraging its potential use as a new theranostic agent for HER2-positive BC lesions. In addition, proteomic profile confirmed that a set of proteins, related to tumor aggressiveness, were positively affected by targeted nanoparticles.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Portadores de Fármacos/química , Nanopartículas/química , Radiofármacos/química , Receptor ErbB-2/metabolismo , Dióxido de Silicio/química , Tecnecio/química , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Doxorrubicina/análogos & derivados , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Endocitosis , Femenino , Fluoresceína-5-Isotiocianato/química , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Polietilenglicoles/química , Polietilenglicoles/farmacología , Polietilenglicoles/uso terapéutico , Proteoma/metabolismo , Proteómica , Radiofármacos/farmacocinética , Tecnecio/farmacocinética , Distribución Tisular/efectos de los fármacos , Tomografía Computarizada de Emisión de Fotón Único , Resultado del Tratamiento
5.
Carbohydr Polym ; 259: 117696, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33673985

RESUMEN

Doxorubicin (DOX), an anthracycline drug, is widely used for the treatment of several cancers like osteosarcoma, cervical carcinoma, breast cancer, etc. DOX lacks target specificity; thereby it also affects normal cells thus resulting in several side-effects. A drug delivery system (DDS) can be used to deliver the drug in a controlled and sustained manner at a targeted site within the body. Various DDS like nanoemulsions, polymeric nanoparticles, and liposomes are used for loading DOX. Alginate, a polysaccharide is widely used for fabricating DDS due to its biodegradable and bio-compatible properties. Alginates, in combination with other biomaterials, have been extensively used as a novel drug delivery carrier for DOX. Alginate provides a platform for drug delivery in different forms like hydrogels, nanogels, nanoparticles, microparticles, graphene oxide systems, magnetic systems, etc. Herein, we briefly describe alginate in combination with other materials as a nanocarrier for targeted delivery of DOX for anti-cancer treatment.


Asunto(s)
Alginatos/química , Antibióticos Antineoplásicos/química , Doxorrubicina/química , Portadores de Fármacos/química , Animales , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/metabolismo , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Humanos , Hidrogeles/química , Nanogeles/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología
6.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652957

RESUMEN

Multidrug resistance (MDR) remains a major problem in cancer therapy and is characterized by the overexpression of p-glycoprotein (P-gp) efflux pump, upregulation of anti-apoptotic proteins or downregulation of pro-apoptotic proteins. In this study, an Apolipoprotein A1 (ApoA1)-modified cationic liposome containing a synthetic cationic lipid and cholesterol was developed for the delivery of a small-molecule chemotherapeutic drug, doxorubicin (Dox) to treat MDR tumor. The liposome-modified by ApoA1 was found to promote drug uptake and elicit better therapeutic effects than free Dox and liposome in MCF-7/ADR cells. Further, loading Dox into the present ApoA1-liposome systems enabled a burst release at the tumor location, resulting in enhanced anti-tumor effects and reduced off-target effects. More importantly, ApoA1-lip/Dox caused fewer adverse effects on cardiac function and other organs in 4T1 subcutaneous xenograft models. These features indicate that the designed liposomes represent a promising strategy for the reversal of MDR in cancer treatment.


Asunto(s)
Apolipoproteína A-I/química , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/análogos & derivados , Apolipoproteína A-I/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Células MCF-7 , Polietilenglicoles/química , Polietilenglicoles/farmacología
7.
Carbohydr Polym ; 260: 117779, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33712135

RESUMEN

Task-specific drug release is essential in the development of hydrogels as drug delivery systems. The aim of the study is to report the effect of porosity on alginate hydrogels, which may be controlled by the design of crosslinkers, on drug release behavior. Two alginate-based hydrogels were prepared: alginate-norbornene (Alg-Nb) crosslinked by disulfide-tetrazine (S-Tz; hydrogel A) and alginate-furfuryl amine (Alg-FA) crosslinked by disulfide-maleimide (S-Ma; hydrogel B). Results showed the porosity of hydrogel A was controllable by adjusting the amount of S-Tz. Gel formation was facilitated by a "click" reaction between Alg-Nb and S-Tz, producing nitrogen gas, which, in turn, acted as an in-situ pore generator. Hydrogel B showed a non-porous morphology, as gelation was processed via addition reaction between Alg-FA and S-Ma, which produced no by-product. The study showed that crosslinker proportion and porosity were significant factors influencing drug release behavior of the alginate hydrogels. The presence of a porous structure increased the drug release while non-porous hydrogels led to a very slow release. In addition, the porous alginate hydrogels could sustainably release doxorubicin for 35 days.


