RESUMEN
A double disulfide tethering depsipeptide dimer, romipeptide A (1) was prepared by NaOH catalyzed dimerization of romidepsin. Its structure was determined by analysis of NMR and HR-ESI-MS data as well as single crystal X-ray diffraction. Bioassay results showed that 1 exhibited good cytotoxic activity against two tumor cell lines B16 and HCT116. This study reported the single crystal data of 1 for the first time. The facile preparation of 1 afforded enough amount for its further biological evaluations.
Asunto(s)
Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Espectroscopía de Resonancia Magnética , Melanoma Experimental/tratamiento farmacológico , Estructura Molecular , Espectrometría de Masa por Ionización de Electrospray , Difracción de Rayos XRESUMEN
We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be utilized in human clinical trials. This class of compounds is designed to carry a payload of a cytotoxic agent and adequately circulate in order to accumulate at a tumor that is being heated. At the target the carrier is activated by heat and releases its contents at high concentrations. We summarize the preclinical and clinical experience of LTLD including its successes and challenges in the development process.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Doxorrubicina/análogos & derivados , Sistemas de Liberación de Medicamentos , Desarrollo de Medicamentos , Hipertermia Inducida , Hipertermia/tratamiento farmacológico , Animales , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Doxorrubicina/síntesis química , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Humanos , Polietilenglicoles/síntesis química , Polietilenglicoles/química , Polietilenglicoles/uso terapéuticoRESUMEN
To overcome high toxicity, low bioavailability and poor water solubility of chemotherapeutics, a variety of drug carriers have been designed. However, most carriers are severely limited by low drug loading capacity and adverse side eï¬ects. Here, a new type of metal-drug nanoparticles (MDNs) was designed and synthesized. The MDNs self-assembled with Fe(III) ions and drug molecules through coordination, resulting in nanoparticles with high drug loading. To assist systemic delivery and prolong circulation time, the obtained MDNs were camouflaged with red blood cell (RBCs) membranes (RBCs@Fe-DOX MDNs) to improve their stability and dispersity. The RBCs@Fe-DOX MDNs presented pH-responsive release functionalities, resulting in drug release accelerated in acidic tumor microenvironments. The outstanding inâ vitro and inâ vivo antitumor therapeutic outcome was realized by RBCs@Fe-DOX MDNs. This study provides an innovative design guideline for chemotherapy and demonstrates the great capacity of nanomaterials in anticancer treatments.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Membrana Celular/química , Doxorrubicina/farmacología , Eritrocitos/química , Compuestos Férricos/farmacología , Nanopartículas/química , Animales , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Férricos/química , Concentración de Iones de Hidrógeno , Ratones , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Tamaño de la PartículaRESUMEN
Epidermal growth factor receptor (EGFR) is overexpressed in many cancers and therefore serves as an excellent target for prodrug activation. Functionalised trans-cyclooctenes (TCO) were conjugated to an EGFR antibody (cetuximab), providing a reagent for pre-targeting and localisation of the bioorthogonal reagent. The TCOs react with a 4-azidobenzyl carbamate doxorubicin prodrug via a [3 + 2]-cycloaddition and subsequent self-immolation leads to release of doxorubicin (click-and-release). In vitro cell-based assays demonstrated proof-of-concept, that cetuximab conjugated to highly strained TCO (AB-d-TCO) could bind to the EGFR in a melanoma cell line, and selectively activate the doxorubicin prodrug. In a non-EGFR expressing melanoma cell line, no significant prodrug activation was observed. In vivo experiments using this combination of AB-d-TCO and the azido-doxorubicin prodrug in a murine melanoma model revealed no significant anti-tumour activity or increased survival, suggesting there was insufficient prodrug activation and drug release at the tumour site.
