Laboratory of Pharmaceutical Nanomaterials Science, Department of Materials Science and Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
Biomater Sci. 2016 Dec 20;5(1):128-140. doi: 10.1039/c6bm00667a.
Two main hurdles persist towards the more extensive bench-to-bed side translation of non-parenteral polymeric micelles. The first pertains to their thermodynamically-driven disassembly under uncontrolled dilution conditions in the biological milieu and upon interaction with biomacromolecules (e.g., proteins). The second is related to the relatively poor understanding of the pathways by which polymeric micelles improve the bioavailability of the payload by mucosal routes (e.g., intestinal). In this work, a chitosan-g-oligo(N-isopropylacrylamide) (CS-g-oligo(NiPAAm)) copolymer was modified with non-cytotoxic amounts of protoporphyrin IX (PP), a planar molecule of amphiphilic character that undergoes self-aggregation in water by forming π-π stacked supramolecular structures, to induce micellization under disfavored conditions and to serve as a fluorescent tracer for the measurement of the micelle permeability across a model of the intestinal epithelium in vitro. Findings indicated that the conjugation of PP amounts as low as 2% w/w induced the formation of micelles at temperatures below the lower critical solution temperature of oligo(NiPAAm) (30-32 °C). Moreover, permeability studies conducted at both 4 °C and 37 °C strongly suggested that despite the relatively large size of the micelles (200-300 nm), they cross the epithelial monolayer mainly by a paracellular pathway due to the opening of tight junctions. Complementary uptake studies by flow cytometry indicated that no endocytosis, though due to passive or facilitated diffusion, some internalization takes place.
非注射型聚合物胶束向更广泛的从实验室到病床的转化仍存在两个主要障碍。第一个障碍与胶束在生物环境中不受控制的稀释条件下以及与生物大分子（如蛋白质）相互作用时，热力学驱动的解组装有关。第二个障碍与人们对聚合物胶束通过黏膜途径（如肠道）提高有效载荷生物利用度的途径的理解相对较差有关。在这项工作中，壳聚糖-g-聚（N-异丙基丙烯酰胺）（CS-g-聚（NiPAAm））共聚物用非细胞毒性量的原卟啉 IX（PP）进行了修饰，PP 是一种具有两亲性的平面分子，在水中通过形成 π-π 堆积超分子结构自组装，在不利条件下诱导胶束形成，并作为荧光示踪剂用于测量模型中肠上皮细胞的体外透皮率。研究结果表明，PP 的结合量低至 2% w/w 即可在低于低临界溶液温度的温度下诱导寡聚（NiPAAm）（30-32°C）形成胶束。此外，在 4°C 和 37°C 进行的渗透性研究强烈表明，尽管胶束的相对尺寸较大（200-300nm），但由于紧密连接的开放，它们主要通过细胞旁途径穿过上皮细胞单层。流式细胞术的补充摄取研究表明，尽管存在被动或促进扩散，但没有内吞作用，有些内化作用发生。
