Preparation Multufunctional Intelligent Mesoporous Bioactivity Glass as Drug Delivery System and Application

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Project title

Code/計畫編號

NSC100-2113-M019-001

Translated Name/計畫中文名

製備多功能智慧型中孔生醫玻璃做為藥物輸送系統與應用

Project Coordinator/計畫主持人

Hsiu-Mei Lin

Funding Organization/主管機關

National Science and Technology Council

Department/Unit

Department of Bioscience and Biotechnology

Website

https://www.grb.gov.tw/search/planDetail?id=2345942

Year

2011

Start date/計畫起

01-08-2011

Expected Completion/計畫迄

31-07-2012

Bugetid/研究經費

1549千元

ResearchField/研究領域

化學
醫學工程
藥學

"治療癌症之化學療法通常受限於嚴重的副作用，因此具有腫瘤特異性的藥物遞送系統在癌症的治療上逐漸引起廣大的興趣。由於普通的藥物遞送系統所表現的遞送效率較差，持續研究其他進階藥物遞送系統成為更重要的項目。在此項研究中，我們將合成出以光控制、pH值控制及葉酸修飾的中孔洞生物活性玻璃(MBG)作為新穎的藥物遞送載體。在第一年的研究中，我們將進行三個部分的研究。首先，我們已於2010年發表合成具光控制特性之香豆素功能化的MBG，以波長大於310奈米之UV光照射，使孔洞關閉將藥物分子儲存於中孔洞內；以250奈米左右的短波長UV光照射則會使閘門打開將儲存之藥物分子釋放於孔洞外。藉由光控制展現開關的特性，作為藥物遞送載體研究其藥物儲存及釋放特性。由先前研究發現載入藥物分子的大小會影響孔洞關閉後的釋放情形，當藥物分子尺寸較小時，即使孔洞關閉仍有滲漏的現象，因此藥物分子的大小與修飾於孔洞的開關基團數量相關，必須研究找到最佳化條件，使其能應用不同分子大小的藥物，例如抗生素或癌症治療藥物。第二部分是在MBG表面進行嫁接修飾，接上兩種不同的控制開關：硼酸離子與奈米金粒子基團。以此兩種基團作為控制孔洞中藥物釋放的開關，使孔洞在酸性環境下打開，而在pH5.5以上關閉，模擬以不同pH值環境作為觸發條件來控制孔洞開關的能力。此特殊修飾的藥物載體能廣泛應用於不同的生理系統，例如消化道在口腔、胃與腸中具有不同的pH值而達到控制釋放的效果；或是正常細胞與腫瘤細胞的環境pH值不同，而控制藥物載體中的釋放情形，使藥物達到最大效用。同樣地，pH控制部分也和開關基團修飾數量相關，必須研究其最佳化條件。第三部分則是在MBG表面修飾上葉酸分子，由目前癌症細胞的研究，得知人體內的癌細胞表面具有過量的葉酸受體表現，因此可利用葉酸在載體表面的修飾，再藉由受體的專一性結合能力，促使細胞進行吞噬作用，進而達到控制釋放及靶向治療的多重治療效果，減少因使用抗癌藥物對於健康細胞所導致的副作用以及生物毒性，並且增進藥物使用的效率。MBG所展現的規則結構及其特色使得此藥物載體在智慧控制藥物遞送系統及疾病治療領域中具有廣大的潛能。在第二年與第三年的研究，我們將根據第一年的研究經驗以最佳化條件來結合pH值控制和葉酸兩者到中孔洞生物活性玻璃上，並載入治療骨質疏鬆的藥物阿侖磷酸鹽(Alendronate)、抗菌藥物新黴素(Neomycin)和抗癌藥物喜樹鹼(Camptothecin)等藥物做為研究。並於第三年結合光控制和葉酸兩者到中孔洞生物活性玻璃上，載入抗菌藥物和抗癌藥物喜樹鹼(Camptothecin)、阿黴素(Doxorubicin)及順鉑(Cisplatin)等藥物做為癌症和抗菌的治療研究。由於光控制部分所使用的紫外光對於生物體較有害，因此將研究使用雙光子光源所產生之非線性效應以可見光激發取代原本短波長的UV光，使之較不容易被生物組織吸收及散射，並減少對生物樣品所造成之光破壞。結合後的材料利用X光繞射儀 (XRD)、穿透式電子顯微鏡 (TEM)、氮氣吸附脫附儀和UV-可見光光譜儀進行結構、型態、性質及光學特性的鑑定。此外，藥物釋放的特性及生化表現也同樣將進行測試。此項研究是嫁接的MBG中第一個例子，不僅參與粒子修飾技術來增加材料的生物相容性，同時也結合光控制開關和葉酸展現出藥物遞送載體的多功能性。我們將更進一步以修飾材料之生化表現為例作為進階的藥物遞送系統。" "Tumor specific drug delivery has become increasingly interesting in cancer therapy, as the use of chemotherapeutics is often limited due to severe side effects. Conventional drug delivery systems have shown low efficiency and a continuous search for more advanced drug delivery principles is therefore of great importance. In this study, mesoporous bioactive glass (MBG) graft photo-controlled, pH-controlled and folate were synthesized for preparing a novel drug delivery. In the first year of this study, we synthesize the functionalized mesoporous bioactive glasses (MBG) with photoactive coumarin, pH-controlled borate ion or gold nanoparticles, and folate. In 2010, we have published the coumarin-modified MBG performed as a drug delivery carrier to investigate the drug storage/release characteristics. Irradiation of UV light (>310 nm) to this coumarin-modified MBG led to close the pore with cyclobutane dimmer for trapping of the guest molecules in the mesopores. On the other hand, irradiated with shorter wavelength UV light (~250 nm) regenerates the coumarin monomer derivative and the trapped guest molecules will be released from the mesopores. Previous studies have found that the size of the loading drug molecules will affect the drug release after being closed of the pores. If the size of the drug was too small, it will turn out to be leaked, therefore, the size of drug molecules was related to the amount of functional group modified