Asunto(s)
Alquenos/farmacología , Antibióticos Antineoplásicos/farmacología , Azidas/farmacología , Doxorrubicina/farmacología , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Alquenos/química , Animales , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Azidas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Doxorrubicina/síntesis química , Doxorrubicina/química , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Profármacos/síntesis química , Profármacos/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
Breast cancer remains one of the leading cancers among women. Cancer stem cells (CSCs) are tumor-initiating cells which drive progression, metastasis, and reoccurrence of the disease. CSCs are resistant to conventional chemo- and radio-therapies and their ability to survive such treatment enables tumor reestablishment. Metastasis is the main cause of mortality in women with breast cancer, thus advances in treatment will depend on therapeutic strategies targeting CSCs. Salinomycin (SAL) is a naturally occurring polyether ionophore antibiotic known for its anticancer activity towards several types of tumor cells. In the present work, a library of 17 C1-single and C1/C20-double modified SAL analogs was screened to identify compounds with improved activity against breast CSCs. Six single- and two double-modified analogs were more potent (IC50 range of 1.1 ± 0.1-1.4 ± 0.2 µM) toward the breast cancer cell line MDA-MB-231 compared to SAL (IC50 of 4.9 ± 1.6 µM). Double-modified compound 17 was found to be more efficacious than SAL against the majority of cancer cell lines in the NCI-60 Human Tumor Cell Line Panel. Compound 17 was more potent than SAL in inhibiting cell migration and cell renewal properties of MDA-MB-231 cells, as well as inducing selective loss of the CD44+/CD24/low stem-cell-like subpopulation in both monolayer (2D) and organoid (3D) culture. The present findings highlight the therapeutic potential of SAL analogs towards breast CSCs and identify select compounds that merit further study and clinical development.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Piranos/farmacología , Antibióticos Antineoplásicos/síntesis química , Antígeno CD24 , División Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Receptores de Hialuranos/metabolismo , Células MCF-7 , Piranos/síntesis químicaRESUMEN
It is important to enhance penetration depth of nanomedicine and realise rapid drug release simultaneously at targeted tumour for improving anti-tumour efficiency of chemotherapeutic drugs. This project employed sodium alginate (Alg) as matrix material, to establish tumour-responsive nanogels with particle size conversion and drug controlled release functions. Specifically, tumour-targeting peptide CRGDK was conjugated with Alg first (CRGDK-Alg). Then, doxorubicin (DOX) was efficiently encapsulated in CRGDK-FeAlg nanogel during the cross-linking process (CRGDK-FeAlg/DOX). This system was closed during circulation. Once reaching tumour, the particle size of nanogels was reduced to â¼25 nm, which facilitated deep penetration of DOX in tumour tissues. After entering tumour cells, the size of nanogels was further reduced to â¼10 nm and DOX was released simultaneously. Meanwhile, FeAlg efficiently catalysed H2O2 to produce â¢OH by Fenton reaction, achieving local chemodynamic therapy without O2 mediation. Results showed CRGDK-FeAlg/DOX significantly inhibited tumour proliferation in vivo with V/V0 of 1.13 after treatment, significantly lower than that of control group with V/V0 of 4.79.
Asunto(s)
Alginatos/síntesis química , Antibióticos Antineoplásicos/síntesis química , Doxorrubicina/síntesis química , Sistemas de Liberación de Medicamentos/métodos , Tamaño de la Partícula , Células A549 , Alginatos/administración & dosificación , Animales , Antibióticos Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/síntesis química , Doxorrubicina/administración & dosificación , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Marine natural products are known for their diverse chemical structures and extensive bioactivities. Renieramycins, the member of tetrahydroisoquinoline family of marine natural products, arouse interests because of their strong antitumor activities and similar structures to the first marine antitumor agent ecteinascidin-743, approved by the European Union. According to the literatures, researches on the pharmacological activities of renieramycins mainly focus on their antitumor activities. In addition, by structural modification, derivatives of renieramycins show stronger antiproliferative activity and less accidental necrosis activity on cells. Nevertheless, the difficulties in extraction and separation hinder their further development. Hence, the synthetic chemistry work of renieramycins plays a key role in their further development. In this review, currently reported researches on the synthetic chemistry, pharmacological activities and structural modification of renieramycins are summarized, which will benefit future drug development and innovation.
