RESUMO
We synthesized an oxidation-responsive polycaprolactone (O-PCL) bearing pendant arylboronic esters as H2O2-responsive motifs. H2O2 induces fast depolymerization of O-PCL within days. Nanoparticles formulated from O-PCL disintegrate and release payload in response to concentrations of H2O2 (50 µM) that are relevant to human disease.
Assuntos
Peróxido de Hidrogênio/química , Nanopartículas/química , Poliésteres/química , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Nanopartículas/administração & dosagem , Oxirredução , Poliésteres/administração & dosagemRESUMO
Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminating worms uses a 4- to 6-week course of doxycycline that targets Wolbachia, a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here, we describe discovery and optimization of quinazolines CBR417 and CBR490 that, with a single dose, achieve >99% elimination of Wolbachia in the in vivo Litomosoides sigmodontis filarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high-content imaging screen with an orthogonal ex vivo validation assay to rapidly quantify Wolbachia elimination in Brugia pahangi filarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, 8 of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent antiwolbachial activity was confirmed in L. sigmodontis, Brugia malayi, and Onchocerca ochengi in vivo preclinical models of filarial disease and in vitro selectivity against Loa loa (a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.
Assuntos
Antibacterianos/uso terapêutico , Descoberta de Drogas , Filariose/tratamento farmacológico , Filariose/parasitologia , Filarioidea/fisiologia , Quinazolinas/uso terapêutico , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Modelos Animais de Doenças , Feminino , Filarioidea/efeitos dos fármacos , Filarioidea/microbiologia , Ensaios de Triagem em Larga Escala , Camundongos , Fenótipo , Quinazolinas/química , Quinazolinas/farmacologia , Bibliotecas de Moléculas Pequenas , Wolbachia/efeitos dos fármacosRESUMO
For conditions with inflammatory flare-ups, fast drug-release from a depot is crucial to reduce cell infiltration and prevent long-term tissue destruction. While this concept has been explored for chronic diseases, preventing acute inflammatory flares has not been explored. To address this issue, a preventative inflammation-sensitive system is developed and applied to acute gout, a condition where millions of inflammatory cells are recruited rapidly, causing excruciating and debilitating pain. Rapid drug release is first demonstrated from a pH-responsive acetalated dextran particle loaded with dexamethasone (AcDex-DXM), reducing proinflammatory cytokines in vitro as efficiently as free drug. Then, using the air pouch model of gout, mice are pretreated 24 h before inducing inflammation. AcDex-DXM reduces overall cell infiltration with decreased neutrophils, increases monocytes, and diminishes cytokines and chemokines. In a more extended prophylaxis model, murine joints are pretreated eight days before initiating inflammation. After quantifying cell infiltration, only AcDex-DXM reduces the overall joint inflammation, where neither free drug nor a conventional drug-depot achieves adequate anti-inflammatory effects. Here, the superior efficacy of disease-triggered drug-delivery to prevent acute inflammation is demonstrated over free drug and slow-release depots. This approach and results promise exciting treatment opportunities for multiple inflammatory conditions suffering from acute flares.
Assuntos
Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Liberação Controlada de Fármacos , Inflamação/patologia , Inflamação/prevenção & controle , Acetilação , Doença Aguda , Animais , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Concentração de Íons de Hidrogênio , Inflamação/tratamento farmacológico , Interleucina-1beta/farmacologia , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da PartículaRESUMO
Chemical amplification is a known strategy for improving the sensitivity of stimuli-responsive polymers. However, the chemical amplification effect has never been fully examined. Many questions remain about its mechanism and efficacy, obstructing its further implementation. Here, we design and demonstrate a reactive oxygen species (ROS) responsive polymer (ROS-ARP) with a chemical amplification strategy to dismiss these concerns. The ROS-ARP is designed to change the hydrophilicity by ROS, revealing a carboxylic acid, which also catalyzes ketal hydrolysis along the polymer backbone. The chemical amplification strategy of ROS-ARP accelerated the polymer degradation up to 17 fold compared to a previously reported ROS-responsive polymer. To investigate the mechanism behind this increased acceleration, we compared the degradation kinetics in various environments. Additionally, other effects such as hydrophilicity changes were excluded. The accelerated degradation of ROS-ARP is evaluated as a potential drug delivery system, demonstrating on-demand cargo release from the formulated polymeric particles.
