RESUMO
Cancer theranostics that combines cancer diagnosis and therapy is a promising approach for personalized cancer treatment. However, current theranostic strategies suffer from low imaging sensitivity for visualization and an inability to target the diseased tissue site with high specificity, thus hindering their translation to the clinic. In this study, we have developed a tumor microenvironment-responsive hybrid theranostic agent by grafting water-soluble, low-fouling fluoropolymers to pH-responsive zeolitic imidazolate framework-8 (ZIF-8) nanoparticles by surface-initiated RAFT polymerization. The conjugation of the fluoropolymers to ZIF-8 nanoparticles not only allows sensitive in vivo visualization of the nanoparticles by 19F MRI but also significantly prolongs their circulation time in the bloodstream, resulting in improved delivery efficiency to tumor tissue. The ZIF-8-fluoropolymer nanoparticles can respond to the acidic tumor microenvironment, leading to progressive degradation of the nanoparticles and release of zinc ions as well as encapsulated anticancer drugs. The zinc ions released from the ZIF-8 can further coordinate to the fluoropolymers to switch the hydrophilicity and reverse the surface charge of the nanoparticles. This transition in hydrophilicity and surface charge of the polymeric coating can reduce the "stealth-like" nature of the agent and enhance specific uptake by cancer cells. Hence, these hybrid nanoparticles represent intelligent theranostics with highly sensitive imaging capability, significantly prolonged blood circulation time, greatly improved accumulation within the tumor tissue, and enhanced anticancer therapeutic efficiency.
Assuntos
Estruturas Metalorgânicas , Nanopartículas , Neoplasias , Humanos , Polímeros de Fluorcarboneto/uso terapêutico , Estruturas Metalorgânicas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Nanopartículas/uso terapêutico , Imageamento por Ressonância Magnética , Interações Hidrofóbicas e Hidrofílicas , Zinco/uso terapêutico , Íons , Microambiente TumoralRESUMO
Central nervous system (CNS) disorders affect as many as 1.5 billion people globally. The limited delivery of most imaging and therapeutic agents into the brain is a major challenge for treatment of CNS disorders. With the advent of nanotechnologies, controlled delivery of drugs with nanoparticles holds great promise in CNS disorders for overcoming the blood-brain barrier (BBB) and improving delivery efficacy. In recent years, magnetic iron oxide nanoparticles (MIONPs) have stood out as a promising theranostic nanoplatform for brain imaging and drug delivery as they possess unique physical properties and biodegradable characteristics. In this review, we summarize the recent advances in MIONP-based platforms as imaging and drug delivery agents for brain diseases. We firstly introduce the methods of synthesis and surface functionalization of MIONPs with emphasis on the inclusion of biocompatible polymers that allow for the addition of tailored physicochemical properties. We then discuss the recent advances in in vivo imaging and drug delivery applications using MIONPs. Finally, we present a perspective on the remaining challenges and possible future directions for MIONP-based brain delivery systems.
Assuntos
Doenças do Sistema Nervoso Central , Nanopartículas , Humanos , Sistemas de Liberação de Medicamentos/métodos , Encéfalo/diagnóstico por imagem , Barreira Hematoencefálica , Nanopartículas Magnéticas de Óxido de Ferro , Preparações Farmacêuticas , Doenças do Sistema Nervoso Central/tratamento farmacológico , Nanopartículas/uso terapêutico , NeuroimagemRESUMO
Gold nanorods (GNRs) are widely used in various biomedical applications such as disease imaging and therapy due to their unique plasmonic properties. To improve their bioavailability, GNRs often need to be coated with hydrophilic polymers so as to impart stealth properties. Poly(ethylene glycol) (PEG) has been long used as such a coating material for GNRs. However, there is increasing acknowledgement that the amphiphilic nature of PEG facilitates its interaction with protein molecules, leading to immune recognition and consequent side effects. This has motivated the search for new classes of low-fouling polymers with high hydrophilicity as alternative low-fouling surface coating materials for GNRs. Herein, we report the synthesis, characterization, and application of GNRs coated with highly hydrophilic sulfoxide-containing polymers. We investigated the effect of the sulfoxide polymer coating on the cellular uptake and in vivo circulation time of the GNRs and compared these properties with pegylated GNR counterparts. The photothermal effect and photoacoustic imaging of these polymer-coated GNRs were also explored, and the results show that these GNRs are promising as nanotheranostic particles for the treatment of cancer.
