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1.
Adv Healthc Mater ; : e2400443, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38898728

RESUMEN

Neutrophils can contribute to inflammatory disease propagation via innate mechanisms intended for inflammation resolution. For example, neutrophil extracellular traps (NETs) are necessary for trapping pathogens but can contribute to clot formation and blood flow restriction, that is, ischemia. Currently, no therapeutics in the clinic directly target NETs despite the known involvement of NETs contributing to mortality and increased disease severity. Vascular-deployed particle-based therapeutics are a novel and robust alternative to traditional small-molecule drugs by enhancing drug delivery to cells of interest. This work designs a high-throughput assay to investigate the immunomodulatory behavior and functionality of salicylic acid-based polymer-based particle therapeutics against NETosis in human neutrophils. Briefly, this work finds that polymeric composition plays a role, and particle size can also influence rates of NETosis. Salicylate-based polymeric (Poly-SA) particles are found to functionally inhibit NETosis depending on the particle size and concentration exposed to neutrophils. This work demonstrates the high throughput method can help fast-track particle-based therapeutic optimization and design, more efficiently preparing this innovative therapeutics for the clinic.

2.
ACS Biomater Sci Eng ; 10(5): 3097-3107, 2024 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-38591966

RESUMEN

To develop a peri-implantitis model in a Gottingen minipig and evaluate the effect of local application of salicylic acid poly(anhydride-ester) (SAPAE) on peri-implantitis progression in healthy, metabolic syndrome (MS), and type-2 diabetes mellitus (T2DM) subjects. Eighteen animals were allocated to three groups: (i) control, (ii) MS (diet for obesity induction), and (iii) T2DM (diet plus streptozotocin for T2DM induction). Maxillary and mandible premolars and first molar were extracted. After 3 months of healing, four implants per side were placed in both jaws of each animal. After 2 months, peri-implantitis was induced by plaque formation using silk ligatures. SAPAE polymer was mixed with mineral oil (3.75 mg/µL) and topically applied biweekly for up to 60 days to halt peri-implantitis progression. Periodontal probing was used to assess pocket depth over time, followed by histomorphologic analysis of harvested samples. The adopted protocol resulted in the onset of peri-implantitis, with healthy minipigs taking twice as long to reach the same level of probing depth relative to MS and T2DM subjects (∼3.0 mm), irrespective of jaw. In a qualitative analysis, SAPAE therapy revealed decreased levels of inflammation in the normoglycemic, MS, and T2DM groups. SAPAE application around implants significantly reduced the progression of peri-implantitis after ∼15 days of therapy, with ∼30% lower probing depth for all systemic conditions and similar rates of probing depth increase per week between the control and SAPAE groups. MS and T2DM conditions presented a faster progression of the peri-implant pocket depth. SAPAE treatment reduced peri-implantitis progression in healthy, MS, and T2DM groups.


Asunto(s)
Periimplantitis , Ácido Salicílico , Porcinos Enanos , Animales , Porcinos , Periimplantitis/tratamiento farmacológico , Periimplantitis/patología , Ácido Salicílico/administración & dosificación , Ácido Salicílico/farmacología , Ácido Salicílico/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Hiperglucemia/tratamiento farmacológico , Masculino , Diabetes Mellitus Experimental/tratamiento farmacológico , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/metabolismo , Implantes Dentales
3.
Transl Neurodegener ; 13(1): 2, 2024 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-38173014

RESUMEN

BACKGROUND: Alzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (Aß) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aß (fAß) burden, microglial modulation, and neuroprotection. METHODS: We designed a nanotechnology approach to regulate the SR-mediated intracellular fAß trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM-NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM-NPs on Aß fibrilization, fAß-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines. RESULTS: AM-NPs interrupted Aß fibrilization, attenuated fAß microglial internalization via targeting the fAß-specific SRs, arrested the fAß-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fAß. Moreover, AM-NPs counteracted the microglial-mediated neurotoxicity after exposure to fAß. CONCLUSIONS: The AM-NP nanotechnology presents a multifactorial strategy to target pathological Aß aggregation and arrest the fAß-mediated pathological progression in microglia and neurons.


