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Synthesis of Nanosized Metal-organic Frameworks (NMOFs) for Drug Delivery
Li Xiuyan Lv Shaowa Wang rui Li Weinan Li Yongji* (College of Pharmacy, Heilongjiang University of TCM, Harbin 150040, China)
Abstracts: Three types of nanoscale Metal-organic Frameworks IRMOF-1, IRMOF-3 and HKUST-1 were synthesized successfully at the room temperature and was characterized by powder X-ray diffraction(PXRD), SEM , TEM and Nitrogen adsorption instrument. Metal-organic frameworks (MOFs) have emerged as a promising platform for drug delivery, owing to their many characters like porosity, high surface areas, unsaturated metal coordination site, preparation simple and versatile structure etc.It is provided with high drug loadings and fixed drug release, so it has received considerable attention. But compared with other carrier materials,the study of the MOFs is only in the primary stage .
Key words:Metal-organic frameworks; MOFs; mesoporous material; drug delivery
Metal-organic Frameworks(MOFs) are a kind of hybrid materials that are built from metal ion connectors and polydentate bridging ligands which have been exploited on the bulk scale for a number of applications, including gas adsorption[1], catalysis[2], nonlinear optics[3] and drug delivery[4]. Moreover, the high structural flexibility of some porous MOFs [5] enables the adaptation of their porosity to the shape of the hosted molecule. Recently, nanoMOFs based on NPs of nontoxic porous iron(III) carboxylates were shown to exhibit important drug loadings and progressive release as well as interesting imaging properties [6]. Herein we report a general method for preparing nanoscale MOFs ( NMOFs ) using pouring rapidly and room-tempreture titrimetry and demonstrate the potential utility of NMOFs as drug carries.
We choose Cu and Zn as the metal connectors because they are necessary trace elements for the health of people. Benzenetricarboxylic acid (H3BTC) and terephthalic acid (H2BDC) are used as the
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bridging ligand for its ability to form stable NMOFs. The particle size is considered one of the most important parameters in the mucosal, tissue and cell uptake of the nanoparticles[7]. Smaller nanoparticles are able to penetrate through the submucosal layers, whereas larger size particles were found to be localized in the epithelial lining[8]. Moreover, smaller nanoparticles were found to show significantly higher transfection efficiency as compared with larger nanoparticles[9]. Therefore, our study aimed to produce NMOFs of relatively smaller size .
1. Materials and methods
1.1 Materials
All of the chemicals used are atleast analytical grade. N,N-Dimethylformamide(DMF) (Tianjin Standard Chemical ReagentCo. Ltd., Tiangin, China),Zn(OAc)2-2H2O(Kaitong Reagent Co. Ltd., Tianjin, China), Terephthalic acid(AladdinReagent Co. Ltd., Shanghai, China),2-aminoterephthalicacid(Chemical Industry Co., LTD., Tokyo, Japen) were used for the preparation ofnanosized IRMOFs. CuAc2(Guangfu Chemical Industry Co. Ltd., Tianjin, China), C6H5COOH (Guangfu Chemical Industry Co. Ltd., Tianjin, China), H3BTC(Henghua Technoligy Co.Ltd., Jinan, China) were used for the preparation ofnanosized HKUST-1. Powder X-ray diffraction(PXRD) analysis was performed on a Phillips Xpert Pro MPD diffractometer , Nitrogen adsorption instrument was carried out on NOVA 3 000(Quantachrome Instrument)
1.2 Synthesis
Different synthesis methods were set up to obtain NPs of rigid or flexible MOFs
1.2.1 IRMOF-1
For atypical preparation of nanosized IRMOF-1 ( MOF-5), a 10 mL DMFsolution ofZn(OAc)22H2O (4mM) was rapidly poured intoa 15 mL DMF solution of terephthalic acid (1mM) at roomtemperature (20 °C). The mixture turned turbid immediately,and after 1 min, the nanocrystals were isolated by centrifugation(12000 rpm), washed withDMF and CH2Q2, and redispersed inCH2Cl2 for coating capillary columns.
1.2.2 IRMOF-3
It was synthesized by rapidly pouring a10 mL DMF solution of Zn(OAc)22H2O (4 mM) into a15 mL DMF solution of 2-aminoterephthalic acid (1 mM) atroom temperature (20 °C). The mixture turned turbid immediately,and after 1 min, the nanocrystals were isolated by centrifugation(12000 rpm), washed with DMF and CH2Cl2, andredispersed in CH2Cl2 for coating capillary columns.