Assuntos
Ouro , Nanotubos , Ouro/farmacologia , Polímeros , Medicina de Precisão , SulfóxidosRESUMO
Extracorporeal membrane oxygenation (ECMO), a critical life-sustaining tool, faces significant challenges for the maintenance of normal haemostasis due to the large volume of circulating blood continuously in contact with artificial surfaces, hyperoxia and excessive shear stresses of the extracorporeal circuit. From a biomaterials perspective, it has been hypothesised that drug eluting coatings composed of haemocompatible hydrogels loaded with an anticoagulant drug could potentially enhance the haemocompatibility of the circuit. Poly(ethylene glycol) (PEG) has been well established as a biocompatible and anti-fouling material with wide biomedical application. Unfractionated heparin is the most commonly used anticoagulant for ECMO. In the present study, the feasibility of using heparin-loaded PEG-based hydrogels as anti-thrombogenic surface coatings for ECMO was investigated. The hydrogels were synthesised by photopolymerisation using poly(ethylene glycol) diacrylate (PEGDA) as the crosslinking monomer and poly(ethylene glycol) methacrylate (PEGMA) as the hydrophilic monomer, with heparin loaded into the pre-gel solution. Factors which could affect the release of heparin were investigated, including the ratio of PEGDA/PEGMA, water content, loading level of heparin and the flow of fluid past the hydrogel. Our results showed that increased crosslinker content and decreased water content led to slower heparin release. The hydrogels with water contents of 60 wt% and 70 wt% could achieve a sustained heparin release by adjusting the ratio of PEGDA/PEGMA. The anticoagulation efficacy of the released heparin was evaluated by measuring the activated clotting time of whole blood. The hydrogels with desirable heparin release profiles were prepared onto poly(4-methyl-1-pentene) (PMP) films with the same chemical composition as the PMP ECMO membranes. The coatings showed sustained heparin release with a cumulative release of 70-80% after 7 days. Haemocompatibility tests demonstrated that PEG hydrogel coatings significantly reduced platelet adhesion and prolonged plasma recalcification time. These results suggest that heparin-loaded PEG hydrogels are potential anti-thrombogenic coatings for ECMO.
Assuntos
Oxigenação por Membrana Extracorpórea , Heparina , Materiais Biocompatíveis/química , Heparina/farmacologia , Hidrogéis/química , Hidrogéis/farmacologia , Polietilenoglicóis/química , ÁguaRESUMO
Amyloid aggregation is a ubiquitous form of protein misfolding underlying the pathologies of Alzheimer's disease (AD), Parkinson's disease (PD) and type 2 diabetes (T2D), three primary forms of human amyloid diseases. While much has been learned about the origin, diagnosis and management of these neurological and metabolic disorders, no cure is currently available due in part to the dynamic and heterogeneous nature of the toxic oligomers induced by amyloid aggregation. Here we synthesized beta casein-coated iron oxide nanoparticles (ßCas IONPs) via a BPA-P(OEGA-b-DBM) block copolymer linker. Using a thioflavin T kinetic assay, transmission electron microscopy, Fourier transform infrared spectroscopy, discrete molecular dynamics simulations and cell viability assays, we examined the Janus characteristics and the inhibition potential of ßCas IONPs against the aggregation of amyloid beta (Aß), alpha synuclein (αS) and human islet amyloid polypeptide (IAPP) which are implicated in the pathologies of AD, PD and T2D. Incubation of zebrafish embryos with the amyloid proteins largely inhibited hatching and elicited reactive oxygen species, which were effectively rescued by the inhibitor. Furthermore, Aß-induced damage to mouse brain was mitigated in vivo with the inhibitor. This study revealed the potential of Janus nanoparticles as a new nanomedicine against a diverse range of amyloid diseases.
RESUMO
Biomimetic nanomaterials have attracted tremendous research interest in the past decade. We recently developed biomimetic core-shell nanoparticles - silica nanocapsules, using a designer dual-functional peptide SurSi under room temperature, neutral pH and without use of any toxic reagents or chemicals. The SurSi peptide is designed capable of not only stabilizing nanoemulsions because of its excellent surface activity, but also inducing the formation of silica through biosilicification at an oil-water interface. However, it remains challenging to precisely control the peptide-induced nucleation and biosilicification specifically at the oil-water interface, thus forming oil-core silica-shell nanocapsules with uniform size and monodispersity. In this study, the fundamental mechanism of silica formation through a peptide catalyzed biosilicification was systematically investigated, so that the formation of oil-core silica-shell nanocapsules can be precisely controlled. The SurSi peptide induced hydrolysis and nucleation of biomineralized silica particles were monitored to study the biosilicification kinetics. Effects of pH, SurSi peptide concentration and pre-hydrolysis of silica precursors were also studied to optimize the formation of biomimetic silica nanocapsules. The fundamental understanding achieved through these systematic studies provides valuable insights for making core-shell nanoparticles via controlling nucleation and reaction at interfaces.
