基于二硫鍵和酯鍵交聯(lián)劑的可降解微凝膠的合成、結(jié)構(gòu)調(diào)控及降解行為研究
發(fā)布時間：2019-01-17 12:14
【摘要】：微凝膠是尺寸在1nm-1μm的交聯(lián)粒子,因其尺寸可調(diào)、表面可功能化及內(nèi)部網(wǎng)絡(luò)結(jié)構(gòu)豐富的特點而非常適合用作藥物載體。而可降解材料用于藥物載體時一方面可以控制藥物釋放速率,另一方面降解之后的產(chǎn)物可以排除人體外,減少長期留存在人體內(nèi)的風(fēng)險,所以理想藥物載體需具備可降解的性質(zhì)。本論文研究了基于含可降解二硫鍵的交聯(lián)劑的微凝膠的合成、降解性能及對藥物的包載與釋放行為和基于含酯鍵交聯(lián)劑的微凝膠的合成及降解性能。在第一部分工作中,以N-異丙基丙烯酰胺(NIPAm)為主單體,過硫酸鉀(KPS)為引發(fā)劑,N,N'-雙丙烯酰胱胺(BAC)為交聯(lián)劑,2-丙烯酰胺基-2-甲基丙磺酸鈉鹽(AMPS-Na)為帶負電荷共單體,通過在NIPAm引發(fā)之后加入交聯(lián)劑BAC,再加入AMPS-Na的方式合成了穩(wěn)定的微凝膠,并研究了加入BAC的時機對微凝膠結(jié)構(gòu)的影響,以及加入AMPS-Na的時機對微凝膠在磷酸緩沖液中的穩(wěn)定性的影響。結(jié)果表明,這種在單體引發(fā)之后加入交聯(lián)劑的方法可以得到窄分布粒徑的微凝膠,隨著BAC在NIPAm引發(fā)之后5 min加入變?yōu)?5min后加入,微凝膠的Rg/Rh值由0.642變?yōu)?.020,所得到的的微凝膠的網(wǎng)絡(luò)結(jié)構(gòu)中心交聯(lián)程度逐漸降低,微凝膠逐漸由實心球變?yōu)榭招那虻慕Y(jié)構(gòu),至最終不能形成完整交聯(lián)的微凝膠粒子。微凝膠在磷酸緩沖液(PBS)中的穩(wěn)定性可以通過改變加入AMPS-Na的時間獲得改善,AMPS-Na在BAC加入之后4 min和6 min時加入可以獲得在25 ℃到49 ℃范圍內(nèi)穩(wěn)定的微凝膠,而AMPS-Na在BAC加入之后8 min時加入,所得微凝膠在溫度高于31 ℃時不穩(wěn)定而發(fā)生聚集。微凝膠的降解程度隨著BAC加入時間的延長而增加,而且在DL-1,4-二硫蘇糖醇(DTT)存在下,降解程度大的微凝膠中包載的鹽酸阿霉素(DOX)的釋放速率要快于降解程度小的微凝膠。在第二部分工作中,我們用1,8-二氮雜二環(huán)[5.4.0]十一碳-7-烯(DBU)催化左旋丙交酯(LLA)開環(huán)聚合合成聚乳酸(PLLA),并進一步用PLLA與4-溴丁酰氯反應(yīng),合成了兩個端基為Br的BrPLLABr。我們用NIPAm作為主單體,4-乙烯基吡啶(4-VP)作為共單體,用合成的BrPLLABr作為交聯(lián)劑,通過4-VP和BrPLLABr發(fā)生季銨化反應(yīng)的方式實現(xiàn)交聯(lián),合成了微凝膠。發(fā)現(xiàn)改變BrPLLABr的量對微凝膠的形貌和尺寸沒有明顯的影響,但是隨著BrPLLABr的減少,微凝膠的溫敏性逐漸增強。合成微凝膠可以在蛋白酶K的催化作用下降解。
[Abstract]:Microgel is a cross-linked particle with the size of 1nm-1 渭 m. Because of its adjustable size, functionalized surface and abundant internal network structure, microgel is very suitable for drug carrier. On the one hand, biodegradable materials can control the release rate of drugs when they are used as drug carriers, on the other hand, the products after degradation can be excluded from the human body and the risk of long-term retention in the human body can be reduced. Therefore, the ideal drug carrier should have degradable properties. In this paper, the synthesis, degradability, encapsulation and release behavior of microgels containing degradable disulfide bonds and the synthesis and degradation properties of microgels based on ester bond crosslinkers were studied. In the first part, N-isopropylacrylamide (NIPAm) was used as the main monomer, potassium persulfate (KPS) as the initiator, and NN-N-diacrylocysteine (BAC) as the crosslinking agent. Sodium 2-acrylamide 2-methylpropanesulfonate (AMPS-Na) was used as negative charge co-monomer to synthesize stable microgel by adding crosslinking agent BAC, and AMPS-Na after NIPAm initiation. The influence of the time of adding BAC on the structure of microgel and the stability of microgel in phosphoric acid buffer were also studied. The results showed that the microgel with narrow particle size could be obtained by adding crosslinking agent after monomer initiation. With the addition of BAC from 5 min to 15min after NIPAm initiation, the Rg/Rh value of microgel changed from 0.642 to 1.020. The degree of central crosslinking of the microgel network was gradually decreased, the microgel gradually changed from the solid sphere to the hollow sphere structure, and finally could not form a complete cross-linked microgel particles. The stability of microgels in phosphoric acid buffer (PBS) can be improved by changing the time of adding AMPS-Na. AMPS-Na can obtain stable microgels in the range of 25 鈩，
本文編號：2410048
[Abstract]:Microgel is a cross-linked particle with the size of 1nm-1 渭 m. Because of its adjustable size, functionalized surface and abundant internal network structure, microgel is very suitable for drug carrier. On the one hand, biodegradable materials can control the release rate of drugs when they are used as drug carriers, on the other hand, the products after degradation can be excluded from the human body and the risk of long-term retention in the human body can be reduced. Therefore, the ideal drug carrier should have degradable properties. In this paper, the synthesis, degradability, encapsulation and release behavior of microgels containing degradable disulfide bonds and the synthesis and degradation properties of microgels based on ester bond crosslinkers were studied. In the first part, N-isopropylacrylamide (NIPAm) was used as the main monomer, potassium persulfate (KPS) as the initiator, and NN-N-diacrylocysteine (BAC) as the crosslinking agent. Sodium 2-acrylamide 2-methylpropanesulfonate (AMPS-Na) was used as negative charge co-monomer to synthesize stable microgel by adding crosslinking agent BAC, and AMPS-Na after NIPAm initiation. The influence of the time of adding BAC on the structure of microgel and the stability of microgel in phosphoric acid buffer were also studied. The results showed that the microgel with narrow particle size could be obtained by adding crosslinking agent after monomer initiation. With the addition of BAC from 5 min to 15min after NIPAm initiation, the Rg/Rh value of microgel changed from 0.642 to 1.020. The degree of central crosslinking of the microgel network was gradually decreased, the microgel gradually changed from the solid sphere to the hollow sphere structure, and finally could not form a complete cross-linked microgel particles. The stability of microgels in phosphoric acid buffer (PBS) can be improved by changing the time of adding AMPS-Na. AMPS-Na can obtain stable microgels in the range of 25 鈩，
本文編號：2410048
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