Asunto(s)
Alcaloides/farmacología , Antiinfecciosos/farmacología , Antibióticos Antineoplásicos/farmacología , Antiprotozoarios/farmacología , Productos Biológicos/farmacología , Neoplasias/tratamiento farmacológico , Tetrahidroisoquinolinas/farmacología , Alcaloides/síntesis química , Alcaloides/química , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Estructura Molecular , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/químicaRESUMEN
Doxorubicin (DOX) is widely used as a clinical first-line anti-cancer drug. However, its clinical application is severely limited due to the lack of tumor specificity of the drug and severe side effects such as myelosuppression, nephrotoxicity, dose-dependent cardiotoxicity, and multi-drug resistance. To improve the bioavailability of DOX, maximize the therapeutic effect, and reduce its toxicity and side effects, many studies have been done on the nanoformulations of DOX, such as liposomes, polymer micelles, dendrimer, and nanogels. Herein, we review the latest progress of DOX nano-preparations and their anti-tumor effects, hoping to provide theoretical references and new research ideas for the development of new dosage forms of the drug and the technical methods available for clinical application.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Doxorrubicina/síntesis química , Doxorrubicina/química , Humanos , Conformación Molecular , Neoplasias/patologíaRESUMEN
X-ray-responsive nanocarriers for anticancer drug delivery have shown great promise for enhancing the efficacy of chemoradiotherapy. A critical challenge remains for development of such radiation-controlled drug delivery systems (DDSs), which is to minimize the required X-ray dose for triggering the cargo release. Herein, we design and fabricate an effective DDS based on diselenide block copolymers (as nanocarrier), which can be triggered to release their cargo with a reduced radiation dose of 2 Gy due to their sensitivity to both X-ray and the high level of reactive oxygen species (ROS) in the microenvironment of cancer cells. The underlying molecular mechanism is further illustrated by proton nuclear magnetic resonance (1H NMR) experiments and density functional theory (DFT) calculations. In vivo experiments on tumor-bearing mice validated that the loaded drugs are effectively delivered to the tumor site and exert remarkable antitumor effects (minimum tumor volume/weight) along with X-ray. Furthermore, the diselenide nanocarriers exhibit no noticeable cytotoxicity. These findings provide new insights for the de novo design of radiation-controlled DDSs for cancer chemoradiotherapy.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Compuestos de Selenio/química , Animales , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Teoría Funcional de la Densidad , Doxorrubicina/síntesis química , Doxorrubicina/química , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Imagen Óptica , Tamaño de la Partícula , Compuestos de Selenio/síntesis química , Propiedades de Superficie , Rayos XRESUMEN
A cyclic tetrapeptide, androsamide (1), was isolated from a marine actinomycete of the genus Nocardiopsis, strain CNT-189. The planar structure of 1 was assigned by the interpretation of 1D and 2D NMR spectroscopic data. The absolute configurations of constituent amino acids of 1 were determined by application of the Marfey's and advanced Marfey's methods. Androsamide (1) strongly suppressed the motility of Caco2 cells caused by epithelial-mesenchymal transition.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Nocardiopsis/química , Aminoácidos/química , Antibióticos Antineoplásicos/síntesis química , Células CACO-2 , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fermentación , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Invasividad NeoplásicaRESUMEN
Development of a delivery system to lower systemic toxicity and enhance doxorubicin (DOX) antitumor efficacy against multi-drug resistant (MDR) tumors is of great clinical significance. Here, lipid/hyaluronic acid (HA)-coated DOX-Fe3O4 was characterized to determine its optimal safety and efficacy on a tumor. DOX was first conjugated onto the Fe3O4 NPs surface, which was subsequently coated with phosphatidylcholine (PC) lipids, which consisted of a tumor cell-targeting HA ligand, to generate a dual-targeting nanoparticle (NP). DOX-Fe3O4 synthesis was validated by the Fourier-transform infrared (FT-IR) analysis results. Core-shell PC/HA@DOX-Fe3O4 formation, which had an average particle size of 48.2 nm, was observed based on the transmission electron microscopy (TEM) and dynamic laser light scattering (DLS) results. The saturation magnetization value of PC/HA@DOX-Fe3O4 was discovered to be 28 emu/g using vibrating-sample magnetometry. Furthermore, the designed PC/HA@DOX-Fe3O4 achieved greater MCF-7/ADR cellular uptake and cytotoxicity as compared with DOX. In addition, PC/HA@DOX-Fe3O4 exhibited significant DOX tumor-targeting capabilities and enhanced tumor growth inhibition activity in the xenograft MCF-7/ADR tumor-bearing nude mice following magnetic attraction and ligand-mediated targeting, with less cardiotoxicity. Therefore, PC/HA@DOX-Fe3O4 is a potential candidate for MDR tumor chemotherapy. Graphical abstract.