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BACKGROUND: Stroke AI platforms assess infarcted core and potentially salvageable tissue (penumbra) to identify patients suitable for mechanical thrombectomy. Few studies have compared outputs of these platforms, and none have been multicenter or considered NIHSS or scanner/protocol differences. Our objective was to compare volume estimates and thrombectomy eligibility from two widely used CT perfusion (CTP) packages, Viz.ai and RAPID.AI, in a large multicenter cohort. METHODS: We analyzed CTP data of acute stroke patients with large vessel occlusion (LVO) from four institutions. Core and penumbra volumes were estimated by each software and DEFUSE-3 thrombectomy eligibility assessed. Results between software packages were compared and categorized by NIHSS score, scanner manufacturer/model, and institution. RESULTS: Primary analysis of 362 cases found statistically significant differences in both software's volume estimations, with subgroup analysis showing these differences were driven by results from a single scanner model, the Canon Aquilion One. Viz.ai provided larger estimates with mean differences of 8cc and 18cc for core and penumbra, respectively (p<0.001). NIHSS subgroup analysis also showed systematically larger Viz.ai volumes (p<0.001). Despite volume differences, a significant difference in thrombectomy eligibility was not found. Additional subgroup analysis showed significant differences in penumbra volume for the Phillips Ingenuity scanner, and thrombectomy eligibility for the Canon Aquilion One scanner at one center (7 % increased eligibility with Viz.ai, p=0.03). CONCLUSIONS: Despite systematic differences in core and penumbra volume estimates between Viz.ai and RAPID.AI, DEFUSE-3 eligibility was not statistically different in primary or NIHSS subgroup analysis. A DEFUSE-3 eligibility difference, however, was seen on one scanner at one institution, suggesting scanner model and local CTP protocols can influence performance and cause discrepancies in thrombectomy eligibility. We thus recommend centers discuss optimal scanning protocols with software vendors and scanner manufacturers to maximize CTP accuracy.
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Circulación Cerebrovascular , Selección de Paciente , Imagen de Perfusión , Valor Predictivo de las Pruebas , Interpretación de Imagen Radiográfica Asistida por Computador , Programas Informáticos , Trombectomía , Humanos , Trombectomía/efectos adversos , Imagen de Perfusión/métodos , Femenino , Masculino , Anciano , Reproducibilidad de los Resultados , Persona de Mediana Edad , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/terapia , Accidente Cerebrovascular Isquémico/cirugía , Accidente Cerebrovascular Isquémico/fisiopatología , Accidente Cerebrovascular Isquémico/diagnóstico , Estudios Retrospectivos , Toma de Decisiones Clínicas , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/cirugía , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/diagnóstico , Tomografía Computarizada por Rayos X , Angiografía por Tomografía Computarizada , Anciano de 80 o más AñosRESUMEN
OBJECTIVES: As Comprehensive Stroke Centers (CSCs) strive to improve neuro-intervention (NIR) times, process improvements are put in place to streamline workflows. Our prior publication (VISIION) demonstrated improvements in key performance indicators (KPIs). The purpose VISIION-S was to analyze whether those results were sustainable. MATERIALS AND METHODS: Consecutive Direct Arriving LVO (DALVO) and telemedicine transfer LVO (BEMI) stroke NIR cases were assessed, including subgroups of DALVO-OnHours, DALVO-OffHours, BEMI-OnHours, and BEMI-OffHours. We analyzed times for the original 6 months pre (6/10/20-1/15/21) and compared them to a 17 month post-implementation period (1/16/21- 6/25/22) to evaluate for sustainability. Mann-Whitney U was utilized. RESULTS: 150 NIR cases were analyzed pre (n = 47) v. post (n = 103) implementation (DALVO-OnHours 7 v. 20, DALVO-OffHours 10 v. 25, BEMI-OnHours 13 v. 20, BEMI-OffHours 17 v. 38). For Door-to-groin (DTG), improvement was noted for DALVO-OffHours 39%(157 min,96 min;p < 0.001), DALVO-ALL 25%(127 min,95 min;p = 0.006), BEMI-OffHours 46%(45 min,25 min;p = 0.023), and BEMI-ALL 40%(42 min,25 min;p = 0.005). Activation-to-groin (ATG), door-to-device (DTD), and door-to-recanalization (DTR) also showed statistical improvements. For DALVO-OffHours, there were reductions in door to CT (DTC) 80%(26 min,5 min;p < 0.001), ATG 32%(90 min,61 min;p = 0.036), DTG 39%(157 min,96 min;p < 0.001), DTD 31%(178 min,123 min;p = 0.002), and DTR 32%(197 min,135 min;p = 0.003). CONCLUSIONS: We noted sustainability over a 17 month period with sustained reduction in KPIs for even more NIR time interval comparisons. In the greatest opportunity subgroup (DALVO-OffHours), we noted a reduction in all 5 time interval metrics. Our sustainability finding is important to show that process improvements continued even after the immediate period, adding credibility to the results. Models such as this could be useful for other centers striving to optimize workflow and improve times.