Assuntos
Polímeros/química , Espécies Reativas de Oxigênio/química , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Nanopartículas/químicaRESUMO
Visualization of biochemical changes associated with disease is of great clinical significance, as it should allow earlier, more accurate diagnosis than structural imaging, facilitating timely clinical intervention. Herein, we report combining stimuli-responsive polymers and near-infrared fluorescent dyes (emission max: 790 nm) to create robust activatable fluorescent nanoprobes capable of simultaneously detecting acidosis and oxidative stress associated with inflammatory microenvironments. The spectrally-resolved mechanism of fluorescence activation allows removal of unwanted background signal (up to 20-fold reduction) and isolation of a pure activated signal, which enables sensitive and unambiguous localization of inflamed areas; target-to-background ratios reach 22 as early as 3 h post-injection. This new detection platform could have significant clinical impact in early detection of pathologies, individual tailoring of drug therapy, and image-guided tumor resection.
Assuntos
Corantes Fluorescentes/química , Inflamação/metabolismo , Imagem Molecular/métodos , Polímeros/química , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Feminino , Humanos , Neoplasias Mamárias Experimentais/diagnóstico , CamundongosRESUMO
Biodegradable polymeric materials are a key area of investigation in drug delivery and disease treatment. This is due to their proven clinical potential for payload protection, responsivity, and surface modification imparted by the versatile array of polymers available for their formulation. Here, we employ a novel biodegradable azide containing polymer in the formulation of polymeric nanoparticles and show that these particles can then be functionalized, with biorthogonal click reactions, to alter their surface appearance and their ability to interact with biological systems.
Assuntos
Química Click , Ácido Láctico/química , Ácido Poliglicólico/química , Azidas/química , Nanopartículas/química , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Propriedades de SuperfícieRESUMO
We introduce a means of efficiently photo-uncaging active compounds from amino-1,4-benzoquinone in aqueous environments. Aqueous photochemistry of this photocage with one-photon red light is typically not efficient unless the photocaged molecules are allowed to assemble into nanoparticles. A variety of biologically active molecules were functionalized with the photocage and subsequently formulated into water-dispersible nanoparticles. Red light irradiation through various mammalian tissues achieved efficient photo-uncaging. Co-encapsulation of NIR fluorescent dyes and subsequent photomodulation provides a NIR fluorescent tool to assess both particle location and successful photorelease.
RESUMO
We describe a means of chemical amplification to accelerate triggered degradation of a polymer and particles composed thereof. We designed a light-degradable copolymer containing carboxylic acids masked by photolabile groups and ketals. Photolysis allows the unmasked acidic groups in the polymer backbone to accelerate ketal hydrolysis even at neutral pH.
Assuntos
Nanopartículas/efeitos da radiação , Nylons/efeitos da radiação , Animais , Sistemas de Liberação de Medicamentos , Ésteres/química , Ésteres/efeitos da radiação , Fluoresceínas/química , Corantes Fluorescentes/química , Concentração de Íons de Hidrogênio , Hidrólise , Camundongos , Nanopartículas/química , Nylons/química , Oxazinas/química , Fotólise , Células RAW 264.7RESUMO
Light is an excellent means to externally control the properties of materials and small molecules for many applications. Light's ability to initiate chemistries largely independent of a material's local environment makes it particularly useful as a bio-orthogonal and on-demand trigger in living systems. Materials responsive to UV light are widely reported in the literature; however, UV light has substantial limitations for in vitro and in vivo applications. Many biological molecules absorb these energetic wavelengths directly, not only preventing substantial tissue penetration but also causing detrimental photochemical reactions. The more innocuous nature of long-wavelength light (>400nm) and its ability at longer wavelengths (600-950nm) to effectively penetrate tissues is ideal for biological applications. Multi-photon processes (e.g. two-photon excitation and upconversion) using longer wavelength light, often in the near-infrared (NIR) range, have been proposed as a means of avoiding the negative characteristics of UV light. However, high-power focused laser light and long irradiation times are often required to initiate photorelease using these inefficient non-linear optical methods, limiting their in vivo use in mammalian tissues where NIR light is readily scattered. The development of materials that efficiently convert a single photon of long-wavelength light to chemical change is a viable solution to achieve in vivo photorelease. However, to date only a few such materials have been reported. Here we review current technologies for photo-regulated release using photoactive organic materials that directly absorb visible and NIR light.
Assuntos
Liberação Controlada de Fármacos , Luz , FótonsRESUMO
Materials that degrade or dissociate in response to low power light promise to enable on-demand, precisely localized delivery of drugs or bioactive molecules in living systems. Such applications remain elusive because few materials respond to wavelengths that appreciably penetrate tissues. The photocage bromohydroxycoumarin (Bhc) is efficiently cleaved upon low-power ultraviolet (UV) and near-infrared (NIR) irradiation through one- or two-photon excitation, respectively. We have designed and synthesized a short Bhc-bearing crosslinker to create light-degradable hydrogels and nanogels. Our crosslinker breaks by intramolecular cyclization in a manner inspired by the naturally occurring ornithine lactamization, in response to UV and NIR light, enabling rapid degradation of polyacrylamide gels and release of small hydrophilic payloads such as an â¼10 nm model protein and murine mesenchymal stem cells, with no background leakage.