Asunto(s)
Enfermedad de Alzheimer , Neuroblastoma , Humanos , Anciano , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/metabolismo , Microglía/metabolismo , Enfermedades Neuroinflamatorias , Neuroblastoma/metabolismo
4.
Nat Commun ; 14(1): 2462, 2023 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-37117163

RESUMEN

The combination of inflammation and thrombosis is a hallmark of many cardiovascular diseases. Under such conditions, platelets are recruited to an area of inflammation by forming platelet-leukocyte aggregates via interaction of PSGL-1 on leukocytes and P-selectin on activated platelets, which can bind to the endothelium. While particulate drug carriers have been utilized to passively redirect leukocytes from areas of inflammation, the downstream impact of these carriers on platelet accumulation in thromboinflammatory conditions has yet to be studied. Here, we explore the ability of polymeric particles to divert platelets away from inflamed blood vessels both in vitro and in vivo. We find that untargeted and targeted micron-sized polymeric particles can successfully reduce platelet adhesion to an inflamed endothelial monolayer in vitro in blood flow systems and in vivo in a lipopolysaccharide-induced, systemic inflammation murine model. Our data represent initial work in developing cargo-free, anti-platelet therapeutics specifically for conditions of thromboinflammation.


Asunto(s)
Neutrófilos , Trombosis , Humanos , Animales , Ratones , Neutrófilos/metabolismo , Inflamación/metabolismo , Tromboinflamación , Trombosis/metabolismo , Plaquetas/metabolismo , Leucocitos/metabolismo , Selectina-P/metabolismo
5.
Adv Nanobiomed Res ; 2(6)2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36051821

RESUMEN

Neuroinflammation is one of the hallmarks contributing to Parkinson's Disease (PD) pathology, where microglial activation occurs as one of the earliest events, triggered by extracellular alpha synuclein (aSYN) binding to the CD36 receptor. Here, CD36-binding nanoparticles (NPs) containing synthetic tartaric acid-based amphiphilic polymers (AMs) were rationally designed to inhibit this aSYN-CD36 binding. In silico docking revealed that four AMs with varying alkyl side chain lengths presented differential levels of CD36 binding affinity and that an optimal alkyl chain length would promote the strongest inhibitory activity towards aSYN-CD36 interactions. In vitro competitive binding assays indicated that the inhibitory activity of AM-based NPs plateaued at intermediate side chain lengths of 12- and 18-carbons, supporting the in silico docking predictions. These 12- and 18-carbon length AM NPs also had significantly stronger effects on reducing aSYN internalization and inhibiting the production of the proinflammatory molecules TNF-α and nitric oxide from aSYN-challenged microglia. All four NPs modulated the gene expression of aSYN-challenged microglia, downregulating the expression of the proinflammatory genes TNF, IL-6, and IL-1ß, and upregulating the expression of the anti-inflammatory genes TGF-ß and Arg1. Overall, this work represents a novel polymeric nanotechnology platform that can be used to modulate aSYN-induced microglial activation in PD.

6.
Adv Healthc Mater ; 11(7): e2101534, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34881524

RESUMEN

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain problematic due to high mortality rates and lack of effective treatments. Neutrophilic injury contributes to mortality in ALI/ARDS. Here, technology for rapid ARDS intervention is developed and evaluated, where intravenous salicylic acid-based polymer microparticles, i.e., Poly-Aspirin (Poly-A), interfere with neutrophils in blood, reducing lung neutrophil infiltration and injury in vivo in mouse models of ALI/ARDS. Importantly, Poly-A particles reduce multiple inflammatory cytokines in the airway and bacterial load in the bloodstream in a live bacteria lung infection model of ARDS, drastically improving survival. It is observed that phagocytosis of the Poly-A microparticles, with salicylic acid in the polymer backbone, alters the neutrophil surface expression of adhesion molecules, potentially contributing to their added therapeutic benefits. Given the proven safety profile of the microparticle degradation products-salicylic acid and adipic acid-it is anticipated that the Poly-A particles represent a therapeutic strategy in ARDS with a rare opportunity for rapid clinical translation.