Asunto(s)
Alginatos/química , Doxorrubicina/química , Portadores de Fármacos/química , Hidrogeles/química , Disulfuros/química , Doxorrubicina/metabolismo , Liberación de Fármacos , Maleimidas/química , Porosidad
8.
Toxicol Lett ; 342: 50-57, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33581289

RESUMEN

Carbonyl reduction biotransformation pathway of anthracyclines (doxorubicin, daunorubicin) is a significant process, associated with drug metabolism and elimination. However, it also plays a pivotal role in anthracyclines-induced cardiotoxicity and cancer resistance. Herein, carbonyl reduction of eight anthracyclines, at in vivo relevant concentrations (20 µM), was studied in human liver cytosol, to describe the relationship between their structure and metabolism. Significant differences of intrinsic clearance between anthracyclines, ranging from 0,62-74,9 µL/min/mg were found and associated with data from in silico analyses, considering their binding in active sites of the main anthracyclines-reducing enzymes: carbonyl reductase 1 (CBR1) and aldo-keto reductase 1C3 (AKR1C3). Partial atomic charges of carbonyl oxygen atom were also determined and considered as a factor associated with reaction rate. Structural features, including presence or absence of side-chain hydroxy group, a configuration of sugar chain hydroxy group, and tetracyclic rings substitution, affecting anthracyclines susceptibility for carbonyl reduction were identified.


Asunto(s)
Aclarubicina/metabolismo , Citosol/metabolismo , Doxorrubicina/análogos & derivados , Hepatocitos/metabolismo , Oxidorreductasas/metabolismo , Aclarubicina/química , Oxidorreductasas de Alcohol/genética , Oxidorreductasas de Alcohol/metabolismo , Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas/genética , Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Sitios de Unión , Biotransformación , Doxorrubicina/química , Doxorrubicina/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Conformación Proteica
9.
ACS Appl Mater Interfaces ; 13(6): 7115-7126, 2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33543935

RESUMEN

The success of cancer therapy is always accompanied by severe side effects due to the high amount of toxic antitumor drugs that off-target normal organs/tissues. Herein, we report the development of a trifunctional layered double hydroxide (LDH) nanosystem for combined photochemotherapy of skin cancer at very low therapeutic doses. This nanosystem (ICG/Cu-LDH@BSA-DOX) is composed of acid-responsive bovine serum albumin-doxorubicin prodrug (BSA-DOX) and indocyanine green (ICG)-intercalated Cu-doped LDH nanoparticle. ICG/Cu-LDH@BSA-DOX is able to release DOX in an acid-triggered manner, efficiently and simultaneously generates heating and reactive oxygen species (ROS) upon 808 nm laser irradiation, and synergistically induces apoptosis of skin cancer cells. In vivo therapeutic evaluations demonstrate that ICG/Cu-LDH@BSA-DOX nearly eradicated the tumor tissues upon one-course treatment using very low doses of therapeutic agents (0.175 mg/kg DOX, 0.5 mg/kg Cu, and 0.25 mg/kg ICG) upon very mild 808 nm laser irradiation (0.3 W/cm2 for 2 min). This work thus provides a novel strategy to design anticancer nanomedicine for efficient combination cancer treatment with minimal side effects in clinical applications.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Hidróxidos/farmacología , Melanoma/terapia , Fotoquimioterapia , Neoplasias Cutáneas/terapia , Animales , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cobre/química , Cobre/farmacología , Relación Dosis-Respuesta a Droga , Doxorrubicina/química , Ensayos de Selección de Medicamentos Antitumorales , Hidróxidos/química , Verde de Indocianina/química , Verde de Indocianina/farmacología , Rayos Láser , Melanoma/metabolismo , Melanoma/patología , Ratones , Estructura Molecular , Tamaño de la Partícula , Especies Reactivas de Oxígeno/metabolismo , Albúmina Sérica Bovina/química , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Propiedades de Superficie
10.
ACS Appl Mater Interfaces ; 13(7): 8940-8951, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33565847