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Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapia , Factores de Tiempo , Tiempo de TratamientoRESUMEN
Nowadays, nanotechnology-based modulation of the immune system is presented as a cutting-edge strategy, which may lead to significant improvements in the treatment of severe diseases. In particular, efforts have been focused on the development of nanotechnology-based vaccines, which could be used for immunization or generation of tolerance. In this review, we highlight how different immune responses can be elicited by tuning nanosystems properties. In addition, we discuss specific formulation approaches designed for the development of anti-infectious and anti-autoimmune vaccines, as well as those intended to prevent the formation of antibodies against biologicals.
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Enfermedades Autoinmunes/terapia , Sistema Inmunológico , Inmunomodulación , Infecciones/terapia , Nanopartículas/uso terapéutico , Nanotecnología , Animales , Humanos , Tolerancia Inmunológica , VacunaciónRESUMEN
A correction to this paper has been published and can be accessed via a link at the top of the paper.
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STUDY DESIGN: Retrospective analysis. OBJECTIVE: To assess the impact of mean arterial blood pressure (MAP) during surgical intervention for spinal cord injury (SCI) on motor recovery. SETTING: Level-one Trauma Hospital and Acute Rehabilitation Hospital in San Jose, CA, USA. METHODS: Twenty-five individuals with traumatic SCI who received surgical and acute rehabilitation care at a level-one trauma center were included in this study. The Surgical Information System captured intraoperative MAPs on a minute-by-minute basis and exposure was quantified at sequential thresholds from 50 to 104 mmHg. Change in International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor score was calculated based on physiatry evaluations at the earliest postoperative time and at discharge from acute rehabilitation. Linear regression models were used to estimate the rate of recovery across the entire MAP range. RESULTS: An exploratory analysis revealed that increased time within an intraoperative MAP range (70-94 mmHg) was associated with ISNCSCI motor score improvement. A significant regression equation was found for the MAP range 70-94 mmHg (F[1, 23] = 5.07, r2 = 0.181, p = 0.034). ISNCSCI motor scores increased 0.039 for each minute of exposure to the MAP range 70-94 mmHg during the operative procedure; this represents a significant correlation between intraoperative time with MAP 70-94 and subsequent motor recovery. Blood pressure exposures above or below this range did not display a positive association with motor recovery. CONCLUSIONS: Hypertension as well as hypotension during surgery may impact the trajectory of recovery in individuals with SCI, and there may be a direct relationship between intraoperative MAP and motor recovery.