Assuntos
Cumarínicos/química , Reagentes de Ligações Cruzadas/química , Hidrogéis/química , Luz , Proteínas/química , Animais , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , SolubilidadeRESUMO
Therapies for macular degeneration and diabetic retinopathy require intravitreal injections every 4-8 weeks. Injections are uncomfortable, time-consuming, and carry risks of infection and retinal damage. However, drug delivery via noninvasive methods to the posterior segment of the eye has been a major challenge due to the eye's unique anatomy and physiology. Here we present a novel nanoparticle depot platform for on-demand drug delivery using a far ultraviolet (UV) light-degradable polymer, which allows noninvasively triggered drug release using brief, low-power light exposure. Nanoparticles stably retain encapsulated molecules in the vitreous, and can release cargo in response to UV exposure up to 30 weeks post-injection. Light-triggered release of nintedanib (BIBF 1120), a small molecule angiogenesis inhibitor, 10 weeks post-injection suppresses choroidal neovascularization (CNV) in rats. Light-sensitive nanoparticles are biocompatible and cause no adverse effects on the eye as assessed by electroretinograms (ERG), corneal and retinal tomography, and histology.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Sistemas de Liberação de Medicamentos , Indóis/administração & dosagem , Nanopartículas/administração & dosagem , Nanopartículas/efeitos da radiação , Animais , Linhagem Celular , Sobrevivência Celular , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos da radiação , Olho/metabolismo , Ácido Láctico/química , Luz , Masculino , Camundongos , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos Sprague-DawleyRESUMO
To address the scarcity of polymers that degrade upon absorption of near infrared (NIR) light, we introduce a new polymer containing moieties in its backbone capable of highly efficient NIR-triggered photocleavage. The polymer rapidly undergoes backbone scission in response to both UV-Vis and near infrared light via two-photon absorption, as revealed by gel permeation chromatography. Cleavage of photosensitive groups from the backbone is confirmed by 1H NMR. These polymers were successfully formulated into particles encapsulating a dye that was released upon irradiation with UV-Vis and NIR light, as indicated by changes in fluorescence characteristic of increased solvent interaction with cargo. Thus, this new polymer is readily photocleaved by UV-Vis and NIR light, giving it a variety of potential applications in photopatterning and on-demand release.
RESUMO
Between November 1970 and September 1984 the senior author performed fifty-three consecutive total hip arthroplasties with cement in forty-one patients with the diagnosis of osteonecrosis of the femoral head. Five hips in three patients with failed renal transplants requiring chronic hemodialysis were excluded. At the time of final review, a minimum of ten years after the procedure, twenty-one patients (twenty-eight hips) were living, fifteen patients (eighteen hips) had died, and two patients (two hips) were lost to follow-up. A minimum ten-year follow-up radiograph was obtained on twenty-two (79%) of the hips in surviving patients. During the follow-up period 17.4% of hips (eight hips) required revision: 13.0% (six hips) for aseptic loosening, 2.2% (one hip) for sepsis, and 2.2% (one hip) for recurrent dislocation. All eight revisions occurred in patients living at time of final review, giving a revision prevalence of 22.9% (17.1% for aseptic loosening, 2.9% for sepsis, and 2.9% for recurrent dislocation) in patients surviving ten years. The prevalence of revision of the femoral component for aseptic loosening was 6.5% (three hips) for all hips and 9.1% (three hips) in patients surviving at least ten years. The prevalence of femoral aseptic loosening, defined as those components revised for aseptic loosening and those that demonstrated definite or probable radiographic loosening, was 13.0% (six hips) for all hips and 28.6% (six hips) for hips with at least ten-year radiographic follow-up. The prevalence of revision of the acetabular component for aseptic loosening was 13.0% (six hips) for all hips and 18.2% (six hips) in patients surviving at least ten years. The prevalence of acetabular aseptic loosening was 15.2% (seven hips) for all hips and 29.2% (seven hips) for hips with at least ten-year radiographic follow-up. In patients with osteonecrosis of the femoral head survivorship was significantly inferior to that in the senior author's overall patient population with regard to revision for aseptic loosening (p=0.019), revision for acetabular loosening (p=0.01), revision for femoral loosening (p=0.008), and aseptic femoral loosening (p=0.004). Survivorship to aseptic acetabular loosening was not significantly different (p=0.32). Young age at the time of surgery significantly increased the risk of subsequent component loosening (p<0.008) and revision due to aseptic loosening (p<0.002). These findings demonstrate the relatively poor durability of cemented total hip arthroplasty in patients with osteonecrosis of the femoral head as compared to patients with other diagnoses and suggest that the younger age in this patient population compromises results.