RESUMEN

Chemotherapy is currently the most universal therapeutics to tumor treatment; however, limited curative effect and undesirable drug resistance effect are the two major clinical bottlenecks. Herein, we develop a two-in-one cross-linking strategy to prepare a stimuli-responsive prodrug nanogel by virtue of delivering a combination of chemotherapeutic drugs of 10-hydroxy camptothecin and doxorubicin for ameliorating the deficiencies of chemotherapy and amplifying the cancer therapeutic efficiency. The obtained prodrug nanogel has both high drug loading capacity and suitable nanoscale size, which are beneficial to the cell uptake and tumor penetration. Moreover, the chemotherapeutic drugs are released from the prodrug nanogel in response to the reductive tumor microenvironment, enhancing tumor growth inhibition in vitro and in vivo by the synergistic DNA damage. Based on these results, the unique prodrug nanogel would be a promising candidate for satisfactory tumor treatment-based chemotherapy by a simple but efficient strategy.


Asunto(s)
Antineoplásicos/farmacología , Camptotecina/farmacología , Reactivos de Enlaces Cruzados/farmacología , Doxorrubicina/farmacología , Profármacos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Camptotecina/química , Cápsulas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Reactivos de Enlaces Cruzados/síntesis química , Reactivos de Enlaces Cruzados/química , Daño del ADN/efectos de los fármacos , Doxorrubicina/química , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Nanogeles/química , Oxidación-Reducción , Tamaño de la Partícula , Polietilenglicoles/química , Polietileneimina/química , Profármacos/síntesis química , Profármacos/química , Propiedades de Superficie , Microambiente Tumoral/efectos de los fármacos
11.
ACS Appl Mater Interfaces ; 13(7): 8060-8070, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33576220

RESUMEN

The high activity of specific enzymes in cancer has been utilized in cancer diagnosis, as well as tumor-targeted drug delivery. NAD(P)H:quinone oxidoreductase-1 (NQO1), an overexpressed enzyme in certain tumor types, maintains homeostasis and inhibits oxidative stress caused by elevated reactive oxygen species (ROS) in tumor cells. The activity of NQO1 in lung and liver cancer cells is increased compared to that in normal cells. Interestingly, NQO1 reacts with trimethyl-locked quinone propionic acid (QPA) and produces a lactone-based group via intramolecular cyclization. Toward this objective, we synthesized an amphiphilic block copolymer (QPA-P) composed of NQO1 enzyme-triggered depolymerizable QPA-locked polycaprolactone (PCL) and poly(ethylene glycol) (PEG) as hydrophobic and hydrophilic constituents, respectively. This QPA-P formed self-assembled micelles in aqueous conditions. It was observed that NQO1 catalyzed the depolymerization of QPA-locked PCL via a cascade two-step cyclization process, which eventually induced the dissociation of micellar structure and triggered the release of loaded drugs at the target cancer cells. Compared to the control group, the NQO1-responsive micelle showed NQO1-triggered intracellular drug release and enhanced anticancer effects. These results indicate that the NQO1-responsive polymeric micelles present a promising potential for improving therapeutic efficacy of an anticancer drug delivery system.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Neoplasias Pulmonares/tratamiento farmacológico , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Polímeros/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Benzoquinonas/química , Benzoquinonas/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclización , Doxorrubicina/química , Doxorrubicina/metabolismo , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Lactonas/química , Lactonas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Micelas , Estructura Molecular , NAD(P)H Deshidrogenasa (Quinona)/química , Tamaño de la Partícula , Polimerizacion , Polímeros/química , Propionatos/química , Propionatos/metabolismo , Propiedades de Superficie , Células Tumorales Cultivadas
12.
J Mater Chem B ; 9(4): 1030-1039, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33398321

