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1.
ACS Appl Mater Interfaces ; 12(5): 5633-5641, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31940165

RESUMO

The synthetic flexibility of metal-organic frameworks (MOFs) with high loading capacities and biocompatibility makes them ideal candidates as drug delivery systems (DDSs). Here, we report the use of CAU-7, a biocompatible bismuth-based MOF, for the delivery of two cancer drugs, sodium dichloroacetate (DCA) and α-cyano-4-hydroxycinnamic acid (α-CHC). We achieved loadings of 33 and 9 wt % for DCA and α-CHC, respectively. Interestingly, CAU-7 showed a gradual release of the drugs, achieving a release time of up to 17 days for DCA and 31 days for α-CHC. We then performed mechanical and thermal amorphization processes to attempt to delay the delivery of guest molecules even more. With the thermal treatment, we were able to achieve an outstanding 32% slower release of α-CHC from the thermally treated CAU-7. Using in vitro studies and endocytosis inhibitors, confocal microscopy, and fluorescence-activated cell sorting, we also demonstrated that CAU-7 was successfully internalized by cancer cells, partially avoiding lysosome degradation. Finally, we showed that CAU-7 loaded either with DCA or α-CHC had a higher therapeutic efficiency compared with the free drug approach, making CAU-7 a great option for biomedical application.

2.
ACS Appl Mater Interfaces ; 10(6): 5255-5268, 2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29356507

RESUMO

The high drug-loading and excellent biocompatibilities of metal-organic frameworks (MOFs) have led to their application as drug-delivery systems (DDSs). Nanoparticle surface chemistry dominates both biostability and dispersion of DDSs while governing their interactions with biological systems, cellular and/or tissue targeting, and cellular internalization, leading to a requirement for versatile and reproducible surface functionalization protocols. Herein, we explore not only the effect of introducing different surface functionalities to the biocompatible Zr-MOF UiO-66 but also the efficacy of three surface modification protocols: (i) direct attachment of biomolecules [folic acid (FA) and biotin (Biot)] introduced as modulators for UiO-66 synthesis, (ii) our previously reported "click-modulation" approach to covalently attach polymers [poly(ethylene glycol) (PEG), poly-l-lactide, and poly-N-isopropylacrylamide] to the surface of UiO-66 through click chemistry, and (iii) surface ligand exchange to postsynthetically coordinate FA, Biot, and heparin to UiO-66. The innovative use of a small molecule with metabolic anticancer activity, dichloroacetate (DCA), as a modulator during synthesis is described, and it is found to be compatible with all three protocols, yielding surface-coated, DCA-loaded (10-20 w/w %) nano-MOFs (70-170 nm). External surface modification generally enhances the stability and colloidal dispersion of UiO-66. Cellular internalization routes and efficiencies of UiO-66 by HeLa cervical cancer cells can be tuned by surface chemistry, and anticancer cytotoxicity of DCA-loaded MOFs correlates with the endocytosis efficiency and mechanisms. The MOFs with the most promising coatings (FA, PEG, poly-l-lactide, and poly-N-isopropylacrylamide) were extensively tested for selectivity of anticancer cytotoxicity against MCF-7 breast cancer cells and HEK293 healthy kidney cells as well as for cell proliferation and reactive oxygen species production against J774 macrophages and peripheral blood lymphocytes isolated from the blood of human donors. DCA-loaded, FA-modified UiO-66 selectively kills cancer cells without harming healthy ones or provoking immune system response in vitro, suggesting a significant targeting effect and great potential in anticancer drug delivery. The results provide mechanistic insight into the design and functionalization of MOFs for drug delivery and underline the availability of various in vitro techniques to potentially minimize early-stage in vivo animal studies following the three Rs: reduction, refinement, and replacement.


Assuntos
Nanopartículas Metálicas/química , Acetatos , Animais , Antineoplásicos , Compostos Clorados , Sistemas de Liberação de Medicamentos , Células HEK293 , Humanos , Sistema Imunitário , Estruturas Metalorgânicas , Polietilenoglicóis
3.
ACS Appl Mater Interfaces ; 9(41): 35516-35525, 2017 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-28925254

RESUMO

A critical bottleneck for the use of metal-organic frameworks (MOFs) as drug delivery systems has been allowing them to reach their intracellular targets without being degraded in the acidic environment of the lysosomes. Cells take up particles by endocytosis through multiple biochemical pathways, and the fate of these particles depends on these routes of entry. Here, we show the effect of functional group incorporation into a series of Zr-based MOFs on their endocytosis mechanisms, allowing us to design an efficient drug delivery system. In particular, naphthalene-2,6-dicarboxylic acid and 4,4'-biphenyldicarboxylic acid ligands promote entry through the caveolin-pathway, allowing the particles to avoid lysosomal degradation and be delivered into the cytosol and enhancing their therapeutic activity when loaded with drugs.

