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1.
Int J Pharm ; 603: 120714, 2021 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-34015380

RESUMEN

Mutations on the epidermal growth factor receptor (EGFR), induction of angiogenesis, and reprogramming cellular energetics are all biological features acquired by tumor cells during tumor development, and also known as the hallmarks of cancer. Targeted therapies that combine drugs that are capable of acting against such concepts are of great interest, since they can potentially improve the therapeutic efficacy of treatments of complex pathologies, such as glioblastoma (GBM). However, the anatomical location and biological behavior of this neoplasm imposes great challenges for targeted therapies. A novel strategy that combines alpha-cyano-4-hydroxycinnamic acid (CHC) with the monoclonal antibody cetuximab (CTX), both carried onto a nanotechnology-based delivery system, is herein proposed for GBM treatment via nose-to-brain delivery. The biological performance of Poly (D,L-lactic-co-glycolic acid)/chitosan nanoparticles (NP), loaded with CHC, and conjugated with CTX by covalent bonds (conjugated NP) were extensively investigated. The NP platforms were able to control CHC release, indicating that drug release was driven by the Weibull model. An ex vivo study with nasal porcine mucosa demonstrated the capability of these systems to promote CHC and CTX permeation. Blot analysis confirmed that CTX, covalently associated to NP, impairs EGRF activation. The chicken chorioallantoic membrane assay demonstrated a trend of tumor reduction when conjugated NP were employed. Finally, images acquired by fluorescence tomography evidenced that the developed nanoplatform was effective in enabling nose-to-brain transport upon nasal administration. In conclusion, the developed delivery system exhibited suitability as an effective novel co-delivery approaches for GBM treatment upon intranasal administration.


Asunto(s)
Glioblastoma , Nanopartículas , Preparaciones Farmacéuticas , Administración Intranasal , Animales , Encéfalo , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Glioblastoma/tratamiento farmacológico , Porcinos
2.
Carbohydr Polym ; 250: 116968, 2020 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-33049864

RESUMEN

Chitosan-based particles are widely proposed as biocompatible drug delivery systems with mucoadhesive and permeation enhancing properties. However, strategies on how to modulate the intended biological responses are still scarce. Considering that particle properties affect the biological outcome, the rational design of the synthesis variables should be proposed to engineer drug delivery systems with improved biological performance. The purpose of this review is to establish a deeper understanding of possible correlations between these variables and the particle properties from theoretical and experimental perspectives. The fundamental physicochemical knowledge of chitosan-based polyelectrolyte complexation and surface modification is discussed focusing on chitosan-TPP, polyelectrolyte complexes, and chitosan-surface modified PLGA or lipid particles. A set of design considerations is proposed to enable future investigation in the development of chitosan particles with modulated properties. The approach presented here contributes to the rational design of chitosan-based particles that meet different requirements for biological activities.


Asunto(s)
Quitosano/química , Sistemas de Liberación de Medicamentos , Nanopartículas/administración & dosificación , Polielectrolitos/química , Nanopartículas/química
3.
Drug Deliv Transl Res ; 10(6): 1729-1747, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32683647

RESUMEN

Nose-to-brain delivery is a promising approach to target drugs into the brain, avoiding the blood-brain barrier and other drawbacks related to systemic absorption, and enabling an effective and safer treatment of diseases such as glioblastoma (GBM). Innovative materials and technologies that improve residence time in the nasal cavity and modulate biological interactions represent a great advance in this field. Mucoadhesive nanoparticles (NPs) based on poly(lactic-co-glycolic acid) (PLGA) and oligomeric chitosan (OCS) were designed as a rational strategy and potential platform to co-deliver alpha-cyano-4-hydroxycinnamic acid (CHC) and the monoclonal antibody cetuximab (CTX) into the brain, by nasal administration. The influence of formulation and process variables (O/Aq volume ratio, Pluronic concentration, PLGA concentration, and sonication time) on the properties of CHC-loaded NPs (size, zeta potential, PDI and entrapment efficiency) was investigated by a two-level full factorial design (24). Round, stable nano-sized particles (213-875 nm) with high positive surface charge (+ 33.2 to + 58.9 mV) and entrapment efficiency (75.69 to 93.23%) were produced by the emulsification/evaporation technique. Optimal process conditions were rationally selected based on a set of critical NP attributes (258 nm, + 37 mV, and 88% EE) for further conjugation with CTX. The high cytotoxicity of CHC-loaded NPs and conjugated NPs was evidenced for different glioma cell lines (U251 and SW1088). A chicken chorioallantoic membrane assay highlighted the expressive antiangiogenic activity of CHC-loaded NPs, which was enhanced for conjugated NPs. The findings of this work demonstrated the potential of this nanostructured polymeric platform to become a novel therapeutic alternative for GBM treatment. Graphical abstract.