RESUMEN

Small intestine-targeted drug delivery by oral administration has aroused the growing interest of researchers. In this work, the child-parent microrobot (CPM) as a vehicle protects the child microrobots (CMs) under a gastric acid environment and releases them in the small intestinal environment. The intelligent hydrogel-based CPMs with sphere, mushroom, red blood cell, and teardrop shapes are fabricated by an extrusion-dripping method. The CPMs package uniform CMs, which are fabricated by designed microfluidic (MF) devices. The fabrication mechanism and tunability of CMs and CPMs with different sizes and shapes are analyzed, modeled, and simulated. The shape of CPM can affect its drug release efficiency and kinetic characteristics. A vision-feedback magnetic driving system (VMDS) actuates and navigates CPM along the predefined path to the destination and continuously releases drug in the simulated intestinal fluid (SIF, a low Reynolds number (Re) regime) using a new motion control method with the tracking-learning-detection (TLD) algorithm. The newly designed CPM combines the advantages of powerful propulsion, good biocompatibility, and remarkable drug loading and release capacity at the intestinal level, which is expected to be competent for oral administration of small intestine-targeted therapy in the future.


Asunto(s)
Doxorrubicina/química , Sistemas de Liberación de Medicamentos , Hidrogeles/química , Nanopartículas de Magnetita/química , Robótica , Células Cultivadas , Niño , Humanos , Dispositivos Laboratorio en un Chip , Fenómenos Magnéticos , Tamaño de la Partícula , Robótica/instrumentación , Propiedades de Superficie
13.
J Mater Chem B ; 9(4): 1049-1058, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33399610

RESUMEN

It is difficult for drug delivery systems to release drugs as expected, often leading to undesired side effects. To solve this problem, a CuS@MSN/DOX@MnO2@membrane (CMDMm) was reasonably designed. It was introduced to release the drug by a double response, similar to using two keys to open two locks at the same time for one door. CuS@MSN was used as a photothermal therapy (PTT) material and carrier, and then the surface of CuS@MSN/DOX was sealed by MnO2 to prevent drug release in advance. MnO2 could be reduced and degraded in a tumor microenvironment. It was applied in MR imaging due to the T1 magnetism of Mn2+ following the reduction of MnO2. Finally, the 4T1 cell membrane was extracted and coated onto the surface of CuS@MSN/DOX@MnO2, which served as a target for 4T1 tumor cells. A noteworthy phenomenon was that the fluorescence of DOX was quenched by the coordination between DOX and CuS, and this greatly improved the interaction between DOX and CuS@MSN. However, the coordination was weakened when DOX was protonated in a tumor microenvironment (∼pH 5.0), leading to the release of DOX and fluorescence recovery. The drug release experiments showed that the release efficiency was higher at pH 5.0 with 10 mmol L-1 GSH. Through in vitro laser confocal imaging, it was successfully observed that DOX was reliably released in specific tumor cells according to the fluorescence recovery, and that there was no leakage in other cells. In short, effective double response drug release was successfully confirmed.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Cobre/farmacología , Doxorrubicina/farmacología , Compuestos de Manganeso/farmacología , Nanopartículas/química , Óxidos/farmacología , Animales , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cobre/química , Doxorrubicina/química , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Compuestos de Manganeso/química , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Óxidos/química , Tamaño de la Partícula , Propiedades de Superficie
14.
ACS Appl Mater Interfaces ; 13(5): 6034-6042, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33499584

RESUMEN

MicroRNA (miRNA) represents a promising class of therapeutic nucleic acid drugs, while delivery challenges remain that impede the advancement of miRNA therapy, largely because of in vivo instability and low delivery efficiency. Herein, we discover the dual roles of metal-organic framework (MOF) nanoparticles (ZIF-8) as nanocarriers for miRNA delivery and adjuvants for chemodynamic therapy. The miR-34a-m@ZIF-8 complex demonstrated efficient cellular uptake and lysosomal stimuli-responsive miRNA release. Zn2+ triggered the generation of reactive oxygen species, which consequently induced apoptosis of tumor cells. Released miR-34a-m led to a remarkable decrease in expression of Bcl-2 at both mRNA and protein levels and enhanced cancer cell apoptosis. In vivo experiments showed high efficacy of using miR-34a-m@ZIF-8 to suppress tumor growth via synergistic gene/chemodynamic therapy in a mouse model of triple-negative breast cancer. Our work demonstrates MOFs as a promising nanoplatform for efficient synergetic gene/chemodynamic therapy.