Assuntos
Nanocápsulas , Nanopartículas , Biomimética , Peptídeos , Dióxido de SilícioRESUMO
PURPOSE: For patients with intractable cancer-related pain, administration of strong opioid analgesics and adjuvant agents by the intrathecal (i.t.) route in close proximity to the target receptors/ion channels, may restore pain relief. Hence, the aim of this study was to use bioerodable polymers to encapsulate an opioid analgesic (hydromorphone) and an adjuvant drug (ketamine) to produce prolonged-release formulations for i.t. injection. METHODS: A two-stage microfluidic method was used to fabricate nanoparticles (NPs). The physical properties were characterised using dynamic light scattering and transmission electron microscopy. A pilot in vivo study was conducted in a rat model of peripheral neuropathic pain. RESULTS: The in vitro release of encapsulated payload from NPs produced with a polymer mixture (CPP-SA/PLGA 50:50) was sustained for 28 days. In a pilot in vivo study, analgesia was maintained over a three day period following i.t. injection of hydromorphone-loaded NPs at 50 µg. Co-administration of ketamine-loaded NPs at 340 µg did not increase the duration of analgesia significantly. CONCLUSIONS: The two-stage microfluidic method allowed efficient production of analgesic/adjuvant drug-loaded NPs. Our proof-of-principle in vivo study shows prolonged hydromorphone analgesic for 78 h after single i.t. injection. At the i.t. dose administered, ketamine released from NPs was insufficient to augment hydromorphone analgesia.
Assuntos
Hidromorfona/administração & dosagem , Ketamina/administração & dosagem , Microfluídica , Nanopartículas/uso terapêutico , Dor Intratável/tratamento farmacológico , Analgésicos Opioides/administração & dosagem , Animais , Composição de Medicamentos/métodos , Injeções Espinhais , Lipídeos/farmacologia , Masculino , Polímeros/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Nanotheranostics have been actively sought in precision nanomedicine in recent years. However, insufficient tumor accumulation and limited cell uptake often impede the nanotheranostic efficacy. Herein, pH-sensitive charge-reversible polymer-coated layered double hydroxide (LDH) nanohybrids are devised to possess long circulation in blood but reserve surface charges in the weakly acidic tumor tissue to re-expose therapeutic LDH nanoparticles for enhanced tumor accumulation and cell uptake. In vitro experimental data demonstrate that charge-reversible nanohybrids mitigate the cell uptake in physiological conditions (pH 7.4), but remarkably facilitate internalization by tumor cells after charge reversion in the weakly acidic environment (pH 6.8). More significantly, about 6.0% of injected charge-reversible nanohybrids accumulate in the tumor tissue at 24 h post injection, far higher than the average accumulation (0.7%) reported elsewhere for nanoparticles. This high tumor accumulation clearly shows the tumor tissues in T1 -weighted magnetic resonance imaging. As a consequence, >95% inhibition of tumor growth in the B16F0-bearing mouse model is achieved via only one treatment combining RNAi and photothermal therapy under very mild irradiation (808 nm laser, 0.3 W cm-2 for 180 s). The current research thus demonstrates a new strategy to functionalize nanoparticles and simultaneously enhance their tumor accumulation and cell internalization for effective cancer theranostics.
Assuntos
Nanopartículas , Neoplasias , Animais , Diagnóstico por Imagem , Hidróxidos , Camundongos , Nanomedicina , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Nanomedicina TeranósticaRESUMO
Incorporation of fluorinated moieties in polymeric nanoparticles has been shown in many instances to increase their uptake by living cells and, hence, has proven to be a useful approach to enhancing delivery to cells. However, it remains unclear how incorporation of fluorine affects critical transport processes, such as interactions with membranes, intracellular transport, and tumor penetration. In this study, we investigate the influence of fluorine on transport properties using a series of rationally designed poly(oligo(ethylene glycol) methyl ether acrylate)-block-perfluoropolyether (poly(OEGA)m-PFPE) copolymers. Copolymers with different fluorine contents were prepared and exhibit aggregate in solution in a manner dependent on the fluorine content. Doxorubicin-conjugated poly(OEGA)20-PFPE nanoparticles with lower fluorine content exist in solution as unimers, leading to greater exposure of hydrophobic PFPE segments to the cell surface. This, in turn, results in greater cellular uptake, deeper tumor penetration, as well as enhanced therapeutic efficacy compared to that with the micelle-state nanoaggregates (poly(OEGA)10-PFPE and poly(OEGA)5-PFPE) with higher fluorine content but with less PFPE exposed to the cell membranes. Our results demonstrate that the aggregation behavior of these fluorinated polymers plays a critical role in internalization and transport in living cells and 3D spheroids, providing important design criteria for the preparation of highly effective delivery agents.
