研究生: |
張雅棻 |
---|---|
論文名稱: |
光交聯聚乳酸-聚乙二醇-聚乳酸三團聯共聚物之水膠奈米粒子之合成及其藥物制放之應用 Synthesis and characterization of photocrosslinked poly(D,L-lactic acid-ethylene glycol-D,L-lactic acid) diacrylate nanogel |
指導教授: |
朱一民
I-Ming Chu |
口試委員: | |
學位類別: |
碩士 Master |
系所名稱: |
工學院 - 化學工程學系 Department of Chemical Engineering |
論文出版年: | 2006 |
畢業學年度: | 94 |
語文別: | 中文 |
論文頁數: | 70 |
中文關鍵詞: | 光交聯 、水膠奈米粒子 、聚乳酸 、聚乙二醇 、喜樹鹼 |
相關次數: | 點閱:3 下載:0 |
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近年來,利用光交聯(photocrosslinking)的方式去製備水膠,一直被認為是一個簡單、不會殘留毒性單體並可在溫和環境下合成的方法。加上水膠的澎潤性質、高通透性與高生物相容性,以及許多水膠對於溫度或pH值很敏感,使得水膠在各方面有相當多的應用。生物可降解性高分子奈米化後應用於藥物載體也已經非常廣泛地被研究,其中尤以兩性團聯共聚物高分子在水相中具有自我組裝成高分子微胞特性,在藥物釋放系統上發展非常迅速。
本研究先製備出具有生物可分解性、高生物相容性及親疏水性的兩性高分子材料PDLLA-PEG-PDLLA,其分子量達到10324且分子量分佈非常均一(PDI =1.12)。使用solvent evaporation方法將此材料製備為微胞粒子,觀測在三種溫度下穩定度發現在4℃下達25天才有些許聚集現象,在25℃以及37℃下達第21天及第15天就有沈澱產生,藥物應用上選擇camptothecin(CPT)為包覆之藥物,可得每20 mg 微胞僅能載入0.01 mg CPT且在一天內釋放出載入量之80 %,欲改善此微胞不穩定性、低包覆量和快速釋放等缺點,便針對PDLLA-PEG-PDLLA高分子進行末端OH基改質後接上雙鍵,接枝率可達26 %,再將此材料形成之微胞進行光交聯後成為水膠奈米粒子(nanogel),可藉著改變交聯劑的成分和添加量,控制nanogel在水中膨潤情形,其中EGDMA交聯劑量越多核內交聯程度越高,使的粒徑會越小;TMPTMA交聯劑則本身具有立體性,量越多會易造成核內體積增長,使的粒徑越大;nanogel在三種溫度下穩定性很好,經過一個月仍無任何沈澱產生且粒徑變動不大,而其製備出之粒徑皆可控制在140 ~201 nm。
在nanogel包覆藥物方面採用兩種方法來載入藥物,一為光交聯前裝填藥物法、二為藉濃度梯度擴散法,不管是利用方法一或方法二製備出之載體內EGDMA交聯劑越多交聯密度越大,因此包覆量越低,釋放速度也依交聯密度增高而趨緩,另一交聯劑TMPTMA交聯劑越多核內體積越大,包覆量隨之增長,釋放速度也一樣增快;保存在4℃、25℃下仍有相當好的穩定性,而此兩種方法製備載體之包覆量落於0.1 ~0.9 mg/20 mg nanogel,皆大於微胞包覆量,且釋放速度相當平緩。
由上述結果可知,核內交聯不僅會令載體變的較穩固,不易快速釋放出CPT,且可藉著改變交聯程度和交聯結構控制釋放速度及粒徑,同時此材料降解行為非常緩慢,載體初期無法靠著降解釋出CPT,僅能靠著濃度擴散,以致核內藥物釋放速度減緩許多,因此本研究製備出之奈米水膠粒子為一個穩定且緩慢釋放之藥
In this study, ABA type amphiphilic triblock copolymers consisting of poly(ethylene glycol) (PEG) (A) as hydrophilic segment and poly(D,L-lactic acid) (PLA) (B) as hydrophobic block were synthesized by ring opening polymerization. These copolymers could form micelles by solvent evaporation method due to their characteristic of self-assembling. These micelles entrapped the hydrophobic drug, Camptothecin (CPT), in their hydrophobic core. Though the size of the micelles was less than 200 nm, the instability restricted the application. Besides, the encapsulation of CPT was only 0.01 mg based on 20 mg micelles, and more than 80 % of the drug released in 1 day. In order to improve these disadvantages of micelles, the nanogels prepared by UV irradiation with PEL diacrylate was developed as a new drug carrier. The diameter of nanogels was easily controlled in a range of 140 ~201 nm by manipulating the concentration of crosslinkers, ethylene glycol dimethacrylate (EGDMA) and trimethylolpropane trimethacrylate (TMPTMA). In the EGDMA system, the increase of EGDMA, size revealed the nanogels swelled less. However, the TMPTMA system showed the different circumstance due to the different structure of these two crosslinkers. All these nanogels exhibited good stability without aggregation in 30 days. CPT encapsulated in these nanogels by two methods: loaded as micelles prepared before radiation and loaded by diffusing CPT into the crosslinked core of nanogels. The encapsulated CPT was amount of 0.1 ~ 0.9 mg based on 20 mg nanogels depended on the encapsulation methods. But these nanogels released CPT in a gradual mechanism and exhibited good stability. As results, these nanogels are very potential in drug controlled release system.
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