RESUMEN
Ruthenium coordination complexes have the potential to serve as novel theranostic agents for cancer. However, a major limitation in their clinical implementation is effective tumor accumulation. In this study, we have developed a liposome-based theranostic nanodelivery system for [Ru(phen)2dppz](ClO4)2 (Lipo-Ru). This ruthenium polypyridine complex emits a strong fluorescent signal when incorporated in the hydrophobic lipid bilayer of the delivery vehicle or in the DNA helix, enabling visualization of the therapeutic agent in tumor tissues. Incubation of MDA-MB-231 breast cancer cells with Lipo-Ru induced double-strand DNA breaks and triggers apoptosis. In a mouse model of triple-negative breast cancer, treatment with Lipo-Ru dramatically reduced tumor growth. Biodistribution studies of Lipo-Ru revealed that more than 20% of the injected dose accumulated in the tumor. These results suggest that Lipo-Ru could serve as a promising theranostic platform for cancer.
Asunto(s)
Antineoplásicos/química , Complejos de Coordinación/química , Portadores de Fármacos/química , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/química , Piridinas/química , Rutenio/química , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/administración & dosificación , Femenino , Humanos , Liposomas , Ratones , Ratones Desnudos , Nanomedicina Teranóstica , Distribución TisularRESUMEN
Point mutations in the BCR-ABL1 domain and primitive chronic myelogenous leukemia (CML) cells existing in the bone marrow environment insensitive to tyrosine kinase inhibitors (TKIs) have become two major challenges in the CML therapy. In this study, combined TKI ponatinib and JAK2 inhibitor SAR302503 short-term treatment effectively suppressed growth and promoted apoptosis of BaF3/T315I cells in cytokine-containing medium in vitro. SAR302503 prevented cytokine-dependent resistance to ponatinib via inhibition of JAK2/STAT5 phosphorylation. Codelivery of ponatinib and SAR302503 by active bone-targeted polymeric micellar formulation greatly increased the drug accumulation in medullary cavity. The therapeutic efficacy of bone-targeted formulation was demonstrated in BaF3/T315I cells inoculated murine model with no dose-limited toxicity detectable in health mice. Thus, the intravenous injectable bone-homing ponatinib and SAR302503 micellar formulation represents a promising strategy for the treatment of therapy-resistant CML.
Asunto(s)
Huesos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Imidazoles/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Polímeros/administración & dosificación , Piridazinas/administración & dosificación , Pirrolidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Animales , Antineoplásicos/administración & dosificación , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Huesos/metabolismo , Línea Celular , Línea Celular Tumoral , Química Farmacéutica/métodos , Femenino , Proteínas de Fusión bcr-abl/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Ratones , Ratones Endogámicos BALB C , Micelas , Inhibidores de Proteínas Quinasas/administración & dosificaciónRESUMEN
Various nanodelivery systems have been designed to release therapeutic agents upon contact with specific enzymes. However, enzyme-triggered release typically takes place in the tissue interstitium, thereby resulting in the extracellular delivery of drugs. Here, we have designed an enzyme-stimulated multistage vector (ESMSV), which enables stimulus-triggered release of drug-encapsulated nanoparticles from a microparticle. Specifically, polymeric nanoparticles with a surface matrix metalloproteinase-2 (MMP2) peptide substrate were conjugated to the surface of porous silicon microparticles. In the presence of MMP2, the polymeric nanoparticles were released into the tumor interstitium. This platform can be used to attain triggered drug release, while simultaneously facilitating the cellular internalization of drugs. The results indicate that nanoparticle release was MMP2-specific and resulted in improved intracellular uptake of hydrophobic agents in the presence of MMP2. Furthermore, in a mouse model of melanoma lung metastasis, systemic delivery of ESMSVs caused a substantial increase in intracellular accumulation of agents in cancer cells in comparison to delivery with non-stimulus-responsive particles.