Asunto(s)
Adyuvantes Farmacéuticos/farmacología , Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Estructuras Metalorgánicas/química , MicroARNs/farmacología , Nanopartículas/química , Adyuvantes Farmacéuticos/química , Animales , Antibióticos Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Ratones , MicroARNs/química , Tamaño de la Partícula , Especies Reactivas de Oxígeno/metabolismo , Propiedades de Superficie , Zeolitas/química , Zeolitas/farmacología
15.
ACS Appl Mater Interfaces ; 13(7): 7890-7896, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33513005

RESUMEN

Nanodrug delivery systems are very promising for highly efficient anticancer drug delivery. However, the present nanosystems are commonly located in the cytoplasm and mediate uncontrolled release of drugs into cytosol, while a large number of anticancer drugs function more efficiently inside the nucleus. Here, we constructed a CRISPR-dCas9-guided and telomerase-responsive nanosystem for nuclear targeting and smart release of anticancer drugs. CRISPR-dCas9 technology has been employed to achieve conjugation of mesoporous silica nanoparticles (MSNs) with a high payload of the active anticancer drug, doxorubicin (DOX). A specifically designed wrapping DNA was used as a telomerase-responsive biogate to encapsulate DOX within MSNs. The wrapping DNA is extended in the presence of telomerase, which is highly activated in tumor cells, but not in normal cells. The extended DNA sequence forms a rigid hairpin-like structure and diffuses away from the MSN surface. CRISPR-dCas9 specifically targets telomere-repetitive sequences at the tips of chromosomes, facilitating the precise delivery of the nanosystem to the nucleus, and effective drug release triggered by telomerase that was enriched around telomeric repeats. This study provides a strategy and nanosystem for nuclear-targeted delivery and tumor-specific release of anticancer drugs that will maximize the efficiency of cancer cell destruction.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Proteína 9 Asociada a CRISPR/química , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Telomerasa/química , Antibióticos Antineoplásicos/química , Proteína 9 Asociada a CRISPR/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Doxorrubicina/química , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Estructura Molecular , Nanopartículas/metabolismo , Imagen Óptica , Tamaño de la Partícula , Porosidad , Propiedades de Superficie , Telomerasa/metabolismo
16.
Int J Nanomedicine ; 16: 457-467, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33488080

RESUMEN

Background: Tumor angiogenesis plays a crucial role in tumor development, and recent efforts have been focused on combining proapoptotic and antiangiogenic activities to enhance antitumor therapy. Methods: In this study, galactose-modified liposomes (Gal-LPs) were prepared for co-delivery of doxorubicin (DOX) and combretastatin A4 phosphate (CA4P). The co-cultured system composed of BEL-7402 and human umbilical vein endothelial cells (HUVEC) cells was established to effectively evaluate in vitro anti-tumor activity through cell viability and cell migration assay. Furthermore, both in vivo bio-distribution and anti-hepatoma effect of DOX&CA4P/Gal-LPs were investigated on H22 tumor cell-bearing mice. Results: The results showed that DOX&CA4P/Gal-LPs were spherical with a mean particle size of 143 nm, and could readily be taken up by BEL-7402 cells. Compared with a mixture of free DOX and CA4P, the DOX&CA4P/Gal-LPs were more effective in inhibiting cell migration and exhibited stronger cytotoxicity against BEL-7402 cells alone or a co-cultured system. The in vitro studies showed that the co-cultured system was a more effective model to evaluate the anti-tumor activity of combination therapy. Moreover, DOX&CA4P/Gal-LPs exhibited a greater anti-hepatoma effect than other drug formulations, indicating that Gal-LPs could promote drug accumulation in the tumor region and improve the anti-tumor activity. Conclusion: Gal-LPs co-loaded with chemotherapeutic and antiangiogenic drugs are a promising strategy for anti-hepatoma therapy.


