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1.
Exp Eye Res ; 243: 109902, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38641196

RESUMEN

Nitrogen mustard (NM) is a potent vesicating chemical warfare agent that is primarily absorbed through skin, inhalation, or ocular surface. Ocular exposure of NM can cause acute to chronic keratopathy which can eventually lead to blindness. There is a current lack of effective countermeasures against ocular exposure of NM despite their imperative need. Herein, we aim to explore the sustained effect of Dexamethasone sodium phosphate (DSP)-loaded polymeric nanoparticles (PLGA-DSP-NP) following a single subconjunctival injection in the management and prevention of corneal injury progression upon exposure to NM. DSP is an FDA approved corticosteroid with proven anti-inflammatory properties. We formulated PLGA-DSP-NP with zinc chelation ion bridging method using PLGA polymer, with particles of approximately 250 nm and a drug loading of 6.5 wt%. Under in vitro sink conditions, PLGA-DSP-NP exhibited a sustained drug release for two weeks. Notably, in NM injured cornea, a single subconjunctival (SCT) injection of PLGA-DSP-NP outperformed DSP eyedrops (0.1%), DSP solution, placebo NP, and saline, significantly mitigating corneal neovascularization, ulceration, and opacity for the two weeks study period. Through PLGA-DSP-NP injection, sustained DSP release hindered inflammatory cytokine recruitment, angiogenic factors, and endothelial cell proliferation in the cornea. This strategy presents a promising localized corticosteroid delivery system to effectively combat NM-induced corneal injury, offering insights into managing vesicant exposure.


Asunto(s)
Dexametasona , Mecloretamina , Nanopartículas , Dexametasona/análogos & derivados , Animales , Mecloretamina/toxicidad , Modelos Animales de Enfermedad , Lesiones de la Cornea/prevención & control , Lesiones de la Cornea/inducido químicamente , Lesiones de la Cornea/patología , Lesiones de la Cornea/tratamiento farmacológico , Glucocorticoides , Sustancias para la Guerra Química/toxicidad , Ratones , Quemaduras Químicas/prevención & control , Quemaduras Químicas/tratamiento farmacológico , Quemaduras Oculares/inducido químicamente , Quemaduras Oculares/prevención & control , Conejos , Córnea/efectos de los fármacos , Córnea/patología , Córnea/metabolismo
2.
Mol Pharm ; 20(4): 2207-2216, 2023 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-36938947

RESUMEN

Pulmonary deposition of lung-targeted therapeutic aerosols can achieve direct drug delivery to the site of action, thereby enhancing the efficacy and reducing systemic exposure. In this study, we investigated the in vitro and in vivo aerosol performance of the novel small animal air-jet dry powder insufflator (Rat AJ DPI) using spray-dried albuterol excipient-enhanced-growth (EEG) powder as a model formulation. The in vitro aerosolization performance of the optimized albuterol EEG powder was first assessed using the Rat AJ DPI. The performance of Rat AJ DPI to deliver albuterol EEG aerosol to rat lungs was then compared to that of the Penn-Century Insufflator. Albuterol EEG powders dispersed using the Rat AJ DPI demonstrated narrow unimodal aerosol size distribution profiles, which were independent of the loaded powder dose (1, 2, and 5 mg). In addition, the span value for Rat AJ DPI (5 mg powder mass) was 1.32, which was 4.2-fold lower than that for Penn-Century insufflator (5 mg powder mass). At a higher loaded mass of 5 mg, the Rat AJ DPI delivered significantly larger doses to rat lungs compared with the Penn-Century DPI. The Rat AJ DPI with hand actuation delivered approximately 85% of the total emitted dose (2 and 5 mg loadings), which was comparatively higher than that for Penn-Century DPI (approximately 75%). In addition, percentage deposition in each of the lung lobes for the Rat AJ DPI was observed to be independent of the administration dose (2 and 5 mg loadings) with coefficients of variation below 12%, except in the right middle lobe. Automatic actuation of a 5 mg powder mass using the Rat AJ DPI demonstrated a similar delivered dose compared to manual actuation of the same dose, with 82% of the total emitted dose reaching the lung lobes. High-efficiency delivery of the aerosol to the lobar lung region and low sensitivity of the interlobar delivery efficiency to the loaded dose highlight the suitability of the new air-jet DPI for administering therapeutic pharmaceutical aerosols to small test animals.