Asunto(s)
Portadores de Fármacos/química , Enzimas/química , Neoplasias/tratamiento farmacológico , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/química , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Femenino , Humanos , Concentración de Iones de Hidrógeno , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Desnudos , Nanopartículas/administración & dosificación , Nanopartículas/química , Tamaño de la Partícula , Polietilenglicoles/química , Polímeros/químicaRESUMEN
Novel aptamer-functionalized polyethylene glycol-polylactic acid (PEG-PLA) (APP) micelles were developed with the objective to target the transferrin receptor on brain endothelial cells. Flurbiprofen, a potential drug for therapeutic management of Alzheimer's disease (AD), was loaded into the APP micelles using the co-solvent evaporation method. Results indicated that 9.03% (w/w) of flurbiprofen was entrapped in APP with good retention capacity in vitro. Targeting potential of APPs was investigated using the transferring receptor-expressing murine brain endothelial bEND5 cell line. APPs significantly enhanced surface association of micelles to bEND5 cells as quantified by fluorescence spectroscopy. Most importantly, APPs significantly enhanced intracellular flurbiprofen delivery when compared to unmodified micelles. These results suggest that APP micelles may offer an effective strategy to deliver therapeutically effective flurbiprofen concentrations into the brain for AD patients.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Aptámeros de Nucleótidos/química , Encéfalo/metabolismo , Sistemas de Liberación de Medicamentos , Flurbiprofeno/administración & dosificación , Micelas , Polietilenglicoles/química , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Aptámeros de Nucleótidos/metabolismo , Secuencia de Bases , Encéfalo/citología , Línea Celular , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Células Endoteliales/metabolismo , Flurbiprofeno/farmacocinética , Ratones , Polietilenglicoles/metabolismo , Receptores de Transferrina/metabolismoRESUMEN
Multi-drug resistance (MDR) in breast cancer poses a great threat to chemotherapy. The expression and function of the ATP binding cassette (ABC) transporter are the major cause of MDR. Herein, a linear polyethylene glycol (PEI) conjugated with dicyandiamide, which called polymeric metformin (PolyMet), was successfully synthesized as a simple and biocompatible polymer of metformin. PolyMet showed the potential to reverse MDR by inhibiting the efflux of the substrate of ATP-binding cassette (ABC) transporter from DOX resistant MCF-7 cells (MCF-7/DOX). To test its MDR reversing effect, PolyMet was combined with DOX to treat mice carrying MCF-7/DOX xenografts. In order to decrease the toxicities of DOX and delivery PolyMet and DOX to tumor at the same time, PolyMet was complexed with poly-γ-glutamic acid-doxorubicin (PGA-DOX) electrostatically at the optimal ratio of 2:3, which were further coated with lipid membrane to form lipid/PolyMet-(PGA-DOX) nanoparticles (LPPD). The particle size of LPPD was 165.8 nm, and the zeta potential was +36.5 mV. LPPD exhibited favorable cytotoxicity and cellular uptake in MCF-7/DOX. Meanwhile, the bioluminescence imaging and immunohistochemical analysis indicated that LPPD effectively conquered DOX-associated MDR by blocking ABC transporters (ABCB1 and ABCC1) via PolyMet. Remarkably, LPPD significantly inhibited the tumor growth and lowered the systemic toxicity in a murine MCF-7/DOX tumor model. This is the first time to reveal that PolyMet can enhance the anti-tumor efficacy of DOX by dampening ABC transporters and activating the AMPK/mTOR pathway, which is a promising strategy for drug-resistant breast cancer therapy.
Asunto(s)
Neoplasias de la Mama , Metformina , Animales , Femenino , Humanos , Ratones , Adenosina Trifosfato , Transportadoras de Casetes de Unión a ATP , Neoplasias de la Mama/patología , Línea Celular Tumoral , Doxorrubicina , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Células MCF-7 , Metformina/farmacología , Polietilenglicoles/metabolismoRESUMEN
Chronic myeloid leukemia (CML) is one type of hematopoietic stem cell diseases. Although BCR-ABL1 tyrosine kinase inhibitors are remarkably effective in inducing remission in chronic phase patients, they are not curative in a majority of patients due to their failure to eradicate residual CML stem/progenitor cells, which reside in bone marrow niches. Here, we presented novel dual oligopeptides-conjugated nanoparticles and demonstrated their effective delivery of arsenic trioxide in bone marrow niches for the elimination of primitive CML cells. We encapsulated As-Ni transitional metal compounds into polymeric nanoparticles based on the reverse micelle rationale. The loading density and stability of arsenic trioxide in nanoparticles were improved. In vitro experiments demonstrated that dual oligopeptides conjugated nanoparticles could deliver arsenic trioxide into bone marrow niches including endosteal niches and vascular niches. The colony-forming activity of CML cells was remarkably restrained in the presence of metaphyseal bone fragments pre-incubated with bone marrow niche targeted arsenic nanoparticles. The in vitro vascular niche model suggested that CML cell proliferation was also successfully inhibited through a tight contact with HUVECs, which were pre-treated using niche-targeted arsenic nanoparticles. This bone marrow niche targeted delivery strategy has a potential usage for the treatment of CML and other malignant hematologic disorders originated from the bone marrow.
