Biodegradable and pH-Responsive Nanoparticles for the Triggered Release of Antibiotics to Infected Wounds

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题名:	Biodegradable and pH-Responsive Nanoparticles for the Triggered Release of Antibiotics to Infected Wounds
作者:	林妙玲;Linh, Lam Dieu
贡献者:	生醫科學與工程學系
关键词:	奈米粒子;生物可降解性;酸鹼觸發釋放;抗生素;傷口敷料;Nanoparticles;biodegradable;pH-triggered release;antibiotics;wound dressing combination
日期:	2022-01-19
上传时间:	2022-07-13 18:12:44 (UTC+8)
出版者:	國立中央大學
摘要:	傷口感染已成為全球性的經濟負擔。目前，傷口照護方法以使用抗生素為主，然而過度使用抗生素容易導致細菌產生抗藥性，且新抗生素研發的速度趕不上抗藥性產生的速度。因此，本研究使用聚琥珀酰亞胺(Polysuccinimide, PSI)開發出具酸鹼應答性且生物可降解性之奈米粒子，並以酸鹼調控抗生素釋放。本研究使用酸鹼應答性之11-氨基十一酸(11-aminoundecanoic acid, AUA)官能化部分的PSI，形成隨機兩性共聚物 (random amphiphilic copolymers, PA)。PA以奈米沉澱法於水溶液中形成奈米粒子，並裝載疏水性的抗生素-立放黴素(Rifampicin, Rif)於疏水性的核心中。AUA上的羧基之酸解離常数(pKa)為4.55。因此，於微酸性無感染傷口中，AUA上的羧基為非離子型，此時PA的碳氫鏈緊密地排列將藥物包埋於奈米粒子中。然而由於細菌增生，導致傷口表面的酸鹼值高於7時，AUA被去質子化導致奈米粒子拆解，同時PSI上的疏水結構也被水解，導致抗生素釋放。最終，殘餘水溶性且具生物可降解性的聚（天冬氨酸）(poly(aspartic acid))衍生共聚物於傷口中。本研究合成三種PA奈米粒子，PA5、PA10、PA25，對應5%、10%、25%莫爾濃度的AUA官能化於PSI，並藉由混濁度與滴定法進行PA奈米粒子的酸鹼響應性鑑定，結果顯示抗生素於酸鹼值5有最低釋放量，而抗生素於酸鹼值7.5增加釋放量。為了證實PA對環境的友善性，PA的可降解性以化學需氧量(Chemical oxygen demand, COD)與凝膠層析滲透儀(Gel Permeation Chromatography, GPC)進行評估。除此之外，本研究將PA與傷口敷料結合，結果顯示結合PA的傷口敷料具有優秀的酸鹼調控抗生素釋放特性，且具有顯著的殺菌效果。因此，本研究開發以酸鹼值調控抗生素釋放之奈米粒子可減緩抗生素濫用的情況，並對治療傷口感染做出貢獻。關鍵字: 奈米粒子、生物可降解性、酸鹼觸發釋放、抗生素、傷口敷料 ;Wound infection has become a health economic burden in the world. Current wound treatment approaches are mostly achieved by using antibiotics. However, the widespread and excessive using antibiotics even without evidence of infection easily causes antibiotic resistance. The new antibiotic productions decline while the elevated antibiotic resistance. Here, we introduce the pH-responsive and biodegradable nanoparticles (NPs) for the pH-triggered release of antibiotics using polysuccinimide (PSI), a forerunner of biodegradable poly(aspartic acid) was functionalized with a pH-responsive amine, 11-aminoundecanoic acid (AUA), to produce random amphiphilic copolymers (PA). The nanoparticle of PA copolymer was formed by the nanoprecipitation method in an aqueous solution and was loaded with hydrophobic antibiotic Rifampicin (Rif) in hydrophobic cores. pKa (COOH) of 4.55 has been determined for 11-aminoundecanoic acid. Therefore, at a slightly acidic pH value of non-infected wounds, the carboxylic groups exist in non-ionic form, the hydrocarbon chains were packed tighter, then the nanoparticles remain and keep the drugs inside. When wound pH value elevates above pH 7 due to proliferation of bacteria, AUA segments were deprotonated leading to disassemble and release drug component, also the hydrolysis of the PSI’s hydrophobic succinimide parts. Finally, the residue was the water-soluble and biodegradable poly(aspartic acid) (PASP) derivative copolymer. In this study, we synthesized PA5, PA10, and PA25 corresponding to 5%, 10%, and 25% AUA functionalized molarity to PSI. The pH-responsive properties were reviewed by turbidity and titration methods. The drug release from the release test displayed that a minimal at acidic pH = 5.0 but amplified at alkaline pH = 7.5. To demonstrate the environmentally friendly property, their degradation assays were conducted using the Chemical oxygen demand and GPC measurements. Moreover, the coordination with wound dressing materials has been carried out. The results revealed the outstanding selected pH-responsive release of drugs after combination with wound dressing with excellent antibacterial properties. Therefore, this material has become a potential candidate for antibiotic stimulus-responsive release in infected wound treatments, contributing mitigation of exessive using antibiotics. Keywords: Nanoparticles, biodegradable, pH-triggered release, antibiotics, wound dressing combination.
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