雙成份雙親性共聚高分子之溫度相依性自組裝和其水凝膠形成之動態效應

Temperature-Dependent Self-assembly and Dynamic Effect of Hydrogel Formation for Binary Amphiphilic Copolymer System

李沁芬(Chin-Fen Lee)

指導教授 ： 陳立仁

國立臺灣大學/工學院/化學工程學研究所/博士(2019年)

https://doi.org/10.6342/NTU201903568

摘要

普朗尼克(Pluronic)三段式共聚合物因其雙親性且生物可分解的特質，無論在工業界、生醫界都有非常廣泛的應用。對於其基礎性質和應用的研究已有相當了解，然而其實際應用在臨床治療時此材料仍有許多未知模糊的地方，因此我們從Pluronic雙成分混和微胞著手，研究分子間的交互作用並進一步延伸至高濃度共聚合物溶液中微胞堆疊所形成的水凝膠，了解實際應用在生物體時造成的不可預測相行為轉變。
一開始，我們從兩種變因去系統性的改變每種分子間的差異組成七個雙成份系統，分別是 : 相同親水性下不同疏水碳鏈長(Fx8)以及相同疏水碳鏈長(Propylene oxide)下不同親水性(F8x)的分子。將七個具有連續性差異的分子分別與Pluronic L92混和，來探討分相系統中大聚集(L92)如何跟形成球狀微胞的分子作用。我們發現疏水碳鏈越長的分子越容易將大聚集分解成小尺寸的混和微胞，然而，疏水碳鏈差異大的分子間不代表無法形成混和微胞，像是L92 + P84的系統。接著我們將L92替換成P123討論純微胞系統內的共微胞化行為，證明了臨界微胞濃度(CMT)較低的成份(P123)會先形成微胞，上升溫度疏水化了具有較高CMT的另一分子，使其向P123微胞聚集並自組裝形成混和微胞。透過小角x光散射實驗，混合微胞是由核及兩個殼層(core-two shells)所組成，其中第一殼層和總殼層的厚度分別為P123以及P123加 F8x或 Fx8的殼層(shell)厚度。小角x光散射實驗顯示了疏水藥物依布洛芬(ibuprofen)一開始會先被包覆在低溫時所形成的微胞核內。更重要的是，我們發現當混和系統中有Pluronic P84 參與時，系統對ibuprofen的溶解效果最好，且系統內粒子的聚集(或微胞)大小亦最小最穩定。
將微胞濃度或系統溫度提高使得疏水作用持續增強，促使微胞進而堆疊成水凝膠。使用Pluronic F108、F108+P103 (2/1 wt%)、F108+P123 (2/1 和 1/1 wt%)，我們專注在溫度改變所引起的水凝膠生成行為。 四個系統為研究目標，除了釐清於升溫時巨觀下的相行為改變，更嘗試探討其背後水凝膠微結構的改變所導致的巨觀行為變化。我們發現當升溫速度低於0.1 °C/min時分子的運動型態趨近於平衡態轉變，且當升溫速度越來越快時，水凝膠存在的溫度範圍將越來越窄。接著，根據小角x光散射實驗，不同升溫速度將影響水凝膠在不同溫度下的晶體結構轉變，當升溫速度上升時(10 °C /min)，六方最密堆積(HCP)結構和面心最密堆積(FCC)的出現機率將大幅上升；當升溫速度下降時(1 °C /min)，體心最密堆積(BCC)結構將會從低溫開始主宰整個水凝膠結構，將疏水藥物ibuprofen包覆進系統會促使水凝膠的生成，但是降低有序列結構的生成範圍。更重要的是，我們發現微胞的外殼層親水鏈段(corona chain)長度越長越一致，微胞越有能力抓住其他微胞的親水鏈段，有趣的是，雖然由混和微胞所形成的水凝膠強度較弱，但是其長度不均勻的外殼層親水碳鏈反而促使其在較低溫的時候就可以形成水凝膠。

關鍵字

普朗尼克 ； 混和微胞 ； 親疏水性 ； 鏈長效應 ； 水凝膠 ； 動態效應

並列摘要

Pluronic, a series of amphiphilic and biodegradable tri-block copolymers, has been widely applied on industry and biomedical science. Fundamental properties of Pluronics and its potential applicability has been kindly realized. However, there often remains unpredictable situations when applying it onto clinical treatment. Hence, we proceeded a series of studies starting from co-micellization between binary Pluronic copolymers to investigate molecular interactions. Then, the studies were extended to hydrogel formed by the stackings of micelles in concentrated solution. It allows us understand the unpredictable phase changes while applying it onto organisms.
Firstly, we established two different perspectives to systematically vary the resemblance between parent copolymers establishing 7 systems: different block chain length at same hydrophilicity (Fx8 = F108, +F98, +F88, and +F68), as well as various hydrophobicities at same moiety of hydrophobic chain (F8x = F88, +F87, and +P84). Seven Pluronics with consecutively different properties were blend with Pluronic L92 to discuss how lamellar aggregates (L92) interact with the molecules which self-assemble into spherical micelles. We discovered that copolymers with longer hydrophobic chain are more capable of breaking down large aggregates into mixed micelles. However, parent copolymers with distinct hydrophobic chain lenghs do not affirmatively lead to non-cooperative binding, such as the system L92 + P84. Successively, Pluronic L92 was substituted by P123 to study co-micellization behaviors in the systems containing only micelles. It was evidenced that micelles are mainly formed by the copolymer (P123) with a lower critical micelle temperature (CMT) initially. Raising temperature dehydrates the other Pluronic with a higher CMT to be integrated into the neat P123 micelles developing mixed micelles. Through the small angle x-ray scattering (SAXS) experiment, mixed micelle is consisted of a core and two shells in which thickness of the first and total shell is equal to that of P123 and F8x or Fx8, respectively. SAXS results also demonstrate that hydrophobic drug - ibuprofen is mainly encapsulated in the core of neat micelles developed at low temperatures. Moreover, we discovered that mixed systems with P84 exhibits the most outstanding solubilization capacity to ibuprofen with its smallest and most stable aggregate (or micelle) sizes.
Raising concentration or temperature of the system promotes the hydrophobic effect and triggers stackings of micelles into hard gel. We focused on the temperature induced changes of gel formation using Pluronic F108, F108 + P103 (2/1 wt%) and F108 + P123 (2/1 and 1/1 wt%). We discovered that molecule motions at heating rate below 0.1 °C/min approaches equilibrium phase changes of gelation process. Furthermore, gelation window (hard gel region) becomes smaller as heating rate gets faster. Moreover, different heating rates lead to microstructural changes of crystalline phases at different temperatures according to the time-resolved SAXS experiments. As heating rate increases (10 °C /min), the possibility of appearance of hexagonal close packing (HCP) and face centered cubic structure (FCC) structures increases. While heating rate decreases (0.1 °C /min), body centered cubic structure (BCC) phases dominate the system from lower temperatures. Also, incorporating ibuprofen into the system promotes hydrogel formation, but decreases the domain of ordered structures. Furthermore, we found that micelles with uniform and long corona chains exhibit higher capacity to tether other micelles. Interestingly, despite weaker stiffness of the hard gel, mixed micelles with non-uniform corona chains promote gel formation at low temperature.

並列關鍵字

Pluronic ； Mixed micelles ； Hydrophilic-hydrophobic property ； Chain length effect ； Gel ； Kinetic effect

參考文獻

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