Asunto(s)
Trióxido de Arsénico/farmacología , Médula Ósea/química , Proliferación Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/prevención & control , Células Madre Neoplásicas/efectos de los fármacos , Oligopéptidos/química , Acetatos/química , Animales , Trióxido de Arsénico/química , Células Cultivadas , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Ratones , Nanopartículas/química , Compuestos Organometálicos/química , Polímeros/química , Ensayo de Tumor de Célula Madre/estadística & datos numéricosRESUMEN
The synovial tissues are natural sites of drug delivery for the treatment of rheumatoid arthritis. Our previous study showed that mixed monoterpenes edge-activated PEGylated transfersomes (MMPTs) could significantly enhance the percutaneous absorption of sinomenine (SIN), an anti-inflammation drug. The aim of this study was to investigate the potential of MMPTs for delivery of SIN to the synovial tissues in joint cavities. To this end, conventional liposomes (LPSs) were used as a reference. Transmission electron microscope, constant pressure extrusion method, and differential scanning calorimetry (DSC) were used for physicochemical characterization of the formulations. Confocal laser scanning microscopy (CLSM) and double-sited microdialysis coupled with LC-MS/MS were exploited to study the distribution of MMPTs in different skin layers and pharmacokinetics of SIN in the blood and the joint cavities. The results showed that mixed monoterpenes could significantly enhance the elasticity of MMPTs, evidenced by a decrease in the main transition temperature (Tm) and transition enthalpy (â³H). CLSM analyses demonstrated that MMPTs were distributed in deep layers of the skin, indicating that MMPTs might transport SIN through the skin. In contrast, LPSs were confined in the stratum corneum, which deterred SIN from penetrating through the skin. The results from double-sited microdialysis pharmacokinetics showed that in the joint cavities the steady state concentration (Css) and AUC0ât of SIN from MMPTs were 2.1-fold and 2.5-fold of those from LPSs, respectively. In contrast, in the blood the Css and AUC0ât of SIN from MMPTs were about 1/3 of those from LPSs. This study suggested that MMPTs could enhance the delivery of SIN to the joint cavities. A combination of CLSM and double-sited microdialysis could give an insight into the mechanism of transdermal and local drug delivery.
Asunto(s)
Portadores de Fármacos/química , Monoterpenos/química , Morfinanos/química , Polietilenglicoles/química , Administración Tópica , Animales , Área Bajo la Curva , Elasticidad , Articulaciones/metabolismo , Masculino , Microdiálisis , Microscopía Confocal , Morfinanos/sangre , Morfinanos/farmacocinética , Curva ROC , Conejos , Ratas , Ratas Sprague-Dawley , Termodinámica , Temperatura de TransiciónRESUMEN
Aptamers have the potential to be used as targeting ligands for cancer treatment as they form unique spatial structures. Methods: In this study, a DNA aptamer (T1) that accumulates in the tumor microenvironment was identified through in vivo selection and validation in breast cancer models. The use of T1 as a targeting ligand was evaluated by conjugating the aptamer to liposomal doxorubicin. Results: T1 exhibited a high affinity for both tumor cells and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Treatment with T1 targeted doxorubicin liposomes triggered apoptosis of breast cancer cells and PMN-MDSCs. Suppression of PMN-MDSCs, which serve an immunosuppressive function, leads to increased intratumoral infiltration of cytotoxic T cells. Conclusion: The cytotoxic and immunomodulatory effects of T1-liposomes resulted in superior therapeutic efficacy compared to treatment with untargeted liposomes, highlighting the promise of T1 as a targeting ligand in cancer therapy.