Asunto(s)
Doxorrubicina/química , Galactosa/química , Liposomas/química , Estilbenos/química , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Composición de Medicamentos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Neoplasias Hepáticas/patología , Ratones , Tamaño de la Partícula , Estilbenos/farmacología
17.
Int J Biol Macromol ; 169: 521-531, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33340628

RESUMEN

In this study, a nanoscale graphene oxide polymer composite drug delivery system was synthesized and investigated for possible oral delivery of doxorubicin. A doxorubicin-loaded nanocomposite composed of graphene oxide/poly(2-hydroxyethylmethacrylate)-g-poly(lactide)-b-polyethyleneglycol-b-poly(2-hydroxyethylmethacrylate)-g-poly(lactide) GO/(PHEMA-g-PLA)-b-PEG-b-(PHEMA-g-PLA) was synthesized via reversible addition fragmentation chain (RAFT) and ring open polymerization (ROP). The GO/(PHEMA-g-PLA)-b-PEG-b- (PHEMA-g-PLA) nanocomposites was characterized by scanning electron microscopy (FE-SEM), thermogravimetry (TG), ultraviolet-visible (UV-Vis) spectroscopy, and dynamic light scattering (DLS). Doxorubicin was successfully loaded into the nanocomposite with a small particle size of 51 nm and an encapsulation efficiency (EE) of 82% ±1.12%. The results showed that DOX was attached to the graphene surface via hydrophobic interactions and π-π stacking. DOX release took place under neutral and acidic conditions, reaching 24.7% and 41.2% respectively after 72 h. Cytotoxicity experiments on 4T1 murine breast cancer cells demonstrated the antitumor activity of the DOX@GO nanocomposite. Biocompatibility, cell uptake, DAPI staining, Annexin V/PI double staining, intracellular reactive oxygen species (ROS) assay, and scratch healing assay were measured. The DOX@graphene nanocomposite system could be promising for breast cancer therapy.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Grafito/química , Poliésteres/química , Animales , Línea Celular Tumoral , Dioxanos , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Doxorrubicina/farmacología , Portadores de Fármacos/química , Humanos , Lactatos , Metacrilatos , Ratones , Nanocompuestos/química , Polietilenglicoles , Polímeros/química , Ácidos Polimetacrílicos
18.
Carbohydr Polym ; 251: 117101, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33142639

RESUMEN

Numbers of UV crosslinkable chitosan hydrogels through chemical modification had drawn increasing attention, however most of these chitosan hydrogels lost the pH-responsive performance because plenty of amino groups (‒NH2) in chitosan were consumed by reacting with other functional groups. To construct a pH-responsive UV-crosslinkable chitosan hydrogel for active modulating drug release with desired behavior, C6-OH selectively modified chitosan via protection/deprotection strategy to amino groups was synthesized, the allyl groups on C6 site and amino groups on C2 site endowed chitosan with UV crosslinking capability and pH responsiveness, respectively. Rapid UV crosslinking gelation (30 s) with low-dose UV irradiation (4 mW/cm2) via "thiol-ene" click chemistry were demonstrated for the patterned microgel and in-situ formed hydrogel in vivo. The swelling and shrinkage of hydrogel could active modulate the opposite release behaviors of doxorubicin (DOX) and bovine serum albumin (BSA) in different pH medium. The smart UV-crosslinkable chitosan hydrogel via click chemistry might provide a new drug carrier for active modulating opposite drug release behaviors.


Asunto(s)
Quitosano/química , Química Clic/métodos , Hidrogeles/química , Compuestos de Sulfhidrilo/química , Animales , Supervivencia Celular , Reactivos de Enlaces Cruzados/química , Doxorrubicina/química , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , Fibroblastos/metabolismo , Concentración de Iones de Hidrógeno , Ratones , Albúmina Sérica Bovina/metabolismo , Inhibidores de Topoisomerasa II/metabolismo , Rayos Ultravioleta
19.
J Mater Chem B ; 9(3): 801-808, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33336680