Asunto(s)
Albuterol , Inhaladores de Polvo Seco , Animales , Ratas , Polvos , Aerosoles , Administración por Inhalación , Excipientes , Tamaño de la Partícula , Pulmón
3.
J Nanosci Nanotechnol ; 18(2): 842-847, 2018 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-29448503

RESUMEN

The exogenous administration of growth factors has been examined for treating wounds and such factors serve as cosmetic agents for skin regeneration. However, the topical application of growth factors is hampered by their limited percutaneous absorption. In this study, we genetically modified basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF-A) using a cell-penetrating peptide to facilitate their permeation into skin and to avoid multiple steps in the chemical or physical modification of biomaterials. Low-molecular-weight protamine (LMWP)-fused bFGF and VEGF-A (LMWP-bFGF and LMWP-VEGF-A) were designed by serial polymerase chain reaction (PCR)-mediated addition of the LMWP codons onto the bFGF and VEGF-A genes and then produced in Escherichia coli. The purified LMWP-bFGF and LMWP-VEGF-A represented >90% of the total proteins, as determined by SDS-PAGE and densitometric quantification, and their actual molecular weights, determined by mass spectroscopy, were 19,026 and 15,715 Da, respectively, corresponding to the theoretical values. N-terminal amino acid sequencing analyses confirmed the N-terminal conjugation of LMWP to bFGF and VEGF-A. Immunoblotting analyses using antibodies against bFGF and VEGF-A, together with the proliferative effects of LMWP-bFGF and LMWP- VEGF-A on human keratinocytes and fibroblasts, demonstrated that the original biological activity of each growth factor was not altered by LMWP conjugation. In addition, the LMWP conjugation did not induce further cytotoxic effects on the skin cells, while the cell membrane-penetrating activities of LMWP-bFGF and LMWP-VEGF-A were significantly enhanced compared with the respective unconjugated growth factors. These results suggest that LMWP-bFGF and LMWP-VEGF-A can be used as effective topical therapeutic or cosmetic agents for skin regeneration and anti-aging treatments.


Asunto(s)
Péptidos de Penetración Celular , Sistemas de Liberación de Medicamentos , Factores de Crecimiento de Fibroblastos/genética , Factor A de Crecimiento Endotelial Vascular/genética , Administración Tópica , Factor 2 de Crecimiento de Fibroblastos , Humanos , Absorción Cutánea
4.
J Nanosci Nanotechnol ; 17(4): 2363-369, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29641166

RESUMEN

Topical administration of growth factors has been suggested as a promising strategy for promoting the healing process and skin regeneration in wound management. However, several restrictions hinder their successful clinical use; specifically, limited percutaneous absorption causes inconsistent efficacy, and various growth factors with specific functionalities are required at different stages of healing. To overcome these shortcomings, previously we have constructed highly skin-permeable analogues of epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and platelet-derived growth factor-A (PDGF-A) (LMWP-EGF, LMWP-IGF-I and LMWP-PDGF-A) by genetically conjugating the low-molecular-weight protamine (LMWP) to their N-terminus. In the present study, we determined the optimal concentration ratio of these growth factors by investigating In Vitro cell proliferation and the scratch wound repairing assay. After confirming synergetic effects of growth factors in combinations, we developed a topical delivery system consisting of a nanoemulsion (NE)-dispersed polyvinylpyrrolidone hydrogel loaded with all three growth factors. In Vitro permeability studies were also performed to assess whether the LMWP-conjugated growth factors in the formulation enhanced their skin permeation compared to native growth factors. Combinations of native or LMWP-fused growth factors significantly promoted fibroblast proliferation and scratch wound recovery, and the synergy of LMWP-EGF, LMWP-IGF-I and LMWP-PDGF-A was optimal at a ratio of 100:100:10 by concentration. The growth factor combination-loaded NE appeared to be spherical under cryo-transmission electron microscopy and the average droplet diameter was 127±4.30 nm. The LMWP-conjugated growth factors allowed significantly higher skin permeation than native growth factors from the NE-dispersed hydrogel. Thus, the LMWP-conjugated growth factor combination-loaded NE-dispersed hydrogel is expected to induce more rapid and prolonged wound healing.