4.
Chem ; 2(4): 561-578, 2017 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-28516168

RESUMO

The high storage capacities and excellent biocompatibilities of metal-organic frameworks (MOFs) have made them emerging candidates as drug-delivery vectors. Incorporation of surface functionality is a route to enhanced properties, and here we report on a surface-modification procedure-click modulation-that controls their size and surface chemistry. The zirconium terephthalate MOF UiO-66 is (1) synthesized as ∼200 nm nanoparticles coated with functionalized modulators, (2) loaded with cargo, and (3) covalently surface modified with poly(ethylene glycol) (PEG) chains through mild bioconjugate reactions. At pH 7.4, the PEG chains endow the MOF with enhanced stability toward phosphates and overcome the "burst release" phenomenon by blocking interaction with the exterior of the nanoparticles, whereas at pH 5.5, stimuli-responsive drug release is achieved. The mode of cellular internalization is also tuned by nanoparticle surface chemistry, such that PEGylated UiO-66 potentially escapes lysosomal degradation through enhanced caveolae-mediated uptake. This makes it a highly promising vector, as demonstrated for dichloroacetic-acid-loaded materials, which exhibit enhanced cytotoxicity. The versatility of the click modulation protocol will allow a wide range of MOFs to be easily surface functionalized for a number of applications.

5.
Dalton Trans ; 46(12): 3915-3920, 2017 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-28265629

RESUMO

Copper-exchanged and acidic zeolites are shown to produce nitric oxide (NO) from a nitrite source in biologically active (nanomolar) concentrations. Four zeolites were studied; mordenite, ferrierite, ZSM-5 and SSZ-13, which had varying pore size, channel systems and Si/Al ratios. ZSM-5 and SSZ-13 produced the highest amounts of NO in both the copper and acid form. The high activity and regeneration of the copper active sites makes them good candidates for long-term NO production. Initial cytotoxicity tests have shown at least one of the copper zeolites (Cu-SSZ-13) to be biocompatible, highlighting the potential usage within biomedical applications.


Assuntos
Materiais Biocompatíveis/química , Cobre/química , Óxido Nítrico/química , Zeolitas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cobre/toxicidade , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Nitritos/química , Temperatura Ambiente
6.
Adv Healthc Mater ; 5(17): 2261-70, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27385477

RESUMO

The pathway of internalization and final fate of a specific metal-organic framework (MOF) in cells has been investigated for the first time. This study is based on two calcein-loaded UiO-66 samples with particle sizes of 150 and 260 nm (i.e., cal@150 UiO-66 and cal@260 UiO-66, respectively), and shows that the active trafficking of cal@150 UiO-66 is done almost exclusively through clathrin-mediated endocytosis, whereas the uptake of cal@260 UiO-66 is a combination of both clathrin and caveolae-mediated endocytosis. Colocalization studies with a lysosomal marker showed that cal@150 UiO-66 is located mostly in lysosomes for further degradation, whereas cal@260 UiO-66 seems to avoid the lysosomal degradation and potentially deliver the cargo molecules in the cytosol, allowing their distribution to different cellular organelles. This study reveals the importance of the internalization processes of MOFs, particularly the relevance of their particle size, and also the critical significance of their final fate to become an efficient drug delivery system. Based on these results, it is possible that extremely small particle-sized MOFs are not the most efficient carriers and instead relatively medium-sized particles are required.


Assuntos
Materiais Revestidos Biocompatíveis , Sistemas de Liberação de Medicamentos/métodos , Endocitose/efeitos dos fármacos , Fluoresceínas , Nanopartículas , Compostos Organometálicos , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Fluoresceínas/química , Fluoresceínas/farmacocinética , Fluoresceínas/farmacologia , Células HeLa , Humanos , Lisossomos/metabolismo , Nanopartículas/química , Nanopartículas/uso terapêutico , Compostos Organometálicos/química , Compostos Organometálicos/farmacocinética , Compostos Organometálicos/farmacologia
7.
Chem Commun (Camb) ; 51(89): 16037-40, 2015 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-26340410

RESUMO

We present experimental and computational evidence that gate-opening modes for zeolitic imidazole frameworks can be observed at terahertz frequencies. Our work highlights the critical importance to correctly optimise the crystal structure prior to computational lattice dynamics analysis. The results support the hypothesis that the low energy vibrational modes do indeed play a significant role in host-guest interactions for ZIFs, such as gas loading.

8.
Chem Commun (Camb) ; 51(73): 13878-81, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26213904

RESUMO

We report the encapsulation of the hydrophilic model molecule calcein in the Zr-based MOF UiO-66, followed by amorphization of the framework by ball-milling. We show controlled release of calcein over more than 30 days, compared with the 2 day release period from crystalline UiO-66.


Assuntos
Complexos de Coordenação/química , Sistemas de Liberação de Medicamentos , Fluoresceínas/química , Zircônio/química , Complexos de Coordenação/administração & dosagem , Fluoresceínas/administração & dosagem , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Zircônio/administração & dosagem
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