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Presión Arterial , Recuperación de la Función , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/cirugía , Adulto , Presión Arterial/fisiología , Determinación de la Presión Sanguínea , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio , Recuperación de la Función/fisiología , Estudios Retrospectivos , Traumatismos de la Médula Espinal/fisiopatología , Factores de TiempoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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The Kirsten Rat Sarcoma Virus (KRAS) oncoprotein, one of the most prevalent mutations in cancer, has been deemed undruggable for decades. The hypothesis of this work was that delivering anti-KRAS monoclonal antibody (mAb) at the intracellular level could effectively target the KRAS oncoprotein. To reach this goal, we designed and developed tLyP1-targeted palmitoyl hyaluronate (HAC16)-based nanoassemblies (HANAs) adapted for the association of bevacizumab as a model mAb. Selected candidates with adequate physicochemical properties (below 150 nm, neutral surface charge), and high drug loading capacity (>10%, w/w) were adapted to entrap the antiKRASG12V mAb. The resulting antiKRASG12V-loaded HANAs exhibited a bilayer composed of HAC16 polymer and phosphatidylcholine (PC) enclosing a hydrophilic core, as evidenced by cryogenic-transmission electron microscopy (cryo-TEM) and X-ray photoelectron spectroscopy (XPS). Selected prototypes were found to efficiently engage the target KRASG12V and, inhibit proliferation and colony formation in KRASG12V-mutated lung cancer cell lines. In vivo, a selected formulation exhibited a tumor growth reduction in a pancreatic tumor-bearing mouse model. In brief, this study offers evidence of the potential to use nanotechnology for developing anti-KRAS precision therapy and provides a rational framework for advancing mAb intracellular delivery against intracellular targets.
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Neuronal intranuclear inclusion disease (NIID), a neurodegenerative disease previously thought to be rare, is increasingly recognized despite heterogeneous clinical presentations. NIID is pathologically characterized by ubiquitin and p-62 positive intranuclear eosinophilic inclusions that affect multiple organ systems, including the brain, skin, and other tissues. Although the diagnosis of NIID is challenging due to phenotypic heterogeneity, a greater understanding of the clinical and imaging presentations can improve accurate and early diagnosis. Here, we present three cases of pathologically proven adult-onset NIID, all presenting with episodes of acute encephalopathy with protracted workups and lengthy time between symptom onset and diagnosis. Case 1 highlights challenges in the diagnosis of NIID when MRI does not reveal classic abnormalities and provides a striking example of hyperperfusion in the setting of acute encephalopathy, as well as unique pathology with neuronal central chromatolysis, which has not been previously described. Case 2 highlights the progression of MRI findings associated with multiple NIID-related encephalopathic episodes over an extended time period, as well as the utility of skin biopsy for antemortem diagnosis.
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Biological macromolecule-based therapeutics irrupted in the pharmaceutical scene generating a great hope due to their outstanding specificity and potency. However, given their susceptibility to degradation and limited capacity to overcome biological barriers new delivery technologies had to be developed for them to reach their targets. This review aims at analyzing the historical seminal advances that shaped the development of the protein/peptide delivery field, along with the emerging technologies on the lead of the current landscape. Particularly, focus is made on technologies with a potential for transmucosal systemic delivery of protein/peptide drugs, followed by approaches for the delivery of antigens as new vaccination strategies, and formulations of biological drugs in oncology, with special emphasis on mAbs. Finally, a discussion of the key challenges the field is facing, along with an overview of prospective advances are provided.
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Productos Biológicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Nanotecnología , Administración a través de la Mucosa , Animales , Sistemas de Liberación de Medicamentos/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Nanotecnología/historia , Neoplasias/tratamiento farmacológico , Péptidos/administración & dosificación , Proteínas/administración & dosificación , Vacunas/administración & dosificaciónRESUMEN
The potential of nanoemulsions for the oral administration of peptides is still in its early stage. The aim of the present work was to rationally design, develop, and fully characterize a new nanoemulsion (NE) intended for the oral administration of hydrophobically modified insulin (HM-insulin). Specific components of the NE were selected based on their enhancing permeation properties as well as their ability to improve insulin association efficiency (Miglyol 812, sodium taurocholate), stability in the intestinal fluids, and mucodiffusion (PEGylated phospholipids and poloxamer 407). The results showed that the NE co-existed with a population of micelles, forming a mixed system that exhibited a 100% of HM-insulin association efficiency. The nanosystem showed good stability and miscibility in different bio-relevant media and displayed an acceptable mucodiffusive behavior in porcine mucus. In addition, it exhibited a high interaction with cell mono-cultures (Caco -2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and co-cultures (C2BBe1 human colon carcinoma Caco-2 clone/HT29-MTX cells). The internalization in Caco-2 monolayers was also confirmed by confocal microscopy. Finally, the promising in vitro behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate, although significant, hypoglycemic response (≈ 20-30%), following intestinal administration to both healthy and diabetic rat models. Overall, this information underlines the crucial steps to address when designing peptide-based nanoformulations to successfully overcome the intestinal barriers associated to the oral modality of administration.