Asunto(s)
Lesión Pulmonar Aguda , Síndrome de Dificultad Respiratoria , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Ratones , Infiltración Neutrófila , Polímeros/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Ácido Salicílico/uso terapéutico
7.
Artículo en Inglés | MEDLINE | ID: mdl-32154238

RESUMEN

Parkinson's Disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, the extracellular accumulation of toxic α-synuclein (αSYN) aggregates, and neuroinflammation. Microglia, resident macrophages of the brain, are one of the critical cell types involved in neuroinflammation. Upon sensing extracellular stimuli or experiencing oxidative stress, microglia become activated, which further exacerbates neuroinflammation. In addition, as the first line of defense in the central nervous system, microglia play a critical role in αSYN clearance and degradation. While the role of microglia in neurodegenerative pathologies is widely recognized, few therapeutic approaches have been designed to target both microglial activation and αSYN aggregation. Here, we designed nanoparticles (NPs) to deliver aggregation-inhibiting antioxidants to ameliorate αSYN aggregation and attenuate activation of a pro-inflammatory microglial phenotype. Ferulic acid diacid with an adipic acid linker (FAA) and tannic acid (TA) were used as shell and core molecules to form NPs via flash nanoprecipitation. These NPs showed a strong inhibitory effect on αSYN fibrillization, significantly diminishing αSYN fibrillization in vitro compared to untreated αSYN using a Thioflavin T assay. Treating microglia with NPs decreased overall αSYN internalization and intracellular αSYN oligomer formation. NP treatment additionally lowered the in vitro secretion of pro-inflammatory cytokines TNF-α and IL-6, and also attenuated nitric oxide and reactive oxygen species production induced by αSYN. NP treatment also significantly decreased Iba-1 expression in αSYN-challenged microglia and suppressed nuclear translocation of nuclear factor kappa B (NF-κB). Overall, this work lays the foundation for an antioxidant-based nanotherapeutic candidate to target pathological protein aggregation and neuroinflammation in neurodegenerative diseases.

8.
Biomacromolecules ; 21(3): 1186-1194, 2020 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-32003982

RESUMEN

The semicrystalline protein structure and impressive mechanical properties of major ampullate (MA) spider silk make it a promising natural alternative to polyacrylonitrile (PAN) fibers for carbon fiber manufacture. However, when annealed using a similar procedure to carbon fiber production, the tensile strength and Young's modulus of MA silk decrease. Despite this, MA silk fibers annealed at 600 °C remain stronger and tougher than similarly annealed PAN but have a lower Young's modulus. Although MA silk and PAN graphitize to similar extents, annealing disrupts the hydrogen bonding that controls crystal alignment within MA silk. Consequently, unaligned graphite crystals form in annealed MA silk, causing it to weaken, while graphite crystals in PAN maintain alignment along the fiber axis, strengthening the fibers. These shortcomings of spider silk when annealed provide insights into the selection and design of future alternative carbon fiber precursors.


Asunto(s)
Seda , Arañas , Animales , Módulo de Elasticidad , Resistencia a la Tracción
9.
Pathog Dis ; 77(8)2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31603505

RESUMEN

Antibiotic resistance and infection recurrence are critical issues in treating bacterial vaginosis, the most common vaginal disorder in women of reproductive age. Novel alternatives to traditional antibiotics, such as peptidomimetics, have the potential to address this challenge. Previously, two series of cationic amphiphiles (CAms) were developed with both hydrophilic head groups and non-polar domains, giving them the ability to self-assemble into supramolecular nanostructures with membrane-lytic properties. Those CAms were shown to be effective against biofilms of Gardnerella vaginalis while preserving the commensal microbiota. Two new series of CAms were designed with varying levels of flexibility between the hydrophilic head groups and the hydrophobic domains. Activities against the vaginal pathogen G. vaginalis ranged from 1.3 to 18.5 µM, while the tested vaginal lactobacilli were significantly more tolerant of CAms, with minimal inhibitory concentration values as high as 208 µM. Minimal biofilm bactericidal concentrations of the tested CAms ranged from 21.47 to <388.3 µM, and were lowest against resistant forms of G. vaginalis, while Lactobacillus biofilms were tolerant of concentrations ≥687 µM. Safety aspects of the CAms were also investigated, and they were found to be safe for use against vaginal ectocervical tissue.