1.2.3 HKUST-1
Dissolve CuAc2 (0.06g) and C6H5COOH (modulator)(0.8g) in the 6mLnormal butyl alcohol and H3BTC (0.16g) in the 6mL DMF, stirred them until they completely dissolved. After that, Drop ligand solution into metal salt solution slowly at room temperature, and make sure that the dropping time was about 30min. Blue sediment can be observed during dropping. Keep stir for 1h after dropping. The obtained NMOFs were recovered by centrifugation at 5600 g for 10min. To remove the solvent and the residual non-reacted organic acids, they were washed by ethanol twice.
1.3 X-ray powder diffraction
X-ray powder diffraction confirmed not only the crystal structure of the different hybrid NPs, but also the smaller particle size as indicated by the larger width of the Bragg peaks.
1.4 Characterization of NMOFs
The particle size were performed by DLS using a Malvern Nano ZS90(Malvern Instruments, Warriewood, UK), which evaluates the mean diameter and size distribution profiles of nanoparticles by light scattering based on laser diffraction. The NMOFs were immersed in an alcoholic medium prior to the measurement at 25 °C .The values reported are shown as the mean ±SD of at least three different of each NMOFs.
1.5 Morphological studies
Surface morphology of NMOFs was characterized by scanning electron microscopy ( Jeol 1640; Jeol, London, UK). For the scanning electron microscope, NMOFs were mounted on metal stubs
previously covered with double-sided adhesive, and coated with gold in a vacuum using an IB-3 ion coater (Eiko Engineering Co., Ltd, Tokyo, Japan). The coated samples were scanned at an accelerating voltage of 15Kv.
1.6 Nitrogen adsorption experiment
Nitrogen adsorption experiments were performed on optimally activated samples, and they confirmed that their structures are indeed highly porous and exhibits an isotherm consistent with mesoporosity
2. Results and discussion
2.1 Synthesis of NMOFs
Nanoparticles of three types of crystalline porous iron(III) carboxylate solids were obtained at room temperature. X-ray powder diffraction confirmed that HKUST-1 and IRMOF-1 have the same shape with the standard patterns(Fig1).
2.2 Physicochemical characteristics
NMOFs were distributed in a narrow particle size range, and the size of them were found to be 270.4nm(Fig3.A) and 248.5nm (Fig3.B). Nanoparticles of IRMOF-3 and HKUST-1 exhibited the smallest sizes (~50-100nm; Fig2.B.C), while the size of IRMOF-1 was about 500nm(Fig2.A ). Investigation done under a scanning electron microscope revealed that the HKUST-1 were found to be in spherical shape(Fig.2.C.), while IRMOF-1 and IRMOF-3 were found to be in square shape(Fig.2.A.B).
(A) (B)
kfkj
L^UL^ju.
I U OU q|J
Fig 1 (A): XRD patterns of the synthetic HKIjs i -i(DiacK) ana stanaara HKUS i -iirecu;
(B): XRD patterns of the synthetic IRMOF-1(black) and standard IRMOF-1(red);
Fig2: TEM and SEM pictures showing the morphology of various nanoparticles made of: (A)IRMOF-1 (SEM) ; (B) IRMOF-3 (SEM); (C) HKUST-1 (SEM); (D) HKUST-1 (TEM);
Size (d.nm)
(B)
Size (d.nm)
Fig^: ine particle size aistriDunon 01 rNiviurs: (aj hkus i - i; (bj iKiviur-j;
Transmission electron microscopy also confirmed that HKUST-1 were approximately 50-100nm in size and nearly spherical in shape(Fig.2.D).
3.Conclusion
In summary, we synthesized three types of nanoscale MOFs under room temperature and . show the potential use of these NMOFs as drug delivery. It is noteworthy that in traditional porous materialssuch as silica and polymeric matrixes, drug loading capacity isusually not sufficiently high and encapsulated drug is difficultto be released specifically. To achieve a high loading and acontrolled release, porous materials possessing large volumesand regular structures are desired. NMOFs with tunablepore size and functionality thus provide a wealth of opportunitiesfor drug delivery.
But compared with other carrier materials ,the study of the MOFs is only in the primary stage . Up to now, there are so many studies on the release and cytology in vitro, We foresee that many other studies onthe biocompatibility and in vivo .
References
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