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Compuestos Férricos/administración & dosificación , Ácido Hialurónico/administración & dosificación , Nanopartículas/administración & dosificación , Animales , Antibióticos Antineoplásicos/síntesis química , Doxorrubicina/síntesis química , Compuestos Férricos/síntesis química , Humanos , Ácido Hialurónico/síntesis química , Lípidos , Células MCF-7 , Ratones , Ratones Desnudos , Nanopartículas/química , Tamaño de la Partícula , Distribución Aleatoria , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Efficient drug delivery into tumor cells while bypassing many biological barriers is still a challenge for cancer therapy. By taking advantage of the palladium (Pd)-mediated in situ activation of a prodrug and the glucose oxidase (GOD)-based ß-d-glucose oxidation reaction, we developed a multisynergistic cancer therapeutic platform that combined doxorubicin (DOX)-induced chemotherapy with GOD-mediated cancer-orchestrated oxidation therapy and cancer starvation therapy. In the present work, we first synthesized DOX prodrugs (pDOXs) and temporarily assembled them with ß-cyclodextrins to reduce their toxic side effects. Then, a nanoreactor was constructed by synthesizing Pd0 nanoparticles in situ within the pores of mesoporous silica nanoparticles for the conversion of pDOX into the active anticancer drug. Furthermore, GOD was introduced to decrease the pH of the tumor microenvironment and induce cancer-orchestrated oxidation/starvation therapy by catalyzing ß-d-glucose oxidation to form hydrogen peroxide (H2O2) and gluconic acid. Our study provides a new strategy that employs a cascade chemical reaction to achieve combined orchestrated oxidation/starvation/chemotherapy for the synergistic killing of cancer cells and the suppression of tumor growth.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Doxorrubicina/uso terapéutico , Nanopartículas/química , Profármacos/uso terapéutico , Animales , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Doxorrubicina/síntesis química , Doxorrubicina/química , Femenino , Glucosa Oxidasa/química , Glucosa Oxidasa/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Desnudos , Estructura Molecular , Paladio/química , Tamaño de la Partícula , Profármacos/síntesis química , Profármacos/química , Propiedades de SuperficieRESUMEN
Nowadays, nanoparticle-based combination therapy has been emerging as huge innovation in cancer treatment. Here, we studied the effect of Stattic (STAT3 inhibitor) loaded in nanostructured lipid carriers (NLCs) on enhancing the efficacy, cytotoxicity, and induction of apoptosis of doxorubicin in B16F10 mouse melanoma cancer cell. The evaluation of Stattic-loaded NLCs has been done in terms of zeta potential, particle size, scanning electron microscope (SEM), and cellular uptake. MTT assay was applied to evaluate the cell proliferation. Apoptotic cell death and identification of early and late apoptosis were assessed by DAPI staining and Annexin V/PI staining, respectively. Real-time RT-PCR was applied to measure the effects of doxorubicin and/or Stattic on key apoptotic genes such as Bad, Survivin, HIF1, and STAT3. The Stattic formulated into NLCs shown mean particle size of 56 ± 7 nm which was confirmed by SEM. The IC50 values for Stattic and doxorubicin were 2.95 ± 0.52 µM and 1.21 ± 0.36 µM, respectively. Stattic-loaded NLCs diminished percent of cell proliferation from 68 ± 6.8 to 54 ± 3.7% (p < 0.05). Combinational treatment of the cells with Stattic-loaded nanoparticles and doxorubicin give rise to a significant increase in the percentage of apoptosis (p < 0.05). The study of gene expression profile has shown a remarkable decrease in anti-apoptotic gene, Survivin, along with smooth decline in HIF1 as angiogenesis intermediator and increase in Bad mRNA levels. Our results recommend that NLCs as novel technology have potent strategy to augment efficacy of current chemotherapeutic agent in melanoma cancer cells.