Assuntos
Nanopartículas , Polímeros , Doxorrubicina/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Micelas , PolietilenoglicóisRESUMO
19 F magnetic resonance imaging (19 F MRI) agents capable of being activated upon interactions with cancer triggers are attracting increasing attention, although challenges still remain for precise and specific detection of cancer tissues. In this study, a novel hybrid 19 F MRI agent for pH-sensitive detection of breast cancer tissues is reported, a composite system designed by conjugating a perfluoropolyether onto the surface of manganese-incorporated layered double hydroxide (Mn-LDH@PFPE) nanoparticles. The 19 F NMR/MRI signals from aqueous solutions of Mn-LDH@PFPE nanoparticles are quenched at pH 7.4, but "turned on" following a reduction in pH to below 6.5. This is due to partial dissolution of Mn2+ from the Mn-LDH nanoparticles and subsequent reduction in the effect of paramagnetic relaxation. Significantly, in vivo experiments reveal that an intense 19 F MR signal can be detected only in the breast tumor tissue after intravenous injection of Mn-LDH@PFPE nanoparticles due to such a specific activation. Thus pH-activated Mn-LDH@PFPE nanoparticles are a potential "smart" 19 F MRI agent for precise and specific detection of cancer diseases.
Assuntos
Neoplasias da Mama/diagnóstico , Polímeros de Fluorcarboneto/química , Imageamento por Ressonância Magnética/métodos , Manganês/química , Nanopartículas/química , Neoplasias da Mama/diagnóstico por imagem , Meios de Contraste/química , Feminino , Humanos , Concentração de Íons de Hidrogênio , Sensibilidade e EspecificidadeRESUMO
Imaging agents that can be targeted to specific diseases and respond to the microenvironment of the diseased tissue are of considerable interest due to their potential in diagnosing and managing diseases. Here we report a new class of branched fluorinated glycopolymers as 19F MRI contrast agents that respond to a reductive environment, for targeted imaging of cancer. The fluorinated glycopolymers can be readily prepared by a one-pot RAFT polymerization of glucose- and fluorine-containing monomers in the presence of a disulfide-containing cross-linking monomer. The incorporation of glucose units along the polymer chain enables these fluorinated glycopolymers to effectively target cancer cells due to interactions with the overexpressed sugar transporters present on the cell surface. In addition, the polymers exhibit an enhanced 19F MRI signal in response to a reductive environment, one of the unique hallmarks of many cancer cells, demonstrating their potential as promising candidates for targeted imaging of cancer.
Assuntos
Meios de Contraste/química , Flúor/química , Glucose/análogos & derivados , Imageamento por Ressonância Magnética/métodos , Neoplasias/diagnóstico por imagem , Polímeros Responsivos a Estímulos/química , Animais , Células CHO , Cricetinae , Cricetulus , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , Células MCF-7 , OxirreduçãoRESUMO
Iron oxide nanoparticles have been widely applied in biomedical applications for their unique physical properties. Despite the relatively mature synthetic approaches for iron oxide nanoparticles, surface modification strategies for obtaining particles with satisfactory biofunctionality are still urgently needed to meet the challenge of nanomedicine. Herein, we report a surface modification and biofunctionalization strategy for iron oxide-based magnetic nanoparticles based on a dibromomaleimide (DBM)-terminated polymer with brushed polyethylene glycol (PEG) chains. PEG acrylate and phosphonate monomers, serving as antibiofouling and surface anchoring compartments for iron oxide nanoparticles, were incorporated utilizing a novel DBM containing reversible addition-fragmentation chain transfer (RAFT) agent. The particles prepared through this new surface architecture possessed high colloidal stability in a physiological buffer and the capacity of covalent conjugation with biomolecules for targeting. Cell tracking of the molecular probes was achieved concomitantly by exploiting DBM conjugation-induced fluorescence of the nanoparticles.
Assuntos
Rastreamento de Células/métodos , Compostos Férricos/química , Fluorescência , Maleimidas/química , Nanopartículas/química , Polietilenoglicóis/química , Polímeros/química , Bromo/química , Sobrevivência Celular , Células HEK293 , Humanos , Células MCF-7 , NanomedicinaRESUMO
Thermo and pH dual-controllable oil/water separation materials are successfully fabricated by photo initiated free radical polymerization of dimethylamino ethyl methacrylate (DMAEMA). The PDMAEMA hydrogel coated mesh shows superhydrophilicity and underwater superoleophobicity at certain temperature and pH. Due to the double responsiveness of PDMAEMA hydrogel, the as-prepared mesh can selectively separate water from oil/water mixtures and make water and oil permeate through the mesh orderly and be collected separately by adjusting the temperature or pH. Water can pass through the as-prepared mesh under 55 °C (pH 7) and pH less than 13 (T = 25 °C) while oil is kept on the mesh. When the temperature is above 55 °C or pH is larger than 13, the water retention capacity of PDMAEMA hydrogel is significantly reduced and the swelling volume is decreased. Therefore, oil can permeate through the mesh and be collected in situ. Additionally, this material has excellent potential to be used in practical applications and has created a new field for water/oil separation in which the process can be diversified and more intelligent.