RESUMO
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.
Assuntos
Materiais Biocompatíveis/química , Sistemas de Liberação de Medicamentos , Melaninas/biossíntese , Melanoma Experimental/tratamento farmacológico , Polímeros/administração & dosagem , Polímeros/química , Pironas/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Melaninas/antagonistas & inibidores , Camundongos , Células NIH 3T3 , Polimerização , Células Tumorais CultivadasRESUMO
Ferulic acid-based polymers with aliphatic linkages have been previously synthesized via solution polymerization methods, yet they feature relatively slow ferulic acid release rates (â¼11 months to 100% completion). To achieve a more rapid release rate as required in skin care formulations, ferulic acid-based polymers with ethylene glycol linkers were prepared to increase hydrophilicity and, in turn, increase ferulic acid release rates. The polymers were characterized using nuclear magnetic resonance and Fourier transform infrared spectroscopies to confirm chemical composition. The molecular weights, thermal properties (e.g., glass transition temperature), and contact angles were also obtained and the polymers compared. Polymer glass transition temperature was observed to decrease with increasing linker molecule length, whereas increasing oxygen content decreased polymer contact angle. The polymers' chemical structures and physical properties were shown to influence ferulic acid release rates and antioxidant activity. In all polymers, ferulic acid release was achieved with no bioactive decomposition. These polymers demonstrate the ability to strategically release ferulic acid at rates and concentrations relevant for topical applications such as skin care products.
Assuntos
Ácidos Cumáricos , Etilenoglicol , Células 3T3 , Administração Tópica , Animais , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Etilenoglicol/química , Etilenoglicol/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Higiene da Pele , Espectrofotometria InfravermelhoRESUMO
The bioaccessibility of salicylic acid (SA) can be effectively modified by incorporating the pharmacological compound directly into polymers such as poly(anhydride-esters). After simulated digestion conditions, the bioaccessibility of SA was observed to be statistically different (p < 0.0001) in each sample: 55.5 ± 2.0% for free SA, 31.2 ± 2.4% the SA-diglycolic acid polymer precursor (SADG), and 21.2 ± 3.1% for SADG-P (polymer). The release rates followed a zero-order release rate that was dependent on several factors, including (1) solubilization rate, (2) macroscopic erosion of the powdered polymer, (3) hydrolytic cleavage of the anhydride bonds, and (4) subsequent hydrolysis of the polymer precursor (SADG) to SA and diglycolic acid.
Assuntos
Amiloide , Ouro/química , Nanopartículas Metálicas/química , Peptídeos , Poliésteres , Ácido Salicílico , Amiloide/síntese química , Amiloide/química , Disponibilidade Biológica , Peptídeos/síntese química , Peptídeos/química , Poliésteres/síntese química , Poliésteres/química , Poliésteres/farmacologia , Ácido Salicílico/química , Ácido Salicílico/farmacocinéticaRESUMO
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 â¼45% 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.
Assuntos
Regeneração Óssea , Ácido Salicílico/química , Alicerces Teciduais/química , Preparações de Ação Retardada/química , PorosidadeRESUMO
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.
Assuntos
Anti-Inflamatórios , Aterosclerose , Ácidos Cumáricos , Células Espumosas/metabolismo , Lipogênese/efeitos dos fármacos , Nanopartículas , Polianidridos , Espécies Reativas de Oxigênio/metabolismo , Anti-Inflamatórios/farmacologia , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/patologia , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Células Espumosas/patologia , Humanos , Nanopartículas/química , Nanopartículas/uso terapêutico , Polianidridos/química , Polianidridos/farmacologiaRESUMO
Poly(anhydride-esters) comprised of naturally occurring, non-toxic phenolic acids, namely syringic and vanillic acid, with antioxidant properties were prepared via solution polymerization methods. Polymer and polymer precursor physiochemical properties were characterized, including polymer molecular weight and thermal properties. In vitro release studies illustrated that polymer hydrolytic degradation was influenced by relative hydrophobicity and degree of methoxy substitution of the phenolic acids. Further, the released phenolic acids were found to maintain antioxidant potency relative to free phenolic acid controls as determined by a 2,2-diphenyl-1-picrylhydrazyl assay. Polymer cytotoxicity was assessed with L929 fibroblasts in polymer-containing media; appropriate cell morphology and high fibroblast proliferation were obtained for the polymers at the lower concentrations. These polymers deliver non-cytotoxic levels of naturally occurring antioxidants, which could be efficacious in topical delivery of antioxidant therapies.
Assuntos
Antioxidantes , Fibroblastos/metabolismo , Hidroxibenzoatos/química , Teste de Materiais , Poliésteres , Animais , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Linhagem Celular , Fibroblastos/citologia , Camundongos , Poliésteres/síntese química , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/farmacologiaRESUMO
Neuroinflammation, a common neuropathologic feature of neurodegenerative disorders including Parkinson disease (PD), is frequently exacerbated by microglial activation. The extracellular protein α-synuclein (ASYN), whose aggregation is characteristic of PD, remains a key therapeutic target, but the control of synuclein trafficking and aggregation within microglia has been challenging. First, we established that microglial internalization of monomeric ASYN was mediated by scavenger receptors (SR), CD36 and SRA1, and was rapidly accompanied by the formation of ASYN oligomers. Next, we designed a nanotechnology approach to regulate SR-mediated intracellular ASYN trafficking within microglia. We synthesized mucic acid-derivatized sugar-based amphiphilic molecules (AM) with optimal stereochemistry, rigidity, and charge for enhanced dual binding affinity to SRs and fabricated serum-stable nanoparticles via flash nanoprecipitation comprising hydrophobe cores and amphiphile shells. Treatment of microglia with AM nanoparticles decreased monomeric ASYN internalization and intracellular ASYN oligomer formation. We then engineered composite deactivating NPs with dual character, namely shell-based SR-binding amphiphiles, and core-based antioxidant poly (ferrulic acid), to investigate concerted inhibition of oxidative activation. In ASYN-challenged microglia treated with NPs, we observed decreased ASYN-mediated acute microglial activation and diminished microglial neurotoxicity caused by exposure to aggregated ASYN. When the composite NPs were administered in vivo within the substantia nigra of fibrillar ASYN-challenged wild type mice, there was marked attenuation of activated microglia. Overall, SR-targeting AM nanotechnology represents a novel paradigm in alleviating microglial activation in the context of synucleinopathies like PD and other neurodegenerative diseases.