Asunto(s)
Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Péptidos Catiónicos Antimicrobianos/síntesis química , Péptidos Catiónicos Antimicrobianos/farmacología , Gardnerella vaginalis/efectos de los fármacos , Antiinfecciosos/toxicidad , Péptidos Catiónicos Antimicrobianos/toxicidad , Biopelículas/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Lactobacillus/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Modelos Teóricos , Resultado del Tratamiento , Vaginosis Bacteriana/tratamiento farmacológico
10.
Langmuir ; 35(43): 14117-14123, 2019 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-31589461

RESUMEN

Synthetic cationic amphiphiles (CAms) with physicochemical properties similar to antimicrobial peptides are promising molecules in the search for alternative antibiotics to which pathogens cannot easily develop resistance. Here, we investigate two types of CAms based on tartaric acid and containing two hydrophobic chains (of 7 or 11 carbons) and two positive charges, located either at the end of the acyl chains (bola-like, B7 and B11) or at the tartaric acid backbone (gemini-like, G7 and G11). The interaction of the CAms with biomimetic membrane models (anionic and neutral liposomes) was studied with zeta potential and dynamic light scattering measurements, isothermal titration calorimetry, and a fluorescent-based leakage assay. We show that the type of molecule determines the mechanism of action of the CAms. Gemini-like molecules (G7 and G11) interact mainly via electrostatics (exothermic process) and reside in the external vesicle leaflet, altering substantially the vesicle surface potential but not causing significant membrane lysis. On the other hand, the interaction of bola-like CAms (B7 and B11) is endothermic and thus entropy-driven, and these molecules reach both membrane leaflets and cause substantial membrane permeabilization, likely after clustering of anionic lipids. The lytic ability is clearly higher against anionic membranes as compared with neutral membranes. Within each class of molecule, longer alkyl chains (i.e., B11 and G11) exhibit higher affinity and lytic ability. Overall, the molecule B11 exhibits a high potential as antimicrobial agent, since it has a high membrane affinity and causes substantial membrane permeabilization.


Asunto(s)
Péptidos Catiónicos Antimicrobianos/química , Liposomas/química , Electricidad Estática
11.
Langmuir ; 35(16): 5557-5567, 2019 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-30888181

RESUMEN

Small-molecule cationic amphiphiles (CAms) were designed to combat the rapid rise in drug-resistant bacteria. CAms were designed to target and compromise the structural integrity of bacteria membranes, leading to cell rupture and death. Discrete structural features of CAms were varied, and structure-activity relationship studies were performed to guide the rational design of potent antimicrobials with desirable selectivity and cytocompatibility profiles. In particular, the effects of cationic conformational flexibility, hydrophobic domain flexibility, and hydrophobic domain architecture were evaluated. Their influence on antimicrobial efficacy in Gram-positive and Gram-negative bacteria was determined, and their safety profiles were established by assessing their impact on mammalian cells. All CAms have a potent activity against bacteria, and hydrophobic domain rigidity and branched architecture contribute to specificity. The insights gained from this project will aid in the optimization of CAm structures.