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Insulina , Nanopartículas , Administración Oral , Animales , Células CACO-2 , Sistemas de Liberación de Medicamentos , Humanos , Micelas , Ratas , PorcinosRESUMEN
Background: Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients. Methods: Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods. Results: Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76-[104-117] mmHg associated with neurological recovery. Conclusions: We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention. Funding: NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB).
Spinal cord injury is a devastating condition that involves damage to the nerve fibers connecting the brain with the spinal cord, often leading to permanent changes in strength, sensation and body functions, and in severe cases paralysis. Scientists around the world work hard to find ways to treat or even repair spinal cord injuries but few patients with complete immediate paralysis recover fully. Immediate paralysis is caused by direct damage to neurons and their extension in the spinal cord. Previous research has shown that blood pressure regulation may be key in saving these damaged neurons, as spinal cord injuries can break the communication between nerves that is involved in controlling blood pressure. This can lead to a vicious cycle of dysregulation of blood pressure and limit the supply of blood and oxygen to the damaged spinal cord tissue, exacerbating the death of spinal neurons. Management of blood pressure is therefore a key target for spinal cord injury care, but so far, the precise thresholds to enable neurons to recover are poorly understood. To find out more, Torres-Espin, Haefeli et al. used machine learning software to analyze previously recorded blood pressure and heart rate data obtained from 118 patients that underwent spinal cord surgery after acute spinal cord injury. The analyses revealed that patients who suffered from either low or high blood pressure during surgery had poorer prospects of recovery. Statistical models confirming these findings showed that the optimal blood pressure range to ensure recovery lies between 76 to 104-117 mmHg. Any deviation from this narrow window would dramatically worsen the ability to recover. These findings suggests that dysregulated blood pressure during surgery affects to odds of recovery in patients with a spinal cord injury. Torres-Espin, Haefeli et al. provide specific information that could improve current clinical practice in trauma centers. In the future, such machine learning tools and models could help develop real-time models that could predict the likelihood of a patient's recovery following spinal cord injury and related neurological conditions.
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Presión Arterial , Recuperación de la Función , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Presión Sanguínea , Humanos , Persona de Mediana Edad , Monitoreo Intraoperatorio , Estudios RetrospectivosRESUMEN
OBJECTIVES: To describe the clinical characteristics and risk factors of male-to-female transgender (transwomen) patients with acute stroke. METHODS: The study population included all patients admitted for stroke at San Francisco General Hospital from October 1, 2010 through August 31, 2017 who self-identified as transwomen. Patient charts were reviewed by the study coauthors for demographics, stroke risk factors, stroke characteristics, and clinical outcomes. Means, percentiles, and ranges were calculated. RESULTS: Eight transwomen (average age, 50±9 y; range, 38 to 61 y) were admitted for stroke (average NIHSS, 8; range, 0 to 27). The majority of patients presented subacutely. The most common type of stroke was ischemic stroke (4, 50%), followed by intracerebral hemorrhage (2, 22%), transient ischemic attack (1, 13%), and concurrent ischemic stroke with subarachnoid hemorrhage (1, 13%). While traditional stroke risk factors were present, these patients also disproportionally had alternative risk factors: stimulant use (5, 63%), tobacco use (5, 63%), hepatitis C (5, 63%), human immunodeficiency virus (3, 38%), and prior stroke or transient ischemic attack (2, 25%). Six patients (75%) used estradiol (oral or injection) or conjugated estrogen as part of gender-affirming treatment at the time of stroke; one patient used estrogen remotely. Only 2 patients (33%) were prescribed their hormone therapy on discharge. CONCLUSIONS: Understanding unique vulnerabilities of the transgender community for cerebrovascular events is essential to provide culturally appropriate counseling for harm reduction.