Asunto(s)
Óxidos S-Cíclicos/administración & dosificación , Doxorrubicina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Melanoma , Nanoestructuras/administración & dosificación , Factor de Transcripción STAT3/antagonistas & inhibidores , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/síntesis química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Óxidos S-Cíclicos/síntesis química , Relación Dosis-Respuesta a Droga , Doxorrubicina/síntesis química , Portadores de Fármacos/síntesis química , Composición de Medicamentos/métodos , Lípidos , Melanoma/tratamiento farmacológico , Melanoma/patología , Ratones , Nanoestructuras/química , Resultado del TratamientoRESUMEN
Dendrimer-based nanoparticles have shown promising applications in delivery of small interference RNA (siRNA) to downregulate proteins that contribute to multidrug resistance (MDR). Various types of modification can further enhance the anti-tumor efficacy of dendrimer-based nanoparticles. In this study, generation 4 polyamodoamine (PAMAM) was conjugated with PEG2k-DOPE. The PAMAM-PEG2k-DOPE co-polymer, together with mPEG2k-DOPE, was formulated into mixed dendrimer micelles (MDMs) that can complex siRNA through the cationic PAMAM moieties and encapsulate hydrophobic drug in the micellar lipid cores. DOPE-conjugated hyaluronic acid (HA) was coated on the surface of MDMs to shield the exposed positive charge on PAMAM and to increase the cellular association with CD44+ cancer cells. The HA-modified MDMs could form stable complexes with siRNA, prevent RNase-mediated siRNA degradation and maintain its integrity. Cellular association and cytotoxicity of HA-modified MDMs were investigated in A2780 ADR, MDA-MB-231 and HCT 116 cell lines. The HA-modified MDMs alleviated the toxicity from cationic charge, increase the cancer cell specificity and enhance the cancer cell killing effect in CD44+ cell line.
Asunto(s)
Dendrímeros/administración & dosificación , Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Ácido Hialurónico/administración & dosificación , Nanopartículas/administración & dosificación , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/síntesis química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Dendrímeros/síntesis química , Relación Dosis-Respuesta a Droga , Doxorrubicina/síntesis química , Resistencia a Múltiples Medicamentos/fisiología , Células HCT116 , Humanos , Ácido Hialurónico/síntesis química , Nanopartículas/químicaRESUMEN
In recent years, zeolitic imidazolate framework-8 (ZIF-8) has become an attractive metal organic framework (MOF) material in drug delivery for cancer chemotherapy. However, as a drug delivery system, ZIF-8 still shows some disadvantages, such as short blood circulation time and poor tumor targeting, leading to reduced drug delivery efficiency and unsatisfactory treatment. Herein, we developed a phosphorylcholine-based zwitterionic copolymer coated ZIF-8 nanodrug (DOX@ZIF-8@P(MPC-co-C7A)), and the obtained nanodrug was prepared via a charge-conversional zwitterionic copolymer coating on DOX@ZIF-8 composites. In this system, DOX was encapsulated in the framework of ZIF-8, which could reduce the drug leakage in the bloodstream. The phosphorylcholine-based zwitterionic copolymer effectively extended the blood circulation time, resulting in enhanced tumor accumulation of the nanodrug. Once the nanodrug reached the tumor site, the surface charge of the system could rapidly convert to positive, resulting in an enhanced tumor cellular uptake. Finally, in the acidic environment inside intracellular organelles, DOX will be released rapidly for chemotherapy owing to the fast disintegration of ZIF-8 frameworks. Therefore, the obtained nanodrug could effectively inhibit the growth of A549-bearing tumors (93.2% tumor inhibition rate) with negligible side effects. Overall, this work significantly improved the drug delivery efficiency of ZIF-8, which may pave the way for the biomedical applications of ZIF-8 crystals in anti-tumor drug delivery.