Asunto(s)
Sistemas de Liberación de Medicamentos , Factor de Crecimiento Epidérmico , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Nanoestructuras/química , Factor de Crecimiento Derivado de Plaquetas , Administración Tópica , Animales , Emulsiones/química , Factor de Crecimiento Epidérmico/administración & dosificación , Factor de Crecimiento Epidérmico/química , Factor de Crecimiento Epidérmico/farmacocinética , Factor de Crecimiento Epidérmico/farmacología , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacología , Ratones , Modelos Biológicos , Células 3T3 NIH , Factor de Crecimiento Derivado de Plaquetas/administración & dosificación , Factor de Crecimiento Derivado de Plaquetas/química , Factor de Crecimiento Derivado de Plaquetas/farmacocinética , Factor de Crecimiento Derivado de Plaquetas/farmacología , Piel/química , Piel/metabolismo , Absorción Cutánea/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos
5.
Molecules ; 22(12)2017 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-29232889

RESUMEN

In this study, we prepared and characterized a callus extract from Citrus junos and assessed its utility as a source of topical anti-aging ingredients. Callus extract was produced by aqueous extraction from Citrus junos grown on Murashige and Skoog medium with picloram as a growth regulator. After measuring the total phenolic and flavonoid contents, the major phenolic compound in calli was identified as p-hydroxycinnamoylmalic acid (1) by spectroscopic analysis. The total phenol content in the extract was determined to be 24.50 ± 0.43 mg/g of gallic acid equivalents; however, the total flavonoid content of the extract was not determined. The biological activities of the callus extract, in terms of skin anti-aging, were assessed by measuring the anti-tyrosinase activity in, and melanogenesis by, melanoma cells; and proliferation of, and procollagen synthesis by, human fibroblasts. The callus extract was incorporated into nanoliposomes (NLs) to improve its percutaneous absorption. Addition of the callus extract resulted in a 1.85-fold decrease in the melanin content of melanocytes compared with that with arbutin. The extract (500 µg/mL) significantly promoted the proliferation of, and procollagen synthesis by, fibroblasts (by 154% and 176%, respectively). In addition, the flux through the human epidermis of Citrus junos callus extract incorporated into NLs was 17.67-fold higher than that of the callus extract alone. These findings suggest that Citrus junos callus extract-loaded NLs have promise as an anti-aging cosmetic, as well as having a skin-lightening effect.


Asunto(s)
Envejecimiento/efectos de los fármacos , Citrus/crecimiento & desarrollo , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Administración Tópica , Compuestos de Bifenilo/farmacología , Proliferación Celular/efectos de los fármacos , Citrus/química , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Flavonoides/química , Ácido Gálico/química , Ácido Gálico/farmacología , Humanos , Monofenol Monooxigenasa/antagonistas & inhibidores , Picratos/farmacología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Procolágeno/biosíntesis , Preparaciones para Aclaramiento de la Piel/química , Preparaciones para Aclaramiento de la Piel/farmacología
6.
Nanotechnology ; 25(48): 485102, 2014 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-25392203

RESUMEN

Resveratrol, a potent natural antioxidant, possesses a wide range of pharmacological activities, but its oral bioavailability is very low due to its extensive hepatic and presystemic metabolism. The aim of the present study was to formulate a kinetically stable nanoemulsion (o/w) using vitamin E:sefsol (1:1) as the oil phase, Tween 80 as the surfactant and Transcutol P as the co-surfactant for the better management of Parkinson's disease. The nanoemulsion was prepared by a spontaneous emulsification method, followed by high-pressure homogenization. Ternary phase diagrams were constructed to locate the area of nanoemulsion. The prepared formulations were studied for globule size, zeta potential, refractive index, viscosity, surface morphology and in vitro and ex vivo release. The homogenized formulation, which contained 150 mg ml(-1) of resveratrol, showed spherical globules with an average globule diameter of 102 ± 1.46 nm, a least poly dispersity index of 0.158 ± 0.02 and optimal zeta potential values of -35 ± 0.02. The cumulative percentage drug release for the pre-homogenized resveratrol suspension, pre-homogenized nanoemulsion and post-homogenized nanoemulsion were 24.18 ± 2.30%, 54.32 ± 0.95% and 88.57 ± 1.92%, respectively, after 24 h. The ex vivo release also showed the cumulative percentage drug release of 85.48 ± 1.34% at 24 h. The antioxidant activity determined by using a DPPH assay showed high scavenging efficiency for the optimized formulation. Pharmacokinetic studies showed the higher concentration of the drug in the brain (brain/blood ratio: 2.86 ± 0.70) following intranasal administration of the optimized nanoemulsion. Histopathological studies showed decreased degenerative changes in the resveratrol nanoemulsion administered groups. The levels of GSH and SOD were significantly higher, and the level of MDA was significantly lower in the resveratrol nanoemulsion treated group.


