Design of self-assembling materials for challenging drug formulations and cell-culture devices

用于挑战药物配方和细胞培养装置的自组装材料的设计 这项研究的概念核心是，在某些自组装的聚合物辅料特征中，“微小的修饰可以产生重大的变化”。几种多羟基材料可以通过强的链间氢键结合和自组装过程来稳定。淀粉是一种天然多糖，呈现双螺旋(B型)或单螺旋(V型)形态，与无序区域共存。V型螺旋结构呈现出适度疏水的内表面，可以容纳碘甚至一些脂肪分子。在目前的药物中，有些药物的溶解度很低(即非类固醇抗炎药，如布洛芬)，因此很难配制成可控释药物。其他药物具有很高的溶解度(如抗糖尿病药物二甲双胍)，也很难配制成缓释药物，由于它们在不适当的部位释放，导致效率低和不良副作用。 这项研究的一个主要目标是构思新的和具有挑战性的药物形式，这些药物因其太低或太高的溶解度而被认为很难配制。 我们的假设是，适当的衍生化可以增加可能定位疏水药物的淀粉V-螺旋的内腔直径。羧甲基(CM)-淀粉是一种带有CM基团的阴离子衍生物，预计会比未变性淀粉的空腔大小更大。因此，CM-淀粉可以容纳更大更疏水的试剂。一种新型的两性淀粉，CM-AE-淀粉，同时带有阴离子(CM)和阳离子氨基乙基(AE)基团，被认为是一种能够延缓药物在肠道或结肠吸收的赋形剂。这种两性赋形剂似乎不仅通过氢缔合，而且通过离子相互作用而自我稳定，似乎足以形成高度溶解的制剂(如二甲双胍)。 第二个主要目标是介绍用于组织培养、植入物和异种移植物(即主动脉假体)的新型生物材料。聚乙烯醇(PVA)聚合物具有很强的自组装能力，是一种具有良好力学和成膜特性的生物材料。然而，以前的报告显示，PVA设备的定植率很低，某些PVA植入物会产生刺激迹象，并在组织周围形成纤维化。壳聚糖是另一种天然碳水化合物，曾被认为与多种生物相容性材料结合在一起，但其溶解性较差，其应用可能受到限制。我们的假设是，将壳聚糖修饰为羧乙基(CE)-壳聚糖与PVA结合，将产生用于植入物和血管移植物以及肝细胞和神经元培养装置的感兴趣的生物材料。

Design of self-assembling materials for challenging drug formulations and cell culture devices The conceptual core of the proposed research is that “Minor modifications can generate Major changes” in certain self-assembling polymeric excipient features. Several polyhydroxylic materials may be stabilized by strong interchain hydrogen association and self-assembling processes. Starch is a natural polysaccharide presenting double helix (B type) or single helix (V type) morphological forms that coexist with disordered regions. The V-type helix structures present a moderately hydrophobic inner surface that can hold iodine or even some fatty molecules. Among the current drugs, some of them are very low soluble (i.e. non-steroidal anti-inflammatory drugs, as ibuprofen) and thus difficult to formulate for controlled delivery. Other drugs present a very high solubility (such as the antidiabetic metformin) and are also difficult to formulate for sustained release, causing low efficiency and undesirable side effects due to their liberation at improper sites. A major objective of this research is to conceive new and challenging pharmaceutical forms of drugs which are known as difficult to formulate because of their too low or too high solubility. Our hypothesis is that a proper derivatization could increase the diameter of the inner cavity of starch V-helices that may locate hydrophobic drugs. The Carboxymethyl(CM)-Starch, an anionic derivative charged with CM groups, is expected to present a cavity size larger than that of nonmodified Starch. Consequently CM-Starch can hold larger and more hydrophobic agents. A new ampholytic Starch, the CM-AE-Starch, carrying both anionic (CM) and cationic aminoethyl (AE) groups is proposed as an excipient able to delay the release of drugs with absorption at lower intestine or colon. This ampholytic excipient is seems self-stabilized not only by hydrogen associations, but also by ionic interactions and appears adequate to formulate highly soluble agents (as Metformin). A second main objective is to introduce novel biomaterials for tissue culture, for implants and xenografts (i.e. aorta prosthesis). Polyvinyl alcohol (PVA) polymer have been proven as acceptable biomaterial with interesting mechanical and film-forming characteristics due to its strong self-assembling capacity. However, previous reports showed a low colonisation of PVA devices and that certain implants of PVA generate signs of irritation and formation of fibrosis surrounding tissues. Chitosan, another natural carbohydrate, was suggested to be associated with several biocompatible materials, but it presents a poor solubility and its applications may be limited. Our hypothesis is that chitosan modified as CarboxyEthyl(CE)-Chitosan in association to PVA will generate biomaterials of interest for implants and vascular grafts and for devices for hepatocyte and neurons in culture.