智慧型磁性水膠及奈米微球於藥物控制釋放之研究

Abstract

在控制藥物釋放的系統中-特別是在外力場刺激下以及可標定式(targeting)作用之智慧型藥物釋放系統-在全球已經引起各學界與業界人士的注意。為了能夠有效地控制藥物釋放的行為，我們已經發展出能夠藉由外加磁場作為驅動力來控制藥物釋放的一系列磁敏感性水膠材料，利用磁場作為驅動力的好處在於磁力是一種超距力(非接觸力)，在生醫材料的應用上比較能夠被操控，因此能夠替代傳統的酸鹼敏感性或熱敏感性的水膠材料。 此論文第一部份，主要著重於直流電(DC)磁場對於ferrogel之控制藥物釋放， 當磁場啟動時， ferrogel 裡的奈米磁性粒子會聚集形成“pearl-chain＂結構，因此造成ferrogel體積及孔洞的縮小及關閉情形，藥物因此較難通過，我們稱為“close＂configuration (關閉效應)，並且在磁場關閉的瞬間會有噴出效應(bursting)的產生，因此在這部分的工作，主要是針對不同無機(氧化鐵)/有機(高分子)比例之ferroge對於磁敏感性、關閉效應及噴出效應之探討，並找出影響這些效應的關鍵因素，包括氧化鐵顆粒大小、孔隙度、磁化強度(magnetization)，高分子交聯度等，找出最佳製作ferroge之條件，進而達到最佳化的磁敏感效應。 而在第二部分中，主要著重在於ferrogel在交流電(AC)磁場下之控制藥物釋放情形。此機制與DC磁場下大不相同，主要是奈米磁性粉體在快速翻轉下造成ferrogel的結構被撐開，或是在溫度敏感型高分子下，奈米磁性粉體快速翻轉所造成之溫度上升(局部放熱效應)，溫度敏感型高分子因此收縮所造成之pumping效應，將藥物噴出(bursting)，因此，我們將結合熱敏感以及磁敏感性兩種特性的材料加以製備成核(磁性材料)-殼(溫度敏感性水膠，Pluronic®)結構的奈米磁性粒子(藥物載體)，並且觀察其奈米粒子在交流電(AC)磁場下(局部加熱效應)之藥物投遞狀況及殺死細胞之情形。首先，利用TEM、XRD、拉曼光譜、XPS來觀察溫度敏感型磁性奈米粒子的表面特性及結構。然後再使用動態光散射(DLS)來量測此藥物載體隨溫度改變之粒徑大小及臨界溫度轉換點(CMT)。當溫度因為局部加熱而升高時，Pluronic®會由原本親水性的結構轉變成疏水性的結構，因此造成整個材料的收縮，而載體中的藥物便能夠藉此收縮作用而被擠壓出來，最後並達到控制釋放藥物之效果，並藉由局部加熱及所釋放之抗癌藥物來殺死腫瘤細胞。最後，此磁性奈米粒子之細胞毒性及免疫反應(生物相容性測試)也將被探討，以確保可以實際應用於人體。 由於磁性奈米粒子（水膠）還能利用MRI來作為細胞追蹤的標的，或是在磁性奈米粒子表面接枝特定抗體，使此特殊架接的奈米粒子可以與特定細胞之抗原結合，以達到標定式之藥物釋放。除此之外，磁性奈米粒子具備可回收性又能夠有效分離特定的細胞，因此此功能性性磁性奈米粒子（水膠）將可以被預期廣泛應用於生物醫學材料上。

Controlled drug release has been received greatest attention worldwide, especially stimuli-responsive- or targeted-drug-delivery systems. In order to accelerate the response of an adaptive gel to stimuli, the use of magnetic field sensitive gels as a new type of actuator has been developed in our preliminary study by direct current (DC) magnetic fields. Magnetic-sensitive polymer is superior to that traditional stimuli response polymer, such as pH or thermal sensitive polymer, because magnetic stimulation is an action-at-distance force (non-contact force) which is easier to adapting to biomedical devices. The magneto-elastic properties of ferrogels could be applicable to a variety of fields as a new driving mechanism. The firt part in this paper is focused on the direct current (DC) magnetic field to control drug release on the ferrogel. The “closure”configuration, which means the pore size of ferrogel would decrease to obstruct the drug to pass through, would take place with the pearl-chain structure formation while DC magnetic field was applied. However, the accumulated drug was spurt (bursting effect) to the environment instantly when the magnetic fields instantly switched “off”. Some factors of the ferrogel would be investigated, ex. ratio of inorganic (iron oxide) and organic (polymer), the size of iron oxide nanoparticles, porosity, magnetization, and crosslinking degree to achieve the optimum magnetic-sensitive behavior. To increase the degree of stimuli-responsive in magnetic fields, core (magnet)-shell (Pluronics®)-typed magnetic nanoparticles (drug-carriers), which combined the thermal and magnetic sensitive properties; therefore, dual-functional drug-carriers would be developed by in-situ co-precipitation process. Furthermore, drug-delivery rate at on-off operation of AC magnetic fields (hyperthermia effects) and the conditions of killing-tumor cells also would be observed. Some characterizations would be investigated using transmission electron microscope (TEM), X-ray diffraction (XRD), Raman spectrometry, X-ray photoelectron spectroscope (XPS), and vibrating sample magnetometer (VSM). The critical micellization temperature (CMT) or lower critical solution temperatures (LCST) would be measured by dynamic light scattering (DLS) or a differential scanning calorimeter (DSC). When the arising temperature of drug-carriers is higher than CMT, the drugs can be burst from the drug-carriers by the volume compressed. In order to in vivo test in the future, some biocompatibility test, including cytotoxicity would be evaluated. In addition, the magnetic nanoparticles still provides some advantages, such as using magnetic resonance image (MRI) techniques for cell-tracking and grafted probe-proteins (such as biotin or antibody) onto magnetic nanoparticles for “target” drug delivery, as well as the magnetic materials could be “recycle” used and separating cells by magnet catching. Therefore, the magnetic drug-carriers (ferrogel) are able to be triggered by thermal and magnetic changes, and especially put emphasis on “target” drug-delivery and the conditions of killing tumor-cells, as well as cell-tracking by MRI, or others detecting technique also would be aniticipated.