Asunto(s)
Encéfalo/efectos de los fármacos , Emulsiones/farmacología , Nanopartículas/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Estilbenos/farmacología , Vitamina E/farmacología , Animales , Antioxidantes/farmacología , Disponibilidad Biológica , Química Farmacéutica , Femenino , Masculino , Tamaño de la Partícula , Polisorbatos/farmacología , Ratas , Ratas Wistar , Resveratrol , Solubilidad , Porcinos , Viscosidad
7.
Int J Pharm ; 662: 124504, 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39053676

RESUMEN

Pulmonary delivery of antibiotics is an effective strategy in treating bacterial lung infection for cystic fibrosis patients, by achieving high local drug concentrations and reducing overall systemic exposure compared to systemic administration. However, the inherent anatomical lung defense mechanisms, formulation characteristics, and drug-device combination determine the treatment efficacy of the aerosol delivery approach. In this study, we prepared a new tobramycin (Tobi) dry powder aerosol using excipient enhanced growth (EEG) technology and evaluated the in vitro and in vivo aerosol performance. We further established a Pseudomonas aeruginosa-induced lung infection rat model using an in-house designed novel liquid aerosolizer device. Notably, novel liquid aerosolizer yields comparable lung infection profiles despite administering 3-times lower P. aeruginosa CFU per rat in comparison to the conventional intratracheal administration. Dry powder insufflator (e.g. Penn-Century DP-4) to administer small powder masses to experimental animals is no longer commercially available. To address this gap, we developed a novel rat air-jet dry powder insufflator (Rat AJ DPI) that can emit 68-70 % of the loaded mass for 2 mg and 5 mg of Tobi-EEG powder formulations, achieving a high rat lung deposition efficiency of 79 % and 86 %, respectively. Rat AJ DPI can achieve homogenous distribution of Tobi EEG powder formulations at both loaded mass (2 mg and 5 mg) over all five lung lobes in rats. We then demonstrated that Tobi EEG formulation delivered by Rat AJ DPI can significantly decrease CFU counts in both trachea and lung lobes at 2 mg (p < 0.05) and 5 mg (p < 0.001) loaded mass compared to the untreated P. aeruginosa-infected group. Tobi EEG powder formulation delivered by the novel Rat AJ DPI showed excellent efficiencies in substantially reducing the P. aeruginosa-induced lung infection in rats.

8.
bioRxiv ; 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38645066

RESUMEN

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo-α-acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt.%) and an average diameter (19 µm) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD.

9.
J Control Release ; 373: 93-104, 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38968971

RESUMEN

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo-α-acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt%) and an average diameter (19 µm) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD.

10.
Food Sci Nutr ; 12(1): 48-83, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38268871

RESUMEN

Vitamins are crucial for sustaining life because they play an essential role in numerous physiological processes. Vitamin deficiencies can lead to a wide range of severe health issues. In this context, there is a need to administer vitamin supplements through appropriate routes, such as the oral route, to ensure effective treatment. Therefore, understanding the pharmacokinetics of vitamins provides critical insights into absorption, distribution, and metabolism, all of which are essential for achieving the desired pharmacological response. In this review paper, we present information on vitamin deficiencies and emphasize the significance of understanding vitamin pharmacokinetics for improved clinical research. The pharmacokinetics of several vitamins face various challenges, and thus, this work briefly outlines the current issues and their potential solutions. We also discuss the feasibility of enhanced nanocarrier-based pharmaceutical formulations for delivering vitamins. Recent studies have shown a preference for nanoformulations, which can address major limitations such as stability, solubility, absorption, and toxicity. Ultimately, the pharmacokinetics of pharmaceutical dosage forms containing vitamins can impede the treatment of diseases and disorders related to vitamin deficiency.