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Nanopartículas/química , Fosforilcolina/farmacología , Polímeros/farmacología , Zeolitas/farmacología , Células A549 , Animales , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Tiempo de Circulación Sanguínea , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/síntesis química , Doxorrubicina/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Imagen Óptica , Tamaño de la Partícula , Fosforilcolina/síntesis química , Fosforilcolina/química , Polímeros/síntesis química , Polímeros/química , Propiedades de Superficie , Zeolitas/síntesis química , Zeolitas/químicaRESUMEN
Specific targeted drug delivery and controllable release of drugs at tumor regions are two of the main challenges for hepatocellular carcinoma (HCC) therapy, particularly post metastasis. Herein, we present a platelet membrane-facilitated local chemo-photothermal therapy strategy, in which polypyrrole (PPy) nanoparticles act as photothermal agents and along with antitumor drug doxorubicin (DOX) are encapsulated into platelet membranes (PLT-PPy-DOX). The particles are endowed with immune evasiveness and tumor targeting abilities from platelet membranes, and are then intravenously injected into an orthotopic mouse model of HCC. As expected, the PLT-PPy-DOX nanoplatforms were abundant in the tumor tissues. Hyperthermia was generated under laser irradiation (808 nm) not only to ablate tumor cells directly but also to increase the triggered release of DOX. This combination of local chemotherapy and photothermal therapy demonstrated excellent antitumor efficiency in suppressing primary tumor growth and inhibiting tumor metastases. This localized therapy which adopts biocompatible natural cell membranes and good biodegradable organic photothermal agents may provide new insights into designing biomimetic nano-vehicles for personalized therapy of HCC.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Materiales Biocompatibles Revestidos/farmacología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas/química , Animales , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Carcinoma Hepatocelular/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Materiales Biocompatibles Revestidos/síntesis química , Materiales Biocompatibles Revestidos/química , Terapia Combinada , Doxorrubicina/síntesis química , Doxorrubicina/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hipertermia Inducida , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos ICR , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Neoplasias Experimentales/secundario , Tamaño de la Partícula , Terapia Fototérmica , Propiedades de Superficie , Células Tumorales CultivadasRESUMEN
The macrocyclic structure of 2,18-seco-lankacidinol A, a newly isolated antitumor antibiotic, has been revised on the basis of a concise modular synthesis inspired by a reconsidered biosynthetic proposal. Notable features include (1) an acid-promoted intramolecular transacetalization of a N-lactoyl-O-methyl-N,O-acetal to construct the 4-oxazolidinone ring and (2) late-stage ß-keto imide aldolizations that give rise to facile, stereodivergent access to all lactonic diastereomers.