Asunto(s)
Aptámeros de Nucleótidos/metabolismo , Doxorrubicina/análogos & derivados , Células Supresoras de Origen Mieloide/metabolismo , Células A549 , Animales , Antígeno CD11b/metabolismo , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacología , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Supresoras de Origen Mieloide/efectos de los fármacos , Polietilenglicoles/química , Polietilenglicoles/farmacología , Receptores de Quimiocina/metabolismoRESUMEN
Surfactants generally have been used as edge activators of transfersomes. However, surfactants edge activated transfersomes frequently lead to cutaneous irritation, skin lipid loss and other side effects after dermal administration. In this study, mixed monoterpenes edge activated PEGylated transfersomes (MMPTs) were prepared by ethanol injection process with sinomenine hydrochloride as a model drug. The formulation of MMPTs was optimized by an orthogonal design. We investigated skin permeation/deposition characteristics and pharmacokinetics of sinomenine hydrochloride loaded in MMPTs by comparing with liposomes using in vitro skin tests and in vivo cutaneous microdialysis. In in vitro study, the accumulative skin permeated quantity (ASPQ) and skin permeation rate (SPR) of simonenine (SIN) in the optimized MMPTs were prominently higher than that in the other MMPTs. The optimized MMPTs had a SIN ASPQ of over three times of SIN ASPQ in the liposomes and much larger SPR of SIN compared with the latter. In contrast, the drug deposition of the optimized MMPTs in the stratum corneum was much less than that of the conventional liposomes. It was noteworthy that the drug deposition curve in the whole skin (stratum corneum-stripped skin, either) for the optimized MMPTs increased initially and then decreased with an obvious peak deposition amount at 12h, while, a relatively steady curve was observed for the liposomes. In in vivo cutaneous pharmacokinetic study, the steady state concentration (Css) and the area under the curve (AUC0ât) of SIN from the optimized MMPTs was 8.7 and 8.2 folds higher than those from the liposomes, respectively. Moreover, the MRT0-inf of SIN from optimal MMPTs got shorter than that from the liposomes. It can be concluded that the optimized MMPTs obviously enhance the percutaneous absorption of sinomenine.
Asunto(s)
Sistemas de Liberación de Medicamentos , Monoterpenos/administración & dosificación , Morfinanos/administración & dosificación , Polietilenglicoles/administración & dosificación , Absorción Cutánea/efectos de los fármacos , Administración Cutánea , Animales , Composición de Medicamentos , Masculino , Microdiálisis , Monoterpenos/química , Monoterpenos/farmacocinética , Morfinanos/química , Morfinanos/farmacocinética , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Conejos , Ratas Sprague-Dawley , Piel/efectos de los fármacos , Piel/metabolismo , Pruebas de Irritación de la PielRESUMEN
The successful treatment of malignant disease generally requires the use of multiple therapeutic agents that are coordinated in a spatiotemporal manner to enable synergy. Here, a porous silicon-based micro/nano composite (MNC) that is capable of simultaneously delivering chemotherapeutic agents and small interfering RNA (siRNA) to the lungs following intravenous injection is designed. The pores of the silicon microparticles are loaded with B-Raf proto-oncogene serine/threonine kinase (BRAF) siRNA-containing liposomes, while the surface is conjugated with docetaxel-encapsulated polymeric nanoparticles. The synergistic antitumor effect of the MNC is demonstrated in vitro in melanoma cells and in vivo using a mouse model for melanoma lung metastasis. The MNC displays superior therapeutic efficacy and increased accumulation in metastatic melanoma lesions in the lungs in comparison to combination therapy with liposomes and polymers. The results indicate that the MNC can be used as an effective delivery vehicle for simultaneous enrichment of multiple therapeutic agents in the lungs.
Asunto(s)
Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Melanoma/patología , Melanoma/terapia , Nanocompuestos/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Terapia Combinada , Docetaxel , Sinergismo Farmacológico , Humanos , Concentración 50 Inhibidora , Ácido Láctico/química , Liposomas/química , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Ratones Desnudos , Microtecnología , Nanocompuestos/ultraestructura , Polietilenglicoles/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas B-raf/metabolismo , ARN Interferente Pequeño/administración & dosificación , Taxoides/farmacología , Taxoides/uso terapéutico , Distribución Tisular/efectos de los fármacos , Resultado del TratamientoRESUMEN
Effective delivery holds the key to successful in vivo application of therapeutic small interfering RNA (siRNA). In this work, we have developed a universal siRNA carrier consisting of a mesoporous silica nanoparticle (MSNP) functionalized with cyclodextrin-grafted polyethylenimine (CP). CP provides positive charge for loading of siRNA through electrostatic interaction and enables effective endosomal escape of siRNA. Using intravital microscopy we were able to monitor tumor enrichment of CP-MSNP/siRNA particles in live mice bearing orthotopic MDA-MB-231 xenograft tumors. CP-MSNP delivery of siRNA targeting the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2) resulted in effective knockdown of gene expression in vitro and in vivo. Suppression of PKM2 led to inhibition of tumor cell growth, invasion, and migration.