11.
Int J Pharm ; 634: 122661, 2023 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-36736964

RESUMEN

Airway mucus is a complex viscoelastic gel that provides a defensive physical barrier and shields the airway epithelium by trapping inhaled foreign pathogens and facilitating their removal via mucociliary clearance (MCC). In patients with respiratory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), non-CF bronchiectasis, and asthma, an increase in crosslinking and physical entanglement of mucin polymers as well as mucus dehydration often alters and typically reduces mucus mesh network pore size, which reduces neutrophil migration, decreases pathogen capture, sustains bacterial infection, and accelerates lung function decline. Conventional aerosol particles containing hydrophobic drugs are rapidly captured and removed by MCC. Therefore, it is critical to design aerosol delivery systems with the appropriate size and surface chemistry that can improve drug retention and absorption with the goal of increased efficacy. Biodegradable muco-adhesive particles (MAPs) and muco-penetrating particles (MPPs) have been engineered to achieve effective pulmonary delivery and extend drug residence time in the lungs. MAPs can be used to target mucus as they get trapped in airway mucus by steric obstruction and/or adhesion. MPPs avoid muco-adhesion and are designed to have a particle size smaller than the mucus network, enhancing lung retention of particles as well as transport to the respiratory epithelial layer and drug absorption. In this review, we aim to provide insight into the composition of airway mucus, rheological characteristics of airway mucus in healthy and diseased subjects, the most recent techniques to study the flow dynamics and particle diffusion in airway mucus (in particular, multiple particle tracking, MPT), and the advancements in engineering MPPs that have contributed to improved airway mucus penetration, lung distribution, and retention.


Asunto(s)
Asma , Fibrosis Quística , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Pulmón , Moco
12.
ACS Macro Lett ; 12(4): 446-453, 2023 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-36951898

RESUMEN

Low mucus penetration ability and cellular uptake seriously limit the effectiveness of local vaginal drug administration because of the rapid foreign particulate and pathogen removal property of the mucus layer. Our previous work proved that nanoparticles with a highly dense polyethylene glycol (PEG) coating can penetrate mucus rapidly (mucus-penetrating nanoparticles, MPPs) and improve drug distribution and retention at mucosal surfaces. However, the "stealth-effect" of the PEG coating also restricts cellular uptake of MPPs. In this work, we designed pH-responsive mucus-penetrating nanoparticles (pMPPs) with hydrazone bonds as the linker to conjugate a dense PEG surface coating, which enabled the pMPPs to rapidly penetrate through the mucus layer. More importantly, the acidic environment of the vaginal mucus induces slow shedding of the PEG layer, leading to a positive charge exposure to facilitate cellular uptake. Overall, pMPPs demonstrate potential as an effective delivery platform for the prophylactic and therapeutic treatment of female reproductive diseases.


Asunto(s)
Moco , Nanopartículas , Humanos , Femenino , Moco/química , Vagina/metabolismo , Transporte Biológico , Nanopartículas/uso terapéutico , Polietilenglicoles/farmacología , Concentración de Iones de Hidrógeno
13.
Biomaterials ; 281: 121334, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34974206

RESUMEN

In this study, we investigated the immune-modulating effects of a novel metronomic chemotherapy (MCT) featuring combined oral oxaliplatin (OXA) and pemetrexed (PMX) for colon cancer. OXA and PMX were ionically complexed with lysine derivative of deoxycholic acid (DCK), and incorporated into nanoemulsions or colloidal dispersions, yielding OXA/DCK-NE and PMX/DCK-OP, respectively, to improve their oral bioavailabilities. MCT was not associated with significant lymphotoxicity whereas the maximum tolerated dose (MTD) afforded systemic immunosuppression. MCT was associated with more immunogenic cell death and tumor cell MHC-class I expression than was MTD. MCT improved the tumor antigen presentation of dendritic cells and increased the number of functional T cells in the tumor. MCT also helped to enhance antigen-specific memory responses both locally and systemically. By combining MCT with anti-programmed cell death protein-1 (αPD-1) therapy, the tumor volume was suppressed by 97.85 ± 84.88% compared to the control, resulting in a 95% complete response rate. Upon re-challenge, all tumor-free mice rejected secondary tumors, indicating the induction of a tumor specific memory response. Thus, MCT using an OXA and PMX combination, together with αPD-1, successfully treated colon cancer by activating both innate and adaptive immune cells and elicited tumor-specific long-term immune memory while avoiding toxicity caused by MTD treatment.