Asunto(s)
Encéfalo , Quitosano , Glioblastoma , Nanopartículas , Administración Intranasal , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Quitosano/uso terapéutico , Glioblastoma/tratamiento farmacológico , Humanos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico
4.
Drug Deliv Transl Res ; 10(3): 594-609, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31981140

RESUMEN

Combination therapy that uses multiple drugs against different molecular targets should be considered as interesting alternatives for treating complex diseases such as glioblastoma (GBM). Drugs like alpha-cyano-4-hydroxycinnamic acid (CHC) and the monoclonal antibody cetuximab (CTX) are already explored for their capacity to act against different hallmarks of cancer. Previous reports suggest that the simultaneous use of these drugs, as a novel combining approach, might result in additive or synergistic effects. Therefore, advances in nanotechnology-based delivery systems will inevitably bring nano-mediated therapeutic gains to the proposed combination since they enable the association of different drugs into a single carrier. The current study provides indications that the new dual therapeutic strategy proposed, in association with nanotechnology, provides significative improvements when compared to the use of isolated drugs. Nanotechnological tools were employed by developing polymeric nanoparticles based on poly(lactic-co-glycolic acid) and chitosan for CHC encapsulation. Furthermore, these structures were conjugated with CTX by supramolecular forces. In summary, the encapsulation of the CHC drug into the nanoparticles increased its individual therapeutic capacity. In addition, conjugation with CTX seemed to enhance therapeutic efficacy, especially for U251 GBM cells. In conclusion, developed nanostructured delivery systems exhibited a set of favorable attributes and potential to be applied as a promising new alternative for GBM treatment. Graphical abstract .


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Cetuximab/farmacología , Ácidos Cumáricos/farmacología , Glioblastoma/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cetuximab/química , Quitosano/química , Ácidos Cumáricos/química , Combinación de Medicamentos , Composición de Medicamentos , Sinergismo Farmacológico , Humanos , Nanopartículas , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química
5.
Colloids Surf B Biointerfaces ; 184: 110523, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31634799

RESUMEN

Hexagonal liquid crystals and supramolecular polymers from meglumine-based supra-amphiphiles were developed as drug delivery systems to be applied on the skin. The influence of fatty acid unsaturation on the structure and mechanical properties was evaluated. Moreover, we have investigated the system biocompatibility and how the type of water could influence its bioadhesive properties. Meglumine-oleic acid (MEG-OA) was arranged as hexagonal liquid crystals at 30-70 wt% water content, probably due to its curvature and increased water solubility. Meglumine-stearic acid (MEG-SA) at 10-80 wt% water content self-assembled as a lamellar polymeric network, which can be explained by the low mobility of MEG-SA in water due to hydrophobic interactions between fatty acid chains and H-bonds between meglumine and water molecules. Both systems have shown suitable mechanical parameters and biocompatibility, making them potential candidates to encapsulate therapeutic molecules for skin delivery. Moreover, a strong positive correlation between the amount of unfrozen bound water in meglumine-based systems and the bioadhesion properties was observed. This work shows that a better understanding of the physicochemical properties of a drug delivery system is extremely important for the correlation with the desired biological response and, thus, improve the product performance for biomedical applications.


Asunto(s)
Sistemas de Liberación de Medicamentos , Meglumina/química , Piel/química , Tensoactivos/química , Agua/química , Adhesión Celular , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Meglumina/síntesis química , Meglumina/farmacología , Tamaño de la Partícula , Relación Estructura-Actividad , Propiedades de Superficie , Tensoactivos/síntesis química , Tensoactivos/farmacología , Viscosidad
6.
Eur J Pharm Biopharm ; 119: 271-282, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28669796

RESUMEN

Anti-vascular endothelial growth factor (anti-VEGF) therapy applied to solid tumors is a promising strategy, yet, the challenge to deliver these agents at high drug concentrations together with the maintenance of therapeutic doses locally, at the tumor site, minimizes its benefits. To overcome these obstacles, we propose the development of a bevacizumab-loaded alginate hydrogel by electrostatic interactions to design a delivery system for controlled and anti-angiogenic therapy under tumor microenvironmental conditions. The tridimensional hydrogel structure produced provides drug stability and a system able to be introduced as a flowable solution, stablishing a depot after local administration. Biological performance by the chick embryo chorioallantoic membrane (CAM) assay indicated a pH-independent improved anti-angiogenic activity (∼50%) compared to commercial available anti-VEGF drug. Moreover, there was a considerable regression in tumor size when treated with this system. Immunohistochemistry highlighted a reduced number and disorganization of microscopic blood vessels resulting from applied therapy. These results suggest that the developed hydrogel is a promising approach to create an innovative delivery system that offers the possibility to treat different solid tumors by intratumoral administration.