on the MBG. We should study the optimal conditions for further applying different size of drugs, such as antibiotics or cancer drugs. The second part of the first year study is to modify borate ion or gold nanoparticles on MBG, which makes it sensitive to the pH. The pores on the MBG were closed under low pH condition and were opened above pH5.5. This specific stimuli condition can be used in diverse physiological systems that have different pH conditions, such as oral cavity, stomach and intestine or normal cells and tumor cells. Folic acid was linked to a MBG, exploiting folic acid as site-specific trigger in cancer therapy. Also, the size of drug molecules was related to the amount of functional group modified on the MBG, we should study the optimal conditions for further applying. We present current strategies in the drug delivery field, focusing on site-specific triggered drug release from our materials in cancerous tissue. Currently marketed drug delivery systems lack the ability to actively release the carried drug and rely on passive diffusion or slow non-specific degradation of the drug carrier. To obtain elevated tumor-to-normal tissue drug ratios, it is important to develop drug delivery strategies where the drug carriers are actively degraded specifically in the tumor tissue. The MBG exhibit the typical ordered characteristics of the mesostructure and the system demonstrates a great potential in the intelligent drug delivery systems (DDS) and disease therapy fields. In the second year of this study, we will use optimal conditions based on first year’s study to combine pH-control and folic acid these two special characteristics together grafted on MBG. Additionally, an osteoporosis drug, alendronate, antibiotic drugs and anticancer drugs camptothecin (CPT) will be incorporated into grafted MBG for used in cancer therapy. In the third year of this study, we’ll combine photo-control and folic acid together grafted on MBG. Then, antibiotic drugs and anticancer drugs camptothecin (CPT), doxorubicin (Dox) or cisplatin was incorporated into grafted MBG for used in cancer therapy. Due to the harm of UV light used in the light controlled function to the living organisms, we will study the use of two-photon light generated by nonlinear effect to replace the original short-wavelength UV light with visible light, which makes it more difficult to be absorbed and scattered by biological tissues, and reduce the damage of biological samples by UV light. The structural, morphological, textural and optical properties of the combined materials will be characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), N2 adsorption/desorption, and Ultraviolet-visible (UV-vis) spectra, respectively. The drug delivery ability and biological performance will also be tested. This study presents the first example of grafted MBG, not only involving a particle modification technique to increase the biocompatibility of materials, but also combining the advantages of the photo-controlled, pH-controlled and folate to exhibit multi-functions for used in drug delivery. We furthermore give examples of the biological performance of the modified materials as advanced drug delivery systems."

Keyword(s)

葉酸標定
癌症治療
藥物控制釋放
智慧型藥物遞送系統
光控制藥物遞送系統
酸鹼藥物遞送系統

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Preparation Multufunctional Intelligent Mesoporous Bioactivity Glass as Drug Delivery System and Application

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