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Accidente Cerebrovascular/epidemiología , Personas Transgénero , Adulto , Isquemia Encefálica/complicaciones , Isquemia Encefálica/epidemiología , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Evaluación del Resultado de la Atención al Paciente , Factores de Riesgo , Accidente Cerebrovascular/complicacionesRESUMEN
Preparation of sophisticated delivery systems for nanomedicine applications generally involve multi-step procedures using organic solvents. In this study, we have developed a simple self-assembling process to prepare docetaxel-loaded hyaluronic acid (HA) nanocapsules by using a self-emulsification process without the need of organic solvents, heat or high shear forces. These nanocapsules, which comprise an oily core and a shell consisting of an assembly of surfactants and hydrophobically modified HA, have a mean size of 130 nm, a zeta potential of -20 mV, and exhibit high docetaxel encapsulation efficiency. The nanocapsules exhibited an adequate stability in plasma. Furthermore, in vitro studies performed using A549 lung cancer cells, showed effective intracellular delivery of docetaxel. On the other hand, blank nanocapsules showed very low cytotoxicity. Overall, these results highlight the potential of self-emulsifying HA nanocapsules for intracellular drug delivery.
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Antineoplásicos/administración & dosificación , Docetaxel/administración & dosificación , Ácido Hialurónico/química , Nanocápsulas/química , Células A549 , Antineoplásicos/farmacología , Docetaxel/farmacología , Sistemas de Liberación de Medicamentos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Tensoactivos/químicaRESUMEN
PURPOSE: Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers. EXPERIMENTAL DESIGN: We have developed a new targeted nanomedicine based on hyaluronic acid-biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both in vitro and in vivo. RESULTS: Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMB-overexpressing cancer cells' behavior in ways such as (i) lowering the in vitro cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells in vivo. Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB. CONCLUSIONS: Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.
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Anticuerpos Monoclonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Movimiento Celular , Resistencia a Antineoplásicos , Proteínas de Neoplasias/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/farmacología , Animales , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Espacio Intracelular , Ratones , Nanocápsulas/química , Proteínas de Neoplasias/metabolismo , Receptor ErbB-2/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chitosan (CS) colloidal carriers, which consist of an oily core and a CS coating, were developed to facilitate a controlled intracellular delivery of docetaxel. The systems presented a particle size of <200 nm and a positive surface charge. As shown by the flow cytometry analysis, fluorescent CS carriers were rapidly internalized by human tumor cells. Fluorescence was observed in more than 80% of MCF7 (human breast adenocarcinoma) and almost 100% of A549 (human lung carcinoma) cells when a 2 h treatment with fluorescent CS carriers was given. A total of 24 h after treatment, docetaxel-loaded CS carriers had an effect on cell proliferation that was significantly greater than that of free docetaxel. These results indicate that docetaxel remains fully active upon its encapsulation into the colloidal carriers and that these systems actively transport docetaxel into cancer cells and, thus, result in a significant increase in its antiproliferative effect.
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Antineoplásicos/administración & dosificación , Quitosano/química , Coloides/química , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Taxoides/administración & dosificación , Línea Celular Tumoral , Proliferación Celular , Química Farmacéutica/métodos , Docetaxel , Colorantes Fluorescentes/química , Humanos , Nanocápsulas/química , Nanopartículas/química , Nanotecnología/métodos , Taxoides/química , Factores de TiempoRESUMEN
Despite the convenience of the oral route for drug administration, the existence of different physiological barriers associated with the intestinal tract greatly lowers the bioavailability of many active compounds. We have previously suggested the potential polymeric nanocapsules, consisting of an oily core surrounded by a polymer shell, as oral drug delivery carriers. Here we present a systematic study of the influence of the surface properties of these nanocapsules on their interaction with the intestinal barriers. Two different surfactants, Pluronic®F68 (PF68) and F127 (PF127), and two polymeric shells, chitosan (CS) and polyarginine (PARG) were chosen for the formulation of the nanocapsules. We analyzed nine different combinations of these polymers and surfactants, and studied the effect of each specific combination on their colloidal stability, enzymatic degradation, and mucoadhesion/mucodiffusion. Our results indicate that both, the polymer shell and the surfactants located at the oil/water interface, influence the interaction of the nanocapsules with the intestinal barriers. More interestingly, according to our observations, the shell components of the nanosystems may have either synergic or disruptive effects on their capacity to overcome the intestinal barriers.