Asunto(s)
Alginatos/química , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Bevacizumab/química , Bevacizumab/farmacología , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Embrión de Pollo , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos/efectos de los fármacos , Ácido Glucurónico/química , Ácidos Hexurónicos/química , Humanos
7.
Polymers (Basel) ; 9(8)2017 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-30971006

RESUMEN

In this study, amphiphilic polymers were investigated as biomaterials that can control dexamethasone (DXM) release. Such materials present interfacial properties in the presence of water and an oily phase that can result in lyotropic liquid crystalline systems (LLCS). In addition, they can form colloidal nanostructures similar to those in living organisms, such as bilayers and hexagonal and cubic phases, which can be exploited to solubilize lipophilic drugs to sustain their release and enhance bioavailability. It was possible to obtain lamellar and hexagonal phases when combining polyoxyethylene (20) cetyl ether (CETETH-20) polymer with oleic acid (OA), N-methylpyrrolidone (P), isopropyl myristate (IM), and water. The phases were characterized by polarized light microscopy (PLM), small-angle X-ray scattering (SAXS), rheological, textural, and bioadhesion analyses followed by an in vitro release assay. All samples showed elastic behavior in the rheology studies and hexagonal samples containing P and IM showed the highest adhesiveness. The drug release profile of all LLCS presented an average lag time of 3 h and was best fitted to the Korsmeyer-Peppas and Weibull models, with controlled release governed by a combination of diffusion and erosion mechanisms. These systems are potential carriers for DXM and can be explored in several routes of administration, providing potential advantages over conventional pharmaceutical forms.

8.
Colloids Surf B Biointerfaces ; 123: 916-23, 2014 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-25466464

RESUMEN

The present work aimed at studying the interaction between insulin and SiNP surfaced with mucoadhesive polymers (chitosan, sodium alginate or polyethylene glycol) and the evaluation of their biocompatibility with HepG2 and Caco-2 cell lines, which mimic in vivo the target of insulin-loaded nanoparticles upon oral administration. Thus, a systematic physicochemical study of the surface-modified insulin-silica nanoparticles (Ins-SiNP) using mucoadhesive polymers has been described. The surfacing of nanoparticle involved the coating of silica nanoparticles (SiNP) with different mucoadhesive polymers, to achieve high contact between the systems and the gut mucosa to enhance the oral insulin bioavailability. SiNP were prepared by a modified Stöber method at room temperature via hydrolysis and condensation of tetraethyl orthosilicate (TEOS). Interaction between insulin and nanoparticles was assessed by differential scanning calorimetry (DSC), X-ray and Fourier-transform infrared (FTIR) studies. The high efficiency of nanoparticles' coating resulted in more stable system. FTIR spectra of insulin-loaded nanoparticles showed amide absorption bands which are characteristic of α-helix content. In general, all developed nanoparticles demonstrated high biocompatible, at the tested concentrations (50-500 µg/mL), revealing no or low toxicity in the two human cancer cell lines (HepG2 and Caco-2). In conclusion, the developed insulin-loaded SiNP surfaced with mucoadhesive polymers demonstrated its added value for oral administration of proteins.


Asunto(s)
Portadores de Fármacos/química , Insulina/administración & dosificación , Insulina/química , Nanopartículas/química , Polímeros/química , Dióxido de Silicio/química , Administración Oral , Alginatos/química , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Quitosano/química , Portadores de Fármacos/efectos adversos , Ácido Glucurónico/química , Células Hep G2 , Ácidos Hexurónicos/química , Humanos , Nanopartículas/efectos adversos , Polietilenglicoles/química , Polímeros/efectos adversos
9.
Int J Pharm ; 473(1-2): 627-35, 2014 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-25089510