Asunto(s)
Aldehídos/química , Antibióticos Antineoplásicos/síntesis química , Lactonas/química , Macrólidos/síntesis química , Antibióticos Antineoplásicos/química , Macrólidos/química , Estructura MolecularRESUMEN
Developing drug delivery platforms that can modulate a tumor microenvironment and deliver multiple therapeutics to targeted tumors is critical for efficient cancer treatment. Achieving these platforms still remains a great challenge. Herein, biodegradable nanocapsules based on MnFe hydroxides (H-MnFe(OH)x) have been developed as a new type of cargo delivery with high loading capacity and catalytic activity, enabling synergetic therapy with promoted efficacy by relieving hypoxia in tumor tissues. As a proof of concept, a photosensitizer (indocyanine green, ICG) and a chemotherapeutic drug (doxorubicin, DOX) are co-loaded in nanocapsules and selectively released upon degradation of the nanocapsules in the acidic tumor microenvironment, and are promoted by near infrared irradiation. Meanwhile, Mn2+/Fe3+ ions released from the degradation of nanocapsules catalyze the conversion of H2O2 in a tumor microenvironment into oxygen, which modulates tumor hypoxia and dramatically boosts multimodal therapies. Remarkable synergistic anticancer outcomes have been demonstrated both in vitro and in vivo, paving the way towards future multifunctional therapeutic platforms.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Hipoxia de la Célula/efectos de los fármacos , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Verde de Indocianina/farmacología , Fármacos Fotosensibilizantes/farmacología , Animales , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/síntesis química , Doxorrubicina/química , Femenino , Humanos , Hidróxidos/química , Hidróxidos/farmacología , Verde de Indocianina/química , Hierro/química , Hierro/farmacología , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Manganeso/química , Manganeso/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanocápsulas/química , Tamaño de la Partícula , Fármacos Fotosensibilizantes/química , Terapia Fototérmica , Porosidad , Propiedades de Superficie , Microambiente Tumoral/efectos de los fármacosRESUMEN
The integration of diagnostic and therapeutic functions in a nanoplatform has been a rapidly emerging method in the management of cancer. The application of imaging technology paves the way to track the pharmacokinetics of the nanoplatforms, to guide the treatment, and to monitor the therapeutic processes and outcomes. Herein, we reported a novel type of monodisperses mesoporous silica-coated superparamagnetic iron oxide-based multifunctional nanoplatform (DOX@MMSN-SS-PEI-cit) for the diagnosis and treatment of cancer. The fabrication process included the surface modification of monodisperses mesoporous silica nanoparticle (MMSN) with branched polyethyleneimine (PEI) via disulfide bonds and the further coupling of citraconic anhydride to PEI. Typically, the hydrolysis of amide bonds in the tumor microenvironment (TME) could lead to a negative-to-positive charge reversion, which can enhance the endosomal escape of the resulting nanoplatform. The rapid release of doxorubicin hydrochloride (DOX) directly killed the cancer cells. Due to the superparamagnetic iron oxide-based high-resolution T2-weighted MR imaging contrast agents, this novel multifunctional nanoplatform successfully realized MR imaging, targeted drug delivery and controlled release in one system, and achieved significant improvement in tumor diagnosis and therapy. In summary, the therapeutic nanoplatform is a promising option in precise cancer treatment.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/farmacología , Imagen por Resonancia Magnética , Nanopartículas/química , Animales , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Doxorrubicina/química , Femenino , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Oxidación-Reducción , Tamaño de la Partícula , Porosidad , Dióxido de Silicio/química , Propiedades de Superficie , Células Tumorales CultivadasRESUMEN
Doxorubicin (DOX) is a widely-used anticancer drug, but its cardiotoxicity severely hampers its potency in chemotherapy. Herein, human serum albumin (HSA) is engaged as a biocompatible nanocarrier to load a pH-sensitive DOX prodrug, DMDOX, generating HSA-DMDOX nanoparticles via self-assembly driven by hydrophobic interactions. HSA-DMDOX disperses well in a physiological environment (â¼40 nm) but aggregates in a tumor acidic microenvironment (pH 6.5, â¼140 nm) owing to the hydrophobicity increase of DMDOX by protonation of carboxylic groups. In vitro anticancer study showed that HSA-DMDOX exhibited enhanced cellular uptake by 4T1 cells and superior cytotoxicity in comparison to HSA-DOX nanoparticles. In vivo study suggested that HSA-DMDOX achieved long blood circulation, aggregation enhanced tumor retention, comparable antitumor efficacy and reduced cardiotoxicity relative to free DOX. Our work presents a facile and effective approach to delivering anthracyclines by HSA-based tumor pH-responsive nanoparticles with aggregation-enhanced tumor retention and reduced toxicity.