Asunto(s)
Antibacterianos/farmacología , Membrana Celular/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Tensoactivos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Cationes/síntesis química , Cationes/química , Cationes/farmacología , Células Cultivadas , Bacterias Gramnegativas/citología , Bacterias Grampositivas/citología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Pruebas de Sensibilidad Microbiana , Tamaño de la Partícula , Propiedades de Superficie , Tensoactivos/síntesis química , Tensoactivos/química
12.
Colloids Surf B Biointerfaces ; 167: 531-537, 2018 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-29730574

RESUMEN

Water-soluble, linear polymers with high-acid functionality are commonly used in oral care formulations to provide benefits such as bioactive complexation and delivery, as well as inhibition of the bacteria deposition and colonization, commonly referred to as 'anti-attachment'. Unfortunately, structure-activity relationship (SAR) studies of these polymers are scarce, thus, a systematic approach to design polymers with a desired property (e.g. anti-attachment) is limited. Multifunctional anti-attachment amphiphilic molecules (AMs) featuring a sugar backbone, hydrophobic arms, a poly(ethylene glycol) tail, and a chemical anchor effectively deposited on soft ceramic surfaces and reduced bacterial adhesion. The chemical compositions of the AMs were fine-tuned to better coordinate with dental enamel surfaces and prevent bacterial colonization. A graft-to approach was used to investigate the effect of the chemical anchor on AM deposition and retention. The chemical composition, absorption/desorption, and wettability properties of the bioactives and bioactive-coated surfaces were investigated using nuclear magnetic resonance, X-ray photon spectroscopy, quartz crystal microbalance, and contact angle. In addition, the ability of the AMs to provide anti-bacterial attachment on a simulated enamel surface was evaluated in vitro using bacterial repulsion assays. The SAR between surface retention and anti-attachment properties of the AMs demonstrates the feasibility and tunability of using these polymers as bioactive agents that provide anti-attachment benefits on dental enamel surfaces.


Asunto(s)
Bacterias/efectos de los fármacos , Adhesión Bacteriana/efectos de los fármacos , Durapatita/metabolismo , Polímeros/farmacología , Bacterias/crecimiento & desarrollo , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Esmalte Dental/efectos de los fármacos , Esmalte Dental/microbiología , Durapatita/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Espectroscopía de Resonancia Magnética , Espectroscopía de Fotoelectrones , Polietilenglicoles/química , Polímeros/química , Tecnicas de Microbalanza del Cristal de Cuarzo , Relación Estructura-Actividad , Propiedades de Superficie , Humectabilidad
13.
Nanomaterials (Basel) ; 8(2)2018 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-29393918

RESUMEN

Previously-designed amphiphilic scorpion-like macromolecule (AScM) nanoparticles (NPs) showed elevated potency to counteract oxidized low-density lipoprotein (oxLDL) uptake in atherosclerotic macrophages, but failed to ameliorate oxLDL-induced inflammation. We designed a new class of composite AScMs incorporating lithocholic acid (LCA), a natural agonist for the TGR5 receptor that is known to counteract atherosclerotic inflammation, with two complementary goals: to simultaneously decrease lipid uptake and inhibit pro-inflammatory cytokine secretion by macrophages. LCA was conjugated to AScMs for favorable interaction with TGR5 and was also hydrophobically modified to enable encapsulation in the core of AScM-based NPs. Conjugates were formulated into negatively charged NPs with different core/shell combinations, inspired by the negative charge on oxLDL to enable competitive interaction with scavenger receptors (SRs). NPs with LCA-containing shells exhibited reduced sizes, and all NPs lowered oxLDL uptake to <30% of untreated, human derived macrophages in vitro, while slightly downregulating SR expression. Pro-inflammatory cytokine expression, including IL-1ß, IL-8, and IL-10, is known to be modulated by TGR5, and was dependent on NP composition, with LCA-modified cores downregulating inflammation. Our studies indicate that LCA-conjugated AScM NPs offer a unique approach to minimize atherogenesis and counteract inflammation.

