Thermoresponsive polymeric micelles with controlled instability based on hydrolytically sensitive N-isopropylacrylamide copolymers
Thermoresponsive polymeric micelles with controlled instability based on hydrolytically sensitive N-isopropylacrylamide copolymers
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DOI：
10.1021/ma011198q
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发表时间：
2001-10-23
期刊：
影响因子：
5.5
通讯作者：
Hennink, WE
中科院分区：
文献类型：
--
作者：
Neradovic, D;van Nostrum, CF;Hennink, WE
导论.近年来，聚合物胶束作为难溶性药物的载体正在研究中。1两亲性AB嵌段共聚物在稀水溶液中自组装成核壳胶束结构。亲水性壳负责胶束的稳定，而疏水性核可以作为水溶性差的药物的储库。各种各样的嵌段共聚物的胶束形成的设计和评价。在大多数这些体系中，聚（乙二醇）（PEG）用作亲水嵌段，而例如聚（L-乳酸）、聚（β-己内酯）或聚（β-苄基L-天冬氨酸酯）用作疏水嵌段。2由于其小尺寸（30-100 nm）和其亲水表面，嵌段共聚物胶束显示出延长的血液循环时间，3并且它们可能通过所谓的EPR（增强的渗透和保留）效应最终进入例如肿瘤组织。4，5最近，嵌段共聚物含有热敏元件，如聚（N-异丙基丙烯酰胺）（PNIPAAm）已被用于聚合物胶束。6众所周知，PNIPAAm在水溶液中表现出可逆的温敏相变：它在低于其浊点（CP）的水溶液中高度可溶，但在CP以上沉淀。结果表明，PNIPAAm与PEG的嵌段共聚物在水溶液中表现出温敏溶解性。8在CP以上，热敏PNIPAAm嵌段沉淀，并且二嵌段共聚物组织在聚合物胶束中，其由PNIPAAm核和PEG的亲水性壳组成。在我们以前的论文中，我们报道了一种新型的热敏NIPAAm基聚合物（聚（NIPAAm-co-HEMA-乳酸酯））与水解敏感的乳酸酯侧基的合成。9在该无规共聚物在水溶液中温育期间，由于疏水乳酸酯侧基的水解，聚合物的CP增加，这产生了具有增加的总体亲水性和31 ℃的CP（与共聚物组成无关）的聚（NIPAAm-共-HEMA）。基于这一概念，我们现在设计了一种新型的聚合物胶束，其来自含有温度敏感嵌段的嵌段共聚物，其在水解时转化为具有高于37 ℃的CP的聚合物。我们预计，这一新的概念将导致聚合物胶束作为一种新的药物输送系统在未来的应用。
Introduction. In recent years polymeric micelles are under investigation as carriers for poorly water-soluble drugs. 1 Amphiphilic AB block copolymers self-assemble in dilute aqueous solutions in core-shell micellar structures. The hydrophilic shell is responsible for the stabilization of the micelle, and the hydrophobic core can play a role as a reservoir for poorly water-soluble drugs. A great variety of block copolymers were designed and evaluated for micelle formation. In most of these systems poly (ethylene glycol)(PEG) is used as hydrophilic block, whereas for example poly (L-lactic acid), poly (ϵ-caprolactone), or poly (β-benzyl L-aspartate) was used as hydrophobic block. 2 Because of their small size (30-100 nm) and their hydrophilic surface, block copolymer micelles show prolonged blood circulation times, 3 and they might end up in for example tumor tissue by the so-called EPR (enhanced permeation and retention) effect. 4, 5 Recently, block copolymers containing thermosensitive elements such as poly (N-isopropylacrylamide)(PNIPAAm) have been used in polymeric micelles. 6 It is well-known that PNIPAAm exhibits a reversible thermoresponsive phase transition in aqueous solutions: it is highly soluble in aqueous solutions below its cloud point (CP) but precipitates above the CP. 7 It was shown that the block copolymers of PNIPAAm with PEG exhibit thermoresponsive solubility in aqueous solutions. 8 Above the CP, the thermosensitive PNIPAAm block precipitates, and the diblock copolymers organize in polymeric micelles, which consist of a PNIPAAm core and hydrophilic shell of PEG. In our previous paper we reported the synthesis of a new type of thermosensitive NIPAAm-based polymer (poly (NIPAAm-co-HEMA-lactate)) with hydrolytically sensitive lactate ester side groups. 9 During the incubation of this random copolymer in aqueous solution the CP of the polymer increased due to the hydrolysis of the hydrophobic lactate ester side group, which yielded poly (NIPAAm-co-HEMA) with an increased overall hydrophilicity and a CP, independent of the copolymer composition, of 31 C. On the basis of this concept, we now designed a novel type of polymeric micelles from block copolymers containing a temperature-sensitive block, which upon hydrolysis converts to a polymer having the CP above 37 C. We anticipate that this new concept will lead to polymeric micelles to be applied as a new drug delivery systems in the future.