BIODEGRADABLE HYDROPHILIC POLYACETALS

这是重新提交拨款申请 1 R21 RR14221-01。该项目的目标是提供新型可生物降解、无毒、生物反应性最小化的高分子材料，用于药理学和生物工程的高级应用。该项目解决了开发“理想生物相容性”材料的基本问题。 这种材料必须不能被任何生物分子和受体识别，不易受到“非特异性”相互作用的影响，在生理条件下稳定，同时可以被细胞（例如吞噬细胞）代谢。目前，尚无此类材料，也没有报道其开发的合理或其他方法。在这项研究中，我们利用一种新颖的“仿生”方法来开发生物相容性材料。 这项工作的基本机制假设表明，可以通过部分模拟细胞表面和生物分子（糖脂、糖蛋白等）上的寡糖和多糖形成的天然界面结构来获得具有最低生物反应性的生物可降解聚合物。 聚合物结构应包含界面碳水化合物的生物惰性结构片段，例如缩醛基团 (O-C-O) 和周围的碳，而由 C1-C2-C3-C4 形成的潜在生物可识别结构必须不存在。铅仿生聚缩醛（聚[氢甲基乙烯羟甲基缩甲醛]）（PHF）的实验样品在敏感的接枝共聚物循环测试中表现出优异的生物相容性、极低的毒性和可忽略不计的体内相互作用。 本研究的目的有两个：（1）进一步检验亲水性聚缩醛的一般生物惰性假设； (2) 启动将这一概念转化为基于 PHF 的新生物医学技术。本研究的预期成果包括：亲水性聚缩醛与生物系统相互作用的新知识；生产用于生物工程、药理学和生物医学研究的先进材料的新技术；用于生物医学研究的新分子工具；以及未来临床前研究的方法学基础。

This is a resubmission of grant application 1 R21 RR14221-01. The goal of this project is to provide new biodegradable, non- toxic macromolecular materials with minimized biological reactivity for advanced applications in pharmacology and bioengineering. The project addresses the fundamental problem of developing an "ideally biocompatible" material. This material must be non- recognizable by any biomolecules and receptors, non-vulnerable to "non-specific" interactions, stable in physiological conditions and, at the same time, metabolizable by cells (e.g., phagocytes). Presently, such materials are not available, and no rational nor other approaches to their development have been reported. In this study, we utilize a novel, "biomimetic" approach to developing biocompatible materials. The underlying mechanistic hypothesis of this work suggests that minimally bioreactive biodegradable polymers can be obtained via partial emulation of natural interface structures formed by oligo- and polycarbohydrates on cell surfaces and biomolecules (glycolipids, glycoproteins, etc.). Polymer structure should comprise the biologically inert structural fragments of interface carbohydrates, e.g., the acetal group (O-C-O) and the surrounding carbons, whereas the potentially biorecognizable structures formed by C1-C2-C3-C4 must be absent. Experimental samples of a lead biomimetic polyacetal, (poly[hydrohymethylethylene hydroxymethylformal]) (PHF), demonstrated excellent biocompatibility, extremely low toxicity and negligible interactions in vivo in a sensitive graft copolymer circulation test. The objective of this research is two-fold: (1) to further test the hypothesis of general bio- inertness of hydrophilic polyacetals; and (2) to initiate translation of the concept into a new biomedical technology on the basis of PHF. The expected outcome of this study includes: new knowledge on interaction of hydrophilic polyacetals with biological systems; new technologies for producing advanced materials for bioengineering, pharmacology, and biomedical research; new molecular tools for biomedical research; and a methodological basis for future preclinical studies.