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Mitochondria play a key role in oncogenesis and constitute one of the most important targets for cancer treatments. Although the most effective way to deliver drugs to mitochondria is by covalently linking them to a lipophilic cation, the in vivo delivery of free drugs still constitutes a critical bottleneck. Herein, we report the design of a mitochondria-targeted metal-organic framework (MOF) that greatly increases the efficacy of a model cancer drug, reducing the required dose to less than 1% compared to the free drug and ca. 10% compared to the nontargeted MOF. The performance of the system is evaluated using a holistic approach ranging from microscopy to transcriptomics. Super-resolution microscopy of MCF-7 cells treated with the targeted MOF system reveals important mitochondrial morphology changes that are clearly associated with cell death as soon as 30 min after incubation. Whole transcriptome analysis of cells indicates widespread changes in gene expression when treated with the MOF system, specifically in biological processes that have a profound effect on cell physiology and that are related to cell death. We show how targeting MOFs toward mitochondria represents a valuable strategy for the development of new drug delivery systems.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Estruturas Metalorgânicas/metabolismo , Mitocôndrias/metabolismo , HumanosRESUMO
Nanoparticle encapsulation inside zirconium-based metal-organic frameworks (NP@MOF) is hard to control, and the resulting materials often have nonuniform morphologies with NPs on the external surface of MOFs and NP aggregates inside the MOFs. In this work, we report the controlled encapsulation of gold nanorods (AuNRs) by a scu-topology Zr-MOF, via a room-temperature MOF assembly. This is achieved by functionalizing the AuNRs with poly(ethylene glycol) surface ligands, allowing them to retain colloidal stability in the precursor solution and to seed the MOF growth. Using this approach, we achieve core-shell yields exceeding 99%, tuning the MOF particle size via the solution concentration of AuNRs. The functionality of AuNR@MOFs is demonstrated by using the AuNRs as embedded probes for selective surface-enhanced Raman spectroscopy (SERS). The AuNR@MOFs are able to both take-up or block molecules from the pores, thereby facilitating highly selective sensing at the AuNR ends. This proof-of-principle study serves to present both the outstanding level of control in the synthesis and the high potential for AuNR@Zr-MOF composites for SERS.
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Labelfree nanoscopy encompasses optical imaging with resolution in the 100 nm range using visible wavelengths. Here, we present a labelfree nanoscopy method that combines coherent imaging techniques with waveguide microscopy to realize a super-condenser featuring maximally inclined coherent darkfield illumination with artificially stretched wave vectors due to large refractive indices of the employed Si3N4 waveguide material. We produce the required coherent plane wave illumination for Fourier ptychography over imaging areas 400 µm2 in size via adiabatically tapered single-mode waveguides and tackle the overlap constraints of the Fourier ptychography phase retrieval algorithm two-fold: firstly, the directionality of the illumination wave vector is changed sequentially via a multiplexed input structure of the waveguide chip layout and secondly, the wave vector modulus is shortend via step-wise increases of the illumination light wavelength over the visible spectrum. We test the method in simulations and in experiments and provide details on the underlying image formation theory as well as the reconstruction algorithm. While the generated Fourier ptychography reconstructions are found to be prone to image artefacts, an alternative coherent imaging method, rotating coherent scattering microscopy (ROCS), is found to be more robust against artefacts but with less achievable resolution.
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Porosity and surface area analysis play a prominent role in modern materials science. At the heart of this sits the Brunauer-Emmett-Teller (BET) theory, which has been a remarkably successful contribution to the field of materials science. The BET method was developed in the 1930s for open surfaces but is now the most widely used metric for the estimation of surface areas of micro- and mesoporous materials. Despite its widespread use, the calculation of BET surface areas causes a spread in reported areas, resulting in reproducibility problems in both academia and industry. To prove this, for this analysis, 18 already-measured raw adsorption isotherms were provided to sixty-one labs, who were asked to calculate the corresponding BET areas. This round-robin exercise resulted in a wide range of values. Here, the reproducibility of BET area determination from identical isotherms is demonstrated to be a largely ignored issue, raising critical concerns over the reliability of reported BET areas. To solve this major issue, a new computational approach to accurately and systematically determine the BET area of nanoporous materials is developed. The software, called "BET surface identification" (BETSI), expands on the well-known Rouquerol criteria and makes an unambiguous BET area assignment possible.
Assuntos
Reprodutibilidade dos Testes , Adsorção , PorosidadeRESUMO
Among a plethora of nano-sized therapeutics, metal-organic frameworks (MOFs) have been some of the most investigated novel materials for, predominantly, cancer drug delivery applications. Due to their large drug uptake capacities and slow-release mechanisms, MOFs are desirable drug delivery vehicles that protect and transport sensitive drug molecules to target sites. The inclusion of other guest materials into MOFs to make MOF-composite materials has added further functionality, from externally triggered drug release to improved pharmacokinetics and diagnostic aids. MOF-composites are synthetically versatile and can include examples such as magnetic nanoparticles in MOFs for MRI image contrast and polymer coatings that improve the blood-circulation time. From synthesis to applications, this review will consider the main developments in MOF-composite chemistry for biomedical applications and demonstrate the potential of these novel agents in nanomedicine. It is concluded that, although vast synthetic progress has been made in the field, it requires now to develop more biomedical expertise with a focus on rational model selection, a major comparative toxicity study, and advanced targeting techniques.
Assuntos
Estruturas Metalorgânicas/química , Sistemas de Liberação de Medicamentos , Nanopartículas , Preparações Farmacêuticas , PolímerosRESUMO
Recent developments in super-resolution microscopy have significantly expanded the requirements for switchable dyes, leading to demand for specially designed molecular switches. We report the synthesis and characterization of a spironaphthoxazine photochromic switch (a derivative of palatinate purple) displaying high photoconversion (85-95%) under readily accessible 405 nm light, broad absorption in the visible, and excellent fatigue resistance. The indole substituent on this spironaphthoxazine is twisted out of conjugation with the naphthalene unit, yet it is crucial for activation with visible light. The open colored merocyanine form of the spironaphthoxazine reverts to the closed form with a lifetime of 4.7 s in dichloromethane at 20 °C; this thermal reversion is even faster in more polar solvents. The photochemical quantum yields for ring-opening and ring-closing are approximately 8% and 1%, respectively, in dichloromethane. The ring-opening and ring-closing reactions have been characterized by time-resolved infrared and transient absorption spectroscopies. Ring opening occurs rapidly (τ = 2.1 ns) and efficiently (â¼90%) from the singlet excited state to form an intermediate (assigned as a cisoid merocyanine), which returns to the closed ground state (τ = 4.5 ns) in competition with relaxation to the transoid open form (τ = 40 ns). Photochemical ring closing is a faster and simpler process: the excited state proceeds to the closed spirooxazine with a time constant of 0.28 ns. This photochromic switch can be used in conjunction with commercial fluorescent dyes to create a small-molecule switchable fluorescent dyad that shows high contrast and good fatigue resistance in living cells. These properties make the dyads suitable for application in RESOLFT microscopy.
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[This corrects the article DOI: 10.1039/C8SC00130H.].