Asunto(s)
Antineoplásicos/uso terapéutico , Productos Biológicos/uso terapéutico , Portadores de Fármacos/administración & dosificación , Nanopartículas/administración & dosificación , Neoplasias/terapia , ARN Interferente Pequeño/uso terapéutico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Productos Biológicos/farmacocinética , Productos Biológicos/farmacología , Ciclodextrinas/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Ratones , Polietileneimina/administración & dosificación , Piruvato Quinasa/antagonistas & inhibidores , ARN Interferente Pequeño/farmacocinética , ARN Interferente Pequeño/farmacología , Dióxido de Silicio/administración & dosificaciónRESUMEN
Gene silencing agents such as small interfering RNA (siRNA) and microRNA offer the promise to modulate expression of almost every gene for the treatment of human diseases including cancer. However, lack of vehicles for effective systemic delivery to the disease organs has greatly limited their in vivo applications. In this study, we developed a high capacity polycation-functionalized nanoporous silicon (PCPS) platform comprised of nanoporous silicon microparticles functionalized with arginine-polyethyleneimine inside the nanopores for effective delivery of gene silencing agents. Incubation of MDA-MB-231 human breast cancer cells with PCPS loaded with STAT3 siRNA (PCPS/STAT3) or GRP78 siRNA (PCPS/GRP78) resulted in 91 and 83% reduction of STAT3 and GRP78 gene expression in vitro. Treatment of cells with a microRNA-18a mimic in PCPS (PCPS/miR-18) knocked down 90% expression of the microRNA-18a target gene ATM. Systemic delivery of PCPS/STAT3 siRNA in murine model of MDA-MB-231 breast cancer enriched particles in tumor tissues and reduced STAT3 expression in cancer cells, causing significant reduction of cancer stem cells in the residual tumor tissue. At the therapeutic dosage, PCPS/STAT3 siRNA did not trigger acute immune response in FVB mice, including changes in serum cytokines, chemokines, and colony-stimulating factors. In addition, weekly dosing of PCPS/STAT3 siRNA for four weeks did not cause signs of subacute toxicity based on changes in body weight, hematology, blood chemistry, and major organ histology. Collectively, the results suggest that we have developed a safe vehicle for effective delivery of gene silencing agents.
Asunto(s)
Silenciador del Gen , MicroARNs/genética , Nanomedicina/métodos , ARN Interferente Pequeño/genética , Animales , Arginina/química , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Chaperón BiP del Retículo Endoplásmico , Femenino , Perfilación de la Expresión Génica , Proteínas de Choque Térmico/genética , Humanos , Cinética , Neoplasias Mamarias Experimentales/terapia , Ratones , Microscopía Electrónica de Rastreo , Nanopartículas/química , Polietileneimina/química , ARN Interferente Pequeño/metabolismo , Factor de Transcripción STAT3/genética , Silicio/químicaRESUMEN
A mixed micelle that comprised of MPEG-PLA (MPP) and Pluronic copolymers was developed for enhanced bioavailability and to overcome multidrug resistance of docetaxel in cancer therapy. The mixed micelles that sufficiently solubilized docetaxel were evaluated for the effect of Pluronic copolymers weight ratio on the mixed micelles with respect to drug loading and drug release. In vitro, cell viability and cytotoxicity studies in KB and KBv cells revealed that the mixed micellar formulations were more potent than the commercial docetaxel formulation (Taxotere). In vivo pharmacokinetics study in rats showed that the mixed micelles significantly enhanced the bioavailability of docetaxel (3.6 fold) than Taxotere. Moreover, antitumor activity assessed in KBv cancer xenograft BALB/C nude mice models showed that the mixed micelles significantly reduced the tumor size than the control (Taxotere). Clear differences in the intracellular uptake of docetaxel between MPP and mixed micelles were observed using confocal laser scanning microscopy. This study presents not only a new micelle structure for a diblock-triblock copolymer system, but also a method for enhanced bioavailability of docetaxel and to overcome some of the limitations on its multidrug resistance in cancer therapy.