14.
Langmuir ; 33(51): 14663-14673, 2017 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-29144759

RESUMEN

Liposomes have become increasingly common in the delivery of bioactive agents due to their ability to encapsulate hydrophobic and hydrophilic drugs with excellent biocompatibility. While commercial liposome formulations improve bioavailability of otherwise quickly eliminated or insoluble drugs, tailoring formulation properties for specific uses has become a focus of liposome research. Here, we report the design, synthesis, and characterization of two series of amphiphilic macromolecules (AMs), consisting of acylated polyol backbones conjugated to poly(ethylene glycol) (PEG) that can serve as the sole additives to stabilize and control hydrophilic molecule release rates from distearoylphosphatidylcholine (DSPC)-based liposomes. As compared to DSPC alone, all AMs enable liposome formation and stabilize their colloidal properties at low incorporation ratios, and the AM's degree of unsaturation and hydrophobe conformation have profound impacts on stability duration. The AM's chemical structures, particularly hydrophobe unsaturation, also impact the rate of hydrophilic drug release. Course-grained molecular dynamics simulations were utilized to better understand the influence of AM structure on lipid properties and potential liposomal stabilization. Results indicate that both hydrophobic domain structure and PEG density can be utilized to fine-tune liposome properties for the desired application. Collectively, AMs demonstrate the potential to simultaneously stabilize and control the release profile of hydrophilic cargo.


Asunto(s)
Liposomas Unilamelares , Interacciones Hidrofóbicas e Hidrofílicas , Lípidos , Sustancias Macromoleculares , Polietilenglicoles
15.
Artículo en Inglés | MEDLINE | ID: mdl-28893789

RESUMEN

Antibiotic resistance and recurrence of bacterial vaginosis (BV), a polymicrobial infection, justify the need for novel antimicrobials to counteract microbial resistance to conventional antibiotics. Previously, two series of cationic amphiphiles (CAms) which self-assemble into supramolecular nanostructures with membrane-lytic properties were designed with hydrophilic head groups and nonpolar domains. The combination of CAms and commonly prescribed antibiotics is suggested as a promising strategy for targeting microorganisms that are resistant to conventional antibiotics. Activities of the CAms against Gardnerella vaginalis ATCC 14018, a representative BV pathogen, ranged from 1.1 to 24.4 µM. Interestingly, the tested healthy Lactobacillus species, especially Lactobacillus plantarum ATCC 39268, were significantly more tolerant of CAms than the selected pathogens. In addition, CAms prevented biofilm formation at concentrations which did not influence the normal growth ability of G. vaginalis ATCC 14018. Furthermore, the biofilm minimum bactericidal concentration (MBC-Bs) of CAms against G. vaginalis ATCC 14018 ranged from 58.8 to 425.6 µM, while much higher concentrations (≥850 µM) were required to produce ≥3-log reductions in the number of biofilm-associated lactobacilli. The conventional antibiotic metronidazole synergized strongly with all tested CAms against planktonic cells and biofilms of G. vaginalis ATCC 14018. The synergism between CAms and the tested conventional antibiotic may be considered a new, effective, and beneficial method of controlling biofilm-associated bacterial vaginosis.


Asunto(s)
Antibacterianos/farmacología , Biopelículas/crecimiento & desarrollo , Gardnerella vaginalis/efectos de los fármacos , Lactobacillus plantarum/efectos de los fármacos , Tensoactivos/farmacología , Vaginosis Bacteriana/tratamiento farmacológico , Adhesión Bacteriana/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Humanos , Metronidazol/farmacología , Pruebas de Sensibilidad Microbiana , Vagina/microbiología , Vaginosis Bacteriana/microbiología
16.
Int J Pharm ; 528(1-2): 406-415, 2017 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-28559214

RESUMEN

In this work, salicylic acid (SA), a non-steroidal anti-inflammatory, was chemically incorporated into hydrogel systems to achieve sustained SA release profiles. With its anti-inflammatory properties, sustained release of SA would be relevant for treating diseases such as diabetes and cancer. In this work, SA was chemically incorporated into hydrogel systems via covalent attachment to an itaconate moiety followed by UV-initiated crosslinking using acrylic acid and poly(ethylene glycol) diacrylate. The chemical composition of the hydrogel system was confirmed using FT-IR spectroscopy. The SA-based hydrogels were designed as pH-responsive hydrogels, collapsing at acidic pH (1.2) values and swelling at higher pH (7.4) values for gastrointestinal-specific delivery. The hydrogel systems exhibited a pH-dependent SA release profile: SA release was much slower at pH 1.2 compared to pH 7.4. Under acidic pH conditions, 30wt% SA was released after 24h, whereas 100wt% SA was released in a sustained manner within 24h in pH 7.4 PBS buffer. The pore structure of the gel networks were studied using SEM and exhibit appropriate pore sizes (15-60µm) for physically encapsulating drugs. In addition, rheological studies of the hydrogels proved that these systems are mechanically strong and robust. Mucoadhesive behaviors were confirmed using a Texture Analyzer, the work of adhesion for the hydrogels was around 290 g·mm and the maximum detachment force was around 135g. The SA-based hydrogels demonstrate great potential for oral delivery of bioactives in combination with SA to treat serious diseases such as cancer and diabetes.