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Intestinos/química , Nanocápsulas/química , Propiedades de Superficie/efectos de los fármacos , Administración Oral , Disponibilidad Biológica , Quitosano/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Péptidos/química , Poloxámero/química , Polietilenos/química , Polímeros/química , Polipropilenos/química , Tensoactivos/químicaRESUMEN
The objective of this work was to investigate the potential utility of nanocapsules composed of an oily core decorated with a single polyarginine (PARG), or double PARG/polyacrylic acid (PAA) layer as oral peptide delivery carrier. A step-by-step formulation optimization process was designed, which involved the study of the influence of the surfactants, oils and polymer shells (PARG of different molecular weight and PAA) on the nanocapsules physicochemical properties, peptide loading efficiency, stability in simulated intestinal fluids (SIF) and capacity to enhance the permeability of the intestinal epithelium. Despite the lipophilic nature of the nanocapsules, it was possible to achieve a moderate loading of the hydrophilic model peptide salmon calcitonin and control its release in SIF, by adjusting the formulation conditions. Finally, studies in the Caco-2 epithelial cell line showed the capacity of the nanocapsules to reduce the transepithelial electric resistance of the monolayer, without compromising their viability. Overall, these properties suggest the capacity of polyarginine nanocapsules for enhancing the transport of peptides across epithelia.
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Portadores de Fármacos/química , Absorción Intestinal , Nanocápsulas , Péptidos/química , Administración Oral , Células CACO-2 , HumanosRESUMEN
We have previously reported the development of novel nanocapsules made of polyarginine (PArg) specifically designed for the delivery of small anticancer drugs into cells. Our goal, in this work, has been to investigate the potential of these nanocarriers for oral delivery of peptide anticancer drugs. To reach this objective, we chose the antitumoral peptide, elisidepsin, and evaluated the characteristics of the PArg nanocapsules in terms of drug loading capacity, stability in simulated intestinal fluids, and ability to interact with the intestinal epithelium both in vitro (Caco-2 model cell line) and in vivo. Our results suggest that elisidepsin can be effectively loaded into the nanocapsules by adjusting the formulation parameters, using a solvent displacement technique. The resulting nanocapsules were stable upon incubation in simulated intestinal fluids and had the ability to reduce, in a transient manner, the transepithelial electrical resistance of the Caco-2 cell monolayer. Confocal images also revealed that PArg nanocapsules were internalized by the monolayer without evident signs of cytotoxicity. Finally, the in vivo fluorescent imaging study illustrates the retention of the nanocapsules in the gastrointestinal tract upon oral administration. Overall, the results underline the potential interest of PArg nanocapsules as carriers for the oral administration of peptide drugs.
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Antineoplásicos/administración & dosificación , Depsipéptidos/administración & dosificación , Nanocápsulas/química , Péptidos/química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Células CACO-2 , Depsipéptidos/farmacocinética , Tracto Gastrointestinal/metabolismo , Humanos , RatonesRESUMEN
Over recent years, a major challenge in drug delivery has been the design of appropriate vehicles for the oral administration of macromolecular drugs (peptides and proteins). Indeed, despite the increasing market value of these complex molecules, their clinical use has been highly limited by their reduced oral bioavailability. Among the different delivery approaches explored so far, those based on the use of the polysaccharide chitosan have opened promising alternatives towards this ambitious goal. This is due to the interesting physicochemical and biopharmaceutical properties of this polymer. This article describes the advances that have been made in the design of chitosan-based systems specially adapted for the oral administration of peptides. These systems include solutions, microspheres, nanoparticles, nanocapsules and liposomes. More specifically, this article discusses the efficacy of the different delivery approaches for improving the absorption of peptides, and analyses the various mechanisms that have been proposed for the understanding of their efficacy.