以二次離子質譜縱深分析研究藥物分子於有機金屬框架內的擴散行為

Abstract

金屬有機框架（MOFs）因其高比表面積、可調孔徑和官能基團等獨特性質，其作為各種應用的材料已被廣泛的討論。然而，MOFs開發中的一個挑戰是瞭解客體分子在其中的擴散。不幸的是，至今只有極少數的研究能夠直接瞭解客體分子在MOFs中的分佈情況，這對MOFs的開發和應用造成了重大障礙。然而，二次離子質譜（SIMS）由於其卓越的空間解析度，分別為小於100奈米的橫向解析度、及小至數奈米的深度解析度，以及其達到百萬分之一（ppm）的靈敏度，都顯示其成為研究MOFs中客體分子分佈的分析技術的潛力。 然而，儘管SIMS可以提供關於樣品組成和分佈的資訊，但是過往的研究指出，在縱深分析過程中的高能離子轟擊會對MOF的化學結構造成損害，尤其是會使有機訊號強度大幅下降。因此，為了瞭解客體分子在MOF中的擴散，不僅需要選擇適當的MOF和客體分子，還需要優化濺射條件以建構MOF的縱深分析。 在實驗之初，首先使用不同方法合成了多種不同形貌的MOF，並在其中挑選適當的材料來進行後續客體分子分布之分析。其中，透過Cathodic deposition製備的Zeolitic imidazolate framework (ZIF-8) 薄膜展現出均勻且緊密的結構，且容易進行縱深分析，因此被挑選為其中最理想的探究對象。另一方面，由於其他MOF在建構縱深分析方面存在困難，或其在縱深分析中未顯示出客體分子的擴散行為，因此不適合作為本實驗的分析平台。 在SIMS分析中，所有樣品都使用脈衝C60+作為分析離子源，而濺射離子源則選用三種離子束，分別為Ar+、C60+和氬氣簇離子團（Ar-GCIB），並分析其建構的縱深分析，以從中挑選出最佳的濺射離子源。在這之中，Ar-GCIB展現其作為最佳濺射離子源的優異性能：它提供了高有機訊號強度和高濺射率。這歸因於Ar-GCIB的能量密度相對較低，對樣品的破壞較小而保留了有機訊號強度；而簇離子團對聚合材料的非線性增強促進了其高剝蝕速率。 確定了合適的材料和最佳的分析條件後，常用鎮痛藥物乙醯氨酚和其輔劑咖啡因被用作於顯示MOF中客體分子的擴散行為，這是因為藥物傳遞是關於MOF擴散中最受關注的應用之一。透過研究藥物擴散進入ZIF-8薄膜的縱深分析可以得知，客體分子在ZIF-8中的擴散不僅取決於客體分子的大小，還取決於用於溶解客體分子的溶劑：乙醯氨酚較小的尺寸（~4.3 Å）使其能夠進入ZIF-8，而咖啡因（~6.0 Å）則不能；此外，溶解在乙醇的乙醯氨酚擴散進入ZIF-8的速度比溶解在二甲基甲醯胺中溶解的乙醯氨酚更高。 最後，利用相同的方法，我們也獲得了雙金屬ZIF的縱深分析，使我們能夠偵測雙金屬MOF中每種金屬的濃度分佈。此實驗顯示了SIMS分析對於MOF材料的潛力，這對於了解這些材料的結構和性質至關重要。總體而言，本研究凸顯了SIMS分析在研究MOF中客體分子擴散以及其他潛在應用的潛力。

Metal-Organic frameworks (MOFs) have become a popular material for various applications due to their unique properties, such as high specific surface area, adjustable pore size, and functional groups. However, one of the challenges in the development of MOFs is to understand the diffusion of guest molecules in MOFs. Unfortunately, there have been limited researches that are capable of directly obtaining the distribution of guest molecules in MOFs. This presents a significant obstacle to the development and application of MOFs. Nonetheless, secondary ion mass spectrometry (SIMS) has shown its potential to be a highly effective analytical technique for investigating the distribution of guest molecules in MOFs due to its exceptional spatial resolution, with lateral resolution of less than 100 nm and depth resolution of several nanometers, as well as its remarkable detection sensitivity of parts per million (ppm). However, although SIMS can provide detailed and comprehensive information regarding the composition and distribution of samples, the bombardment of high-energy ions has been reported to introduce damages to MOFs during depth profiling, especially for organic signals. Therefore, in order to understand diffusion of guest molecules in MOFs, it requires not only careful selection of appropriate MOF and guest molecules, but also optimization of sputtering parameters for constructing depth profiles of MOFs. First of all, several MOFs were synthesized using various methods to identify the appropriate material for analyzing the distribution of guest molecules within its structure. Among them, the zeolitic imidazolate framework (ZIF-8) thin film prepared via cathodic deposition was shown to be the most ideal one due to its uniform and well-intergrown structure, as well as its accessibility to depth profiling. On the other hand, other MOFs presented challenges in constructing depth profiles or failed to show diffusion behavior in their depth profiles. For SIMS analysis, a pulsed C60+ beam was used as the acquisition beam for all samples, while three ion beams, namely Ar+, C60+, and argon gas cluster ion beam (Ar-GCIB), were employed as the sputtering sources. Remarkably, the Ar-GCIB exhibited superior performance as the optimal sputtering source, as it provided both a high intensity of organic signal and a high sputtering rate. This is attributed to the fact that Ar-GCIB has relatively low energy density, resulting in less damage to the sample, while the nonlinear enhancement of sputter yield from cluster beam for polymeric materials contributes to its high sputtering rate. Having established both the appropriate material and optimal analysis conditions, depth profiles of ZIF-8 loaded with guest molecules were obtained using the common analgesic drug acetaminophen and its adjuvant caffeine as the model drugs since drug delivery is one of the crucial fields concerning diffusion in MOFs. The findings revealed that the diffusion of guest molecules in ZIF-8 not only depends on the size of the guest molecules, but also on the solvent used to dissolve them. Specifically, the smaller size of acetaminophen (~4.3 Å) enabled its entry into ZIF-8, while caffeine (~6.0 Å) could not. Additionally, acetaminophen dissolved in ethanol exhibited a higher diffusivity compared to acetaminophen dissolved in dimethylformamide (DMF). Finally, using the same protocol, depth profiles of bimetallic ZIFs were also obtained to demonstrate the potential of SIMS analysis for MOFs. These depth profiles enabled the determination of the concentration profile of each metal in the bimetallic ZIFs, which is crucial for understanding the structure and properties of these materials. Overall, this study highlights the capabilities of SIMS analysis for investigating the diffusion of guest molecules in MOFs as well as other possible potentials.