Asunto(s)
Sistemas de Liberación de Medicamentos , Hidrogeles/química , Ácido Salicílico/química , Administración Oral , Reactivos de Enlaces Cruzados , Concentración de Iones de Hidrógeno , Espectroscopía Infrarroja por Transformada de Fourier
17.
Acta Biomater ; 57: 85-94, 2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28522412

RESUMEN

Enhanced bioactive anti-oxidant formulations are critical for treatment of inflammatory diseases, such as atherosclerosis. A hallmark of early atherosclerosis is the uptake of oxidized low density lipoprotein (oxLDL) by macrophages, which results in foam cell and plaque formation in the arterial wall. The hypolipidemic, anti-inflammatory, and antioxidative properties of polyphenol compounds make them attractive targets for treatment of atherosclerosis. However, high concentrations of antioxidants can reverse their anti-atheroprotective properties and cause oxidative stress within the artery. Here, we designed a new class of nanoparticles with anti-oxidant polymer cores and shells comprised of scavenger receptor targeting amphiphilic macromolecules (AMs). Specifically, we designed ferulic acid-based poly(anhydride-ester) nanoparticles to counteract the uptake of high levels of oxLDL and regulate reactive oxygen species generation (ROS) in human monocyte derived macrophages (HMDMs). Compared to all compositions examined, nanoparticles with core ferulic acid-based polymers linked by diglycolic acid (PFAG) showed the greatest inhibition of oxLDL uptake. At high oxLDL concentrations, the ferulic acid diacids and polymer nanoparticles displayed similar oxLDL uptake. Treatment with the PFAG nanoparticles downregulated the expression of macrophage scavenger receptors, CD-36, MSR-1, and LOX-1 by about 20-50%, one of the causal factors for the decrease in oxLDL uptake. The PFAG nanoparticle lowered ROS production by HMDMs, which is important for maintaining macrophage growth and prevention of apoptosis. Based on these results, we propose that ferulic acid-based poly(anhydride ester) nanoparticles may offer an integrative strategy for the localized passivation of the early stages of the atheroinflammatory cascade in cardiovascular disease. STATEMENT OF SIGNIFICANCE: Future development of anti-oxidant formulations for atherosclerosis applications is essential to deliver an efficacious dose while limiting localized concentrations of pro-oxidants. In this study, we illustrate the potential of degradable ferulic acid-based polymer nanoparticles to control macrophage foam cell formation by significantly reducing oxLDL uptake through downregulation of scavenger receptors, CD-36, MSR-1, and LOX-1. Another critical finding is the ability of the degradable ferulate-based polymer nanoparticles to lower macrophage reactive oxygen species (ROS) levels, a precursor to apoptosis and plaque escalation. The degradable ferulic acid-based polymer nanoparticles hold significant promise as a means to alter the treatment and progression of atherosclerosis.