RESUMEN

The present study reports the production and characterization of PEG-coated silica nanoparticles (SiNP-PEG) containing insulin for oral administration. High (PEG 20,000) and low (PEG 6000) PEG molecular weights were used in the preparations. SiNP were produced by sol-gel technology followed by PEG adsorption and characterized for in vitro release by Franz diffusion cells. In vitro permeation profile was assessed using everted rat intestine. HPLC method has been validated for the determination of insulin released and permeated. Insulin secondary structure was performed by circular dichroism (CD). Uncoated SiNP allowed slower insulin release in comparison to SiNP-PEG. The coating with high molecular weight PEG did not significantly (p> 0.05) alter insulin release. The slow insulin release is attributed to the affinity of insulin for silanol groups at silica surface. Drug release followed second order kinetics for uncoated and SiNP-PEG at pH 2.0. On the other hand, at pH 6.8, the best fitting was first-order for SiNP-PEG, except for SiNP which showed a Boltzmann behavior. Comparing the values of half-live, SiNP-PEG 20,000 showed a faster diffusion followed by Si-PEG 6000 and SiNP. CD studies showed no conformational changes occurring after protein release from the nanoparticles under gastrointestinal simulated conditions.


Asunto(s)
Portadores de Fármacos/química , Insulina Regular Humana/química , Nanopartículas/química , Polietilenglicoles/química , Dióxido de Silicio/química , Administración Oral , Animales , Cromatografía Líquida de Alta Presión , Dicroismo Circular , Portadores de Fármacos/administración & dosificación , Composición de Medicamentos , Técnicas In Vitro , Insulina Regular Humana/administración & dosificación , Absorción Intestinal , Intestino Delgado/metabolismo , Masculino , Nanopartículas/administración & dosificación , Polietilenglicoles/administración & dosificación , Ratas Wistar , Dióxido de Silicio/administración & dosificación
10.
Biol. Res ; 42(3): 357-364, 2009. ilus, tab
Artículo en Inglés | LILACS | ID: lil-531969

RESUMEN

The development and validation of a simple and accurate method based on HPLC with ultraviolet detection for the quantification of zidovudine in rat plasma and its application to a pharmacokinetic study following a single intranasal dose zidovudine is described. Zidovudine was extracted from the plasma using a single-step deproteinization. Chromatographic separation of zidovudine from interfering components was achieved with a C-18 reverse phase column, a mobile phase consisting of a mixture of sodium acetate buffer (55mM) with pH adjusted to 7.0 and acetonitrile (91:9 v/v) and UV detection set at 265 nm. The method was linear from 100 to 10000 ng.mL"¹ (r² > 0.9995), and zidovudine had a mean recovery from plasma of 92.8 percent. The coefficient of variation of inter-day and intra-day quality control samples was less than 15 percent. After a single intranasal dose of zidovudine administered to rats, pharmacokinetic parameters (AUC0 24, Cmax, t , t1/2) were determined. The proposed method was found to be simple, specific, accurate, and precise and could be applied to the quantitative analysis of clinical pharmacokinetic studies of zidovudine in rats.


Asunto(s)
Animales , Masculino , Ratas , Antirretrovirales , Cromatografía Líquida de Alta Presión/métodos , Zidovudina , Administración Intranasal , Antirretrovirales/administración & dosificación , Antirretrovirales/sangre , Antirretrovirales/farmacocinética , Ratas Wistar , Estándares de Referencia , Reproducibilidad de los Resultados , Espectrofotometría Ultravioleta , Zidovudina/administración & dosificación , Zidovudina/sangre , Zidovudina/farmacocinética
11.
Int J Pharm ; 295(1-2): 157-62, 2005 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-15848000

RESUMEN

Praziquantel (PZQ) is effective against all known species of Schistosomes that infect humans. The failure of mass treatment of schistosomiasis has been attributed to the fact that therapy is not sufficiently long-lasting. This effect may be due to the low bioavailability of PZQ that has a low hydrosolubility and fast metabolism. Liposomes have been used to prolong drug levels, reduce the side effects, direct drugs to specific sites and increase bioavailability after administration. The aim of this work was to study the effect of phosphatidylcholine (PC)-containing liposomes to vehiculate PZQ to improve the treatment of schistosomiasis. The in vitro study was carried out using Schistosoma mansoni parasites recovered by perfusion from the hepatic portal system of infected mice. Suspensions of liposomes with PZQ and free PZQ were administered p.o. in mice after 14 days of infection. The effect of both preparations in vitro on S. mansoni culture was similar. In the in vivo test, PZQ-liposomes caused a decrease in amounts of eggs and parasites. Liposomes improve the antischistosomal activity of praziquantel. This can be used as a starting point to investigate alternative administration routes or dosage forms and to examine the mechanism of intestinal absorption of PRZ.


Asunto(s)
Fosfatidilcolinas/administración & dosificación , Praziquantel/administración & dosificación , Esquistosomicidas/administración & dosificación , Animales , Liposomas , Ratones , Ratones Endogámicos BALB C , Praziquantel/química , Solubilidad
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