RESUMEN

Multi stimuli-responsive polymersomes are in high demand as smart drug carriers, particularly for the treatment of complex cancers. However, most polymersomes have multi-responsiveness that does not affect each other and focus on single drug loading. Here, we have designed photo-crosslinked temperature and pH dual-responsive polymersomes by the self-assembly of a triblock polymer of methoxyl poly(ethylene glycol)-b-poly(N-isopropylacrylamide)-b-poly[2-(diethylamino)ethyl methacrylate-co-2-hydroxy-4-(methacryloyloxy)benzophenone] (mPEG-b-PNIPAM-b-P(DEAEMA-co-BMA)) synthesized via reversible addition-fragmentation chain transfer polymerization (RAFT). The dual-responsive polymersomes had a layered membrane, resulting in tunable permeability. Importantly, the polymersomes were proved to have a pH-controlled temperature-responsiveness. A hydrophilic-hydrophobic drug pair (doxorubicin hydrochloride, DOX, and paclitaxel, PTX) could be co-encapsulated in the fabricated polymersomes. The membrane permeability based on its layered structure was triggered by the change in temperature and pH to permit the separate control on the release of DOX and PTX. In a simulated tumor microenvironment, DOX and PTX encapsulated in the polymersomes could take effect for a relatively longer period and could work synergistically. Thus, the photo-crosslinked and dual-responsive polymersomes can be considered as promising drug carriers in the field of tumor combination chemotherapy.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Antineoplásicos Fitogénicos/farmacología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Paclitaxel/farmacología , Polímeros/química , Animales , Antibióticos Antineoplásicos/química , Antineoplásicos Fitogénicos/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Reactivos de Enlaces Cruzados/síntesis química , Reactivos de Enlaces Cruzados/química , Doxorrubicina/química , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Estructura Molecular , Paclitaxel/química , Tamaño de la Partícula , Polímeros/síntesis química , Propiedades de Superficie , Temperatura , Microambiente Tumoral/efectos de los fármacos
20.
Int J Nanomedicine ; 15: 10271-10284, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33364758

RESUMEN

Introduction: Cancer theragnosis involving cancer diagnosis and targeted therapy simultaneously in one integrated system would be a promising solution of cancer treatment. Herein, a convenient and practical cancer theragnosis agent was constructed by combining gold nanocages (AuNCs) covered with selenium and a chitosan (CS) shell (AuNCs/Se) to incorporate the anti-cancer drug doxorubicin (DOX) as a multifunctional targeting nanocomposite (AuNCs/DOX@Se-iRGD) for photoacoustic imaging (PAI)-guided chemo-photothermal synergistic therapy that contributes to enhanced anti-cancer efficacy. The novel design of AuNCs/DOX@Se-iRGD gives the nanocomposite two outstanding properties: (1) AuNCs, with excellent LSPR property in the NIR region, act as a contrast agent for enhanced PAI and photothermal therapy (PTT); (2) Se acts as an anti-cancer nanoagent and drug delivery cargo. Methods: The photothermal performance of these nanocomposites was evaluated in different concentrations with laser powder densities. These nanocomposites were also incubated in pH 5.3, 6.5, 7.4 PBS and NIR laser to study their drug release ability. The cellular uptake was studied by measuring the Se and Au concentrations inside the cells using inductively coupled plasma-mass spectrometry (ICP-MS). Besides, in vitro and in vivo anti-tumor activity were carried out by cytotoxicity assay MTT and tumor model nude mice, respectively. As for imaging, the PA value and images of these nanocomposites accumulated in the tumor site were sequentially collected at specific time points for 48 h. Results and Discussion: The prepared AuNCs/DOX@Se-iRGD showed excellent biocompatibility and physiological stability in different media. In vivo results indicated that the targeting nanocomposite presented the strongest contrast-enhanced PAI signals, which could provide contour and location information of tumor, 24 h after intravenous injection. Likewise, the combined treatment of chemo- and photothermal synergistic therapy significantly inhibited tumor growth when compared with the two treatments carried out separately and showed negligible acute toxicity to the major organs. Conclusion: This study demonstrates that AuNCs/DOX@Se-iRGD has great prospect to become a multifunctional anti-tumor nanosystem for PAI-guided chemo- and photothermal synergistic therapy.


Asunto(s)
Portadores de Fármacos/química , Oro/química , Técnicas Fotoacústicas , Selenio/química , Nanomedicina Teranóstica/métodos , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Terapia Combinada , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Humanos , Ratones , Ratones Desnudos
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