Asunto(s)
Neoplasias del Colon , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Inmunoterapia , Ratones , Oxaliplatino/uso terapéutico
14.
Int J Pharm ; 621: 121790, 2022 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-35504432

RESUMEN

Biomimetic nanotechnology could serve as an advancement in the domain of drug delivery and diagnosis with the application of natural cell membrane or synthetically-derived membrane nanoparticles (NPs). These biomimetic NPs endow significant therapeutic and diagnostic efficacy by their unique properties, such as immune invasion and better targeting ability. Additionally, these NPs have a unique ability to retain the inherent properties of cell membrane and membrane's intrinsic functionalities, which helps them to exhibit superior therapeutic effects. In this review, we describe how these membrane-clocked NPs endow superior therapeutic effects by immune invasion; along with this, the development of membrane-coated NPs and their method of preparation and characterization has been clearly described in the manuscript. Moreover, Various developed membrane-coated NPs such as red blood cell membrane-coated NPs, white blood cells membrane-coated NPs, platelet membrane coated, cancer cell membrane coated, bacterial membrane vesicles and, mesenchymal stem cells membrane-coated NPs have been established in this manuscript. At last, the discussion on the role of membrane-coated NPs as theranostics, and notably, the literature that demonstrates the shreds of evidences of these NPs in targeting and neutralizing the SARS-CoV-2 virus have also been incorporated.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Nanopartículas , Membrana Celular , Sistemas de Liberación de Medicamentos , Humanos , SARS-CoV-2
15.
Int J Anal Chem ; 2021: 9749474, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34712328

RESUMEN

Serratiopeptidase (SRP) is a proteolytic enzyme that emerged as one of the most potent anti-inflammatory and analgesic drugs. The purpose of the present study was to formulate and evaluate enteric-coated tablets for SRP and investigate their stability using a simple and validated analytical method by ultraviolet (UV) spectroscopy. The colloidal silicon dioxide (2.50%), sodium starch glycolate (3.44%), and crospovidone (2.50%) were used as appropriate excipients for the development of core part of tablets. To protect the prepared tablets from acidic environment in the stomach, white shellac, castor oil, HPMC phthalate 40, and ethyl cellulose were used. The seal coating and enteric coating attained were 2.75% and 6.74%, respectively. SRP was found to be linear at 265 nm in the concentration range of 25-150 µg/mL. The results revealed that our developed method was linear (R 2 = 0.999), precise (RSD % = 0.133), and accurate (% recovery = 99.96-103.34). The formulated SRP tablets were found to be stable under accelerated conditions as well as under room temperature for 6 months (assay %: >97.5%). The in vitro drug release study demonstrated that enteric-coated tablets were able to restrict SRP release in both acidic environments: 0.1 N HCl and simulated gastric fluid (pH 1.2). Moreover, at 60 minutes, the formulated SRP tablets revealed 13.0% and 8.98% higher drug release in phosphate buffer (pH 6.8) and simulated intestinal fluid (pH 6.8), respectively, compared to the marketed tablet formulation. This study concludes that enteric-coated tablets of SRP with higher drug release in the intestine can be prepared and examined for their stability using validated analytical technique of UV spectroscopy.

16.
Pharmaceutics ; 13(5)2021 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-33925457

RESUMEN

In this study, a stable and highly skin-permeable topical delivery system for itraconazole (ITZ) was designed to provide effective treatment against superficial mycosis. Herein, ITZ was incorporated into a solution composed of ethanol, benzyl alcohol, hydrochloric acid, Transcutol P, and cyclomethicone as a delivery vehicle, solubilizer, protonating agent, permeation enhancer, and spreading agent, respectively. At 72 h, the optimal topical ITZ formulation (ITZ-TF#11) exhibited 135% enhanced skin permeability, which led to increases in drug deposition in the stratum corneum, epidermis, and dermis of 479%, 739%, and 2024%, respectively, compared with the deposition of 1% ITZ in ethanol (control). Moreover, on day 7, ITZ-TF#11 demonstrated 2.09- and 2.30-fold enhanced nail flux and drug deposition, compared with the control. At a dose of 40 mg/kg/day, ITZ-TF#11 showed 323% greater lesion recovery, a 165% lower mean erythema severity score, and a 37% lower mean logarithm of viable fungal cells in skin in the treated area, compared with mice that received oral ITZ at the same dose. Overall, the findings imply that ITZ-TF#11 is a superior alternative to oral ITZ for treatment of superficial mycosis.