Asunto(s)
Antiinflamatorios , Aterosclerosis , Ácidos Cumáricos , Células Espumosas/metabolismo , Lipogénesis/efectos de los fármacos , Nanopartículas , Polianhídridos , Especies Reactivas de Oxígeno/metabolismo , Antiinflamatorios/farmacología , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Aterosclerosis/patología , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacología , Células Espumosas/patología , Humanos , Nanopartículas/química , Nanopartículas/uso terapéutico , Polianhídridos/química , Polianhídridos/farmacología
18.
Biomacromolecules ; 18(2): 363-373, 2017 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-28026947

RESUMEN

Kojic acid (KA) is a naturally occurring fungal metabolite that is utilized as a skin-lightener and antibrowning agent owing to its potent tyrosinase inhibition activity. While efficacious, KA's inclination to undergo pH-mediated, thermal-, and photodegradation reduces its efficacy, necessitating stabilizing vehicles. To minimize degradation, poly(carbonate-esters) and polyesters comprised of KA and natural diacids were prepared via solution polymerization methods. In vitro hydrolytic degradation analyses revealed KA release was drastically influenced by polymer backbone composition (e.g., poly(carbonate-ester) vs polyester), linker molecule (aliphatic vs heteroatom-containing), and release conditions (physiological vs skin). Tyrosinase inhibition assays demonstrated that aliphatic KA dienols, the major degradation product under skin conditions, were more potent then KA itself. All dienols were found to be less toxic than KA at all tested concentrations. Additionally, the most lipophilic dienols were statistically more effective than KA at inhibiting melanin biosynthesis in cells. These KA-based polymer systems deliver KA analogues with improved efficacy and cytocompatible profiles, making them ideal candidates for sustained topical treatments in both medical and personal care products.


Asunto(s)
Materiales Biocompatibles/química , Sistemas de Liberación de Medicamentos , Melaninas/biosíntesis , Melanoma Experimental/tratamiento farmacológico , Polímeros/administración & dosificación , Polímeros/química , Pironas/química , Animales , Supervivencia Celular/efectos de los fármacos , Melaninas/antagonistas & inhibidores , Ratones , Células 3T3 NIH , Polimerizacion , Células Tumorales Cultivadas
19.
J Biomed Mater Res A ; 105(1): 311-318, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27671834

RESUMEN

In previous work, we observed that localized and sustained delivery of an anti-inflammatory drug, salicylic acid (SA), via a SA-based polymer (SAP) powder significantly enhanced diabetic bone regeneration through long-term mitigation of local inflammation. In this study, SAP was formulated into uniform microspheres and then sintered into a scaffold with an interconnected porous structure and modulus suitable for bone regeneration. The SAP scaffolds have ∼45% SA loading, which is the highest among drug-eluting bone regeneration scaffolds to-date. In addition, the scaffold provides localized, controlled and sustained SA release that has been proven to enhance diabetic bone regeneration. With the combination of physical (interconnected porosity) and chemical therapeutic features (high drug loading and sustained release), the novel SAP scaffolds offer unique therapeutic advantages and are promising diabetic bone regeneration candidates. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 311-318, 2017.


Asunto(s)
Regeneración Ósea , Ácido Salicílico/química , Andamios del Tejido/química , Preparaciones de Acción Retardada/química , Porosidad
20.
Nanomedicine ; 13(2): 343-352, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27520722

RESUMEN

Inspired by high promise using naturally occurring antimicrobial peptides (AMPs) to treat infections caused by antimicrobial-resistant bacteria, cationic amphiphiles (CAms) were strategically designed as synthetic mimics to overcome associated limitations, including high manufacture cost and low metabolic stability. CAms with facially amphiphilic conformation were expected to demonstrate membrane-lytic properties and thus reduce tendency of resistance development. By systematically tuning the hydrophobicity, CAms with optimized compositions exhibited potent broad-spectrum antimicrobial activity (with minimum inhibitory concentrations in low µg/mL range) as well as negligible hemolytic activity. Electron microscope images revealed the morphological and ultrastructure changes of bacterial membranes induced by CAm treatment and validated their membrane-disrupting mechanism. Additionally, an all-atom molecular dynamics simulation was employed to understand the CAm-membrane interaction on molecular level. This study shows that these CAms can serve as viable scaffolds for designing next generation of AMP mimics as antimicrobial alternatives to combat drug-resistant pathogens.


Asunto(s)
Antiinfecciosos/química , Péptidos Catiónicos Antimicrobianos , Hemólisis , Interacciones Hidrofóbicas e Hidrofílicas , Pruebas de Sensibilidad Microbiana , Estructura Molecular
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