RESUMEN
In the past decade, the study of exosomes, nanosized vesicles (50-150 nm) released into the extracellular space via the fusion of multivesicular bodies with the plasma membrane, has burgeoned with impressive achievements in theranostics applications. These nanosized vesicles have emerged as key players in homeostasis and in the pathogenesis of diseases owing to the variety of the cargos they can carry, the nature of the molecules packaged inside the vesicles, and the robust interactions between exosomes and target cells or tissues. Accordingly, the development of exosome-based liquid biopsy techniques for early disease detection and for monitoring disease progression marks a new era of precision medicine in the 21st century. Moreover, exosomes possess intrinsic properties - a nanosized structure and unique "homing effects" - that make them outstanding drug delivery vehicles. In addition, targeted exosome-based drug delivery systems can be further optimized using active targeting ligands such as nucleic acid aptamers. Indeed, the aptamers themselves can function as therapeutic and/or diagnostic tools based on their attributes of unique target-binding and non-immunogenicity. This review aims to provide readers with a current picture of the research on exosomes and aptamers and their applications in cancer theranostics, highlighting recent advances in their transition from the bench to the clinic.
Asunto(s)
Vesículas Extracelulares/metabolismo , Neoplasias , Medicina de Precisión/métodos , Sistemas de Liberación de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/tendencias , Exosomas/metabolismo , Humanos , Oncología Médica/métodos , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Técnica SELEX de Producción de Aptámeros/métodos , Técnica SELEX de Producción de Aptámeros/tendenciasRESUMEN
The long history of discovery and recently encouraging studies of the anti-cancer effect of aspirin promise a closer step to widely used aspirin-based medication in cancer therapy. To resolve the poor water-solubility of aspirin and low encapsulation efficiency of exosomes for further developing a new delivery of aspirin as anti-cancer treatment, our nanoamorphous exosomal delivery platform was established. In this study, the anti-tumour effects of nanoamorphous aspirin-loaded exosomes with exosomes derived from breast and colorectal cancer cells, were comprehensively studied using both in vitro and in vivo models. These exosomes displayed enhanced cellular uptake via both clathrin-dependent and -independent endocytosis pathways, and significantly improved cytotoxicity of aspirin to breast and colorectal cancer cells, accompanied by the enhanced apoptosis and autophagy. Remarkably, this nanoamorphous exosomal platform endowed aspirin with the unprecedented cancer stem cell eradication capacity. Further animal study demonstrated that this developed exosomal system was able to efficiently deliver aspirin to in vivo tumours. The active targeting of these exosomes to tumour was further improved by conjugating an aptamer specifically targeting EpCAM protein. Hence, this nanoamorphous structured exosome system effectively transformed aspirin into a potential cancer stem cell killer with distinguished properties for clinical translation.
Asunto(s)
Antineoplásicos/farmacología , Aspirina/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Portadores de Fármacos , Sistemas de Liberación de Medicamentos/instrumentación , Exosomas/metabolismo , Nanopartículas , Células Madre Neoplásicas/efectos de los fármacos , Animales , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Aspirina/administración & dosificación , Aspirina/química , Autofagia/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Endocitosis , Femenino , Células HT29 , Humanos , Ratones Endogámicos NOD , Ratones SCID , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) pathogenesis involves multiple pathways, and combined antifibrotic therapy is needed for future IPF therapy. Inhaled interferon-γ (IFN-γ) was recently shown to be safe and without systemic effects in patients with IPF. AIM: To examine the in vitro effects of individual and combined treatment with IFN-γ and pirfenidone (PFD) on normal and IPF fibroblast activation and extracellular matrix remodeling after TGF-ß1 and PDGF-BB stimulation. METHODS: IPF and normal human lung fibroblasts (NHLF) were treated with IFN-γ, PFD or a combination of both drugs in the presence of either TGF-ß1 or PDGF-BB. The effects of TGF-ß1 and PDGF-BB treatment on cell viability, proliferation, differentiation and migration were examined. The expression of collagen 1, matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs) was analyzed using qPCR, Western blotting and gelatin zymography. Total collagen content in conditioned media was also measured using a Sircol assay. RESULTS: Compared to that of PFD, the effect of IFN-γ in downregulating normal and IPF lung fibroblast differentiation to myofibroblasts in response to TGF-ß1 was more potent. Importantly, the combination of IFN-γ and PFD had a possibly synergistic/additive effect in inhibiting the TGF-ß1- and PDGF-BB-induced proliferation, migration and differentiation of normal and IPF lung fibroblasts. Furthermore, both drugs reversed TGF-ß1-induced effects on MMP-1, - 2, - 3, - 7, and - 9, while only PFD promoted TIMP-1 and-2 expression and release. CONCLUSIONS: Our findings demonstrate that the antifibrotic effects of IFN-γ and PFD on normal and IPF lung fibroblasts are different and complementary. Combination therapy with inhaled IFN-γ and PFD in IPF is promising and should be further explored in IPF clinical trials.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Diferenciación Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Interferón gamma/administración & dosificación , Piridonas/administración & dosificación , Adulto , Anciano , Diferenciación Celular/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Fibroblastos/metabolismo , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Adulto JovenRESUMEN
Despite their great potential, the nano-sized extracellular vesicles are yet to become effective delivery systems for poorly water-soluble drugs. Here, we present a novel platform of exosomes as a drug delivery system by engineering of a poorly water-soluble drug into a poloxamer-based molecular nanostructured dispersion composed of a hydrophilic and a hydrophobic moiety for an enhanced anticancer efficacy. For the first time, aspirin was loaded into exosomes as an anticancer agent via a one-step fabrication combining the nano-matrix formation of the nanostructured dispersion and exosomes loading. Our approach could transform crystalline aspirin to a nanoamorphous form in the nano-matrix structured exosomes, leading to increased drug encapsulation efficiency for exosomes, improved dissolution and strongly enhanced cytotoxicity of aspirin to cancer cells. Interestingly, cytotoxicity of aspirin to both breast and colorectal cancer cells could be strongly enhanced by the nanoamorphous aspirin-loaded exosomes, and this cytotoxic effect was more pronounced to parental cells of the exosomes, reminiscent of homing effect. Hence, this study has pioneered a novel nanoplatform of nanoamorphous exosomal delivery system to transform an anti-inflammatory drug into a potent anti-cancer agent.
Asunto(s)
Antineoplásicos/administración & dosificación , Aspirina/administración & dosificación , Sistemas de Liberación de Medicamentos , Exosomas , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos Epoxi/administración & dosificación , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Poloxámero/administración & dosificación , Vitamina E/administración & dosificaciónRESUMEN
BACKGROUND: More than 60% of the active pharmaceutical ingredients, which are classified as Biopharmaceutics Classification System class II. The limited solubility of these drug may lead to low therapeutic effects. METHODS: Nanoprecipitation presents some advantages because it is a straightforward method with low-cost equipment that is easy to scale up. RESULTS: However, there are two technical issues of concern related to this method. First, the two solvents used for this approach must be miscible; concomitantly, the drug has to be soluble enough in a solvent but not in the antisolvent. Second, the particle growth needs to be adjusted by surfactant addition. CONCLUSION: In this review, nanoprecipitation methods and solvent removal techniques for poorly water soluble drugs will be discussed.
Asunto(s)
Nanopartículas/química , Preparaciones Farmacéuticas/química , Precipitación Química , Solubilidad , Agua/químicaRESUMEN
The effects of the lumbosacral Lumbostab orthosis on intervertebral mobility, spinal geometry, and the geometrical deformations of discs have been investigated with a three-dimensional (3-D) reconstruction technique of the lumbar spine. Positions studied are neutral standing, maximal flexion, extension, left lateral bending, and left axial rotation. Results from this preliminary study indicate that the orthosis has a tendency to reduce vertebral mobility and discal deformations mainly at the upper segments (L1-L3), while it seems to increase vertebral displacements and discal deformations at the lower levels.