17.
Drug Deliv ; 28(1): 2313-2328, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34730056

RESUMEN

In this study, we developed oral pemetrexed (PMX) for metronomic dosing to enhance antitumor immunity. PMX was electrostatically complexed with positively charged lysine-linked deoxycholic acid (DL) as an intestinal permeation enhancer, forming PMX/DL, to enhance its intestinal permeability. PMX/DL was also incorporated into a colloidal dispersion (CD) comprised of the block copolymer of poly(ethylene oxide) and poly(propylene oxide), and caprylocaproyl macrogol-8 glycerides (PMX/DL-CD). CD-containing PMX/DL complex in a 1:1 molar ratio [PMX/DL(1:1)-CD] showed 4.66- and 7.19-fold greater permeability than free PMX through the Caco-2 cell monolayer and rat intestine, respectively. This resulted in a 282% improvement in oral bioavailability in rats. In addition, low-dose metronomic PMX led to more immunogenic cell death in CT26.CL25 cells compared to high PMX concentrations at the maximum tolerated dose. In CT26.CL25 tumor-bearing mice, oral metronomic PMX/DL-CD elicited greater antitumor immunity not only by enhancing the number of tumor-infiltrating lymphocytes but also by suppressing T cell functions. Oral PMX/DL-CD substantially increased programmed cell death protein ligand-1 (PD-L1) expression on tumor cells compared to the control and PMX-IV groups. This increased antitumor efficacy in combination with anti-programmed cell death protein-1 (aPD-1) antibody in terms of tumor rejection and immunological memory compared to the combination of PMX-IV and aPD-1. These results suggest that oral metronomic scheduling of PMX/DL-CD in combination with immunotherapy has synergistic antitumor effects.


Asunto(s)
Administración Metronómica , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Neoplasias/patología , Pemetrexed/administración & dosificación , Pemetrexed/farmacología , Administración Oral , Animales , Antígeno B7-H1/efectos de los fármacos , Línea Celular Tumoral , Química Farmacéutica , Ácido Desoxicólico/química , Relación Dosis-Respuesta a Droga , Portadores de Fármacos/química , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Ensayos Antitumor por Modelo de Xenoinjerto
18.
J Nanosci Nanotechnol ; 20(9): 5515-5519, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32331128

RESUMEN

Hearing loss is one of the major complications of diabetes mellitus and significantly lowers the quality of life of diabetic patients. In studies using diabetic animal models hearing loss have been frequently associated with damages to cochlear afferent fibers. Recent studies suggested that cochlear afferent neurons are composed of heterogeneous populations and a subgroup of neurons equipped with low level of calretinin might be more vulnerable to various noxious stimuli such as noise and neurotoxins. Here, we tested if cochlear afferent neurons deficient in the Ca2+-buffering protein calretinin are more vulnerable to hyperglycemic insults. Streptozotocin-induced (50 mg/kg, i.p.) hyperglycemic mice (>250 mg/dl) were tested. The expression patterns of calretinin in peripheral processes and the cell bodies of cochlear afferent nerve fibers were examined using immunohistochemistry and confocal microscopy. The proportion of calretinin-poor cochlear afferent fibers was much lower in hyperglycemic mice compared to the normoglycemic control group. (30.0 vs. 55.5% in the peripheral process; 15.7 vs. 24.4 % in spiral ganglion neuron). The results suggest that calretinin-poor cochlear nerve fibers may be selectively lost after the hyperglycemic insults. The finding also supports a calretinin's neuroprotective role against diabetic neuropathy in cochlear afferent neurons.


Asunto(s)
Calbindina 2 , Cóclea/efectos de los fármacos , Hiperglucemia/patología , Fibras Nerviosas , Calidad de Vida , Animales , Hiperglucemia/inducido químicamente , Ratones , Ratones Obesos , Neuronas Aferentes , Estreptozocina
19.
Int J Nanomedicine ; 15: 7719-7743, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33116497

