BIODEGRADABLE HYDROPHILIC POLYACETALS

这是对拨款申请1 R21 RR14221-01的重新提交。本项目的目标是提供新的可生物降解的、无毒的、具有最小生物反应性的大分子材料，用于药理学和生物工程的先进应用。该项目解决了开发“理想生物相容性”材料的基本问题。该材料必须不被任何生物分子和受体识别，不容易受到“非特异性”相互作用的影响，在生理条件下稳定，同时可被细胞（如吞噬细胞）代谢。目前，这种材料是不可用的，也没有合理的或其他的方法来开发它们的报道。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。这项工作的潜在机制假设表明，通过部分模拟细胞表面和生物分子（糖脂、糖蛋白等）上由低聚碳水化合物和聚碳水化合物形成的自然界面结构，可以获得最低生物反应性的可生物降解聚合物。聚合物结构应该包括界面碳水化合物的生物惰性结构片段，例如缩醛（O-C-O）和周围的碳，而C1-C2-C3-C4形成的潜在生物可识别的结构必须不存在。在一个敏感的接枝共聚物循环测试中，一种铅仿生聚缩醛（聚[氢甲基乙烯羟甲基甲醛]）（PHF）的实验样品显示出良好的生物相容性、极低的毒性和可忽略的体内相互作用。本研究的目的有两方面：(1)进一步验证亲水聚缩醛的一般生物惰性假说；(2)在PHF的基础上开始将这一概念转化为新的生物医学技术。本研究的预期结果包括：对亲水聚缩醛与生物体系相互作用的新认识；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；生物医学研究的新分子工具；为未来的临床前研究提供了方法学基础。

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.