RESUMEN

OBJECTIVE: The anticancer efficacy of orally administered chemotherapeutics is often constrained by low intestinal membrane permeability and oral bioavailability. In this context, we designed a solid oral formulation of oxaliplatin (OP), a third-generation cisplatin analog, to improve oral bioavailability and investigate its application in metronomic chemotherapy. METHODS: An ion-pairing complex of OP with a permeation enhancer, N α-deoxycholyl-l-lysyl-methylester (DLM), was successfully prepared and then mixed with dispersing agents (including poloxamer 188 and Labrasol) to form the solid, amorphous oral formulation OP/DLM (OP/DLM-SF; hereafter, ODSF). RESULTS: The optimized powder formulation was sized in the nanoscale range (133±1.47 nm). The effective permeability of OP increased by 12.4-fold after ionic complex formation with DLM and was further increased by 24.0-fold after incorporation into ODSF. ODSF exhibited respective increases of 128% and 1010% in apparent permeability across a Caco-2 monolayer, compared to OP/DLM and OP. Furthermore, inhibition of bile acid transporters by actinomycin D and caveola-mediated uptake by brefeldin in Caco-2 cell monolayers reduced the apparent permeability values of ODSF by 58.4% and 51.1%, respectively, suggesting predominant roles for bile acid transporters and caveola-mediated transport in intestinal absorption of ODSF. In addition, macropinocytosis and paracellular and transcellular passive transport significantly influenced the intestinal permeation of ODSF. The oral bioavailabilities of ODSF in rats and monkeys were 68.2% and 277% higher, respectively, than the oral bioavailability of free OP. In vivo analyses of anticancer efficacy in CT26 and HCT116 cell-bearing mice treated with ODSF demonstrated significant suppression of tumor growth, with respective maximal tumor volume reductions of 7.77-fold and 4.07-fold, compared to controls. CONCLUSION: ODSF exhibits therapeutic potential, constituting an effective delivery system that increases oral bioavailability, with applications to metronomic chemotherapy.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Portadores de Fármacos/administración & dosificación , Oxaliplatino/administración & dosificación , Oxaliplatino/farmacocinética , Administración Metronómica , Administración Oral , Animales , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Femenino , Glicéridos/química , Humanos , Absorción Intestinal/efectos de los fármacos , Lisina/análogos & derivados , Lisina/química , Macaca fascicularis , Masculino , Ratones Endogámicos BALB C , Poloxámero/química , Ratas Sprague-Dawley
20.
Drug Deliv ; 27(1): 1501-1513, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33107339

RESUMEN

In this study, a system for oral delivery of etoposide (ETP) was designed to avoid the problems associated with low and variable bioavailability of a commercially available ETP emulsion comprised of polyethylene glycol, glycerol, and citric acid anhydrous. ETP was complexed with low-molecular-weight methylcellulose (ETP/LMC) and loaded into a water-in-oil-in-water multiple nanoemulsion to formulate an ETP/LMC-nanoemulsion (ELNE). To further enhance the oral bioavailability, an ionic complex formed by anionic lipid 1,2-didecanoyl-sn-glycero-3-phosphate (sodium salt) and cationic N α-deoxycholyl-l-lysyl-methylester was incorporated into ELNE, yielding ELNE#7. As expected, ELNE#7 showed 4.07- and 2.25-fold increases in artificial membrane and Caco-2/HT29-MTX-E12 permeability (Papp ), respectively, resulting in 224% greater oral bioavailability compared with the commercially available ETP emulsion. In contrast, inhibition of clathrin- and caveola-mediated endocytosis, macropinocytosis, and bile acid transporters by chlorpromazine, genistein, amiloride, and actinomycin D in Caco-2/HT-29-MTX-E12 monolayers reduced the Papp by 45.0%, 20.5%, 28.8%, and 31.1%, respectively. These findings suggest that these routes play important roles in enhancing the oral absorption of ELNE#7. In addition, our mechanistic study suggested that P-glycoprotein did not have an inhibitory effect on the permeation of ELNE#7. Notably, ELNE#7 showed significantly enhanced toxicity in LLC and A549 cells compared with ETP-E. These observations support the improved oral absorption of ETP in ELNE#7, suggesting that it is a better alternative than ETP emulsion.


Asunto(s)
Ácido Desoxicólico/química , Emulsiones/química , Etopósido/química , Lípidos/química , Células A549 , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Línea Celular Tumoral , Ácido Cítrico/química , Ácido Desoxicólico/metabolismo , Emulsiones/metabolismo , Glicerol/química , Células HT29 , Humanos , Absorción Intestinal/efectos de los fármacos , Permeabilidad/efectos de los fármacos , Polietilenglicoles/química , Ratas , Ratas Sprague-Dawley
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