第七章药用高分子

4
高分子药物缓释体
1.4 高分子药物传输体系的医学理论：
1.4.1 Passive Drug Targeting and Specific Tissue Targeting: The EPR Effect 被动靶向
高分 子药 物在 组织 内的 富集
The entry of macromolecules into tumor tissue takes place in the capillaries where blood flow is diminished and nutrients transfer into the tissue. In contrast to the blood capillaries in most normal tissues, the endothelial layer （血管内皮层） of the capillaries in the tumor tissue is fenestrated （穿孔） and leaky so that macromolecules and other nanoparticles reach the malignant （恶性） tissue. Tumor tissue generally has a defective lymphatic drainage system with the result that macromolecules are retained and can subsequently accumulate in solid tumors. The size of the macromolecule is a crucial factor with respect to uptake by the tumor. The EPR effect is observed for macromolecules with molecular weights greater than 20 kDa.
内吞， 细胞间质， 核内体， 溶酶体
Drug–polymer conjugates or complexes should be sufficiently stable in the blood stream prior to the drug being liberated at the site of action. In principle, the polymer-bound drug can be released in the body by unspecific hydrolysis by enzymes, by reduction, or in a pH-dependent manner. In an ideal case, cleavage of the drug–polymer conjugate at the tumor site is triggered by a biochemical or physiological property unique for the individual tumor. Although such truly tumor-specific features are rarely encountered, the over expression of certain enzymes, an acidic and hypoxic environment in solid tumors, as well as the endocytotic pathway of macromolecules offer several options for designing drug– polymer conjugates that are preferentially cleaved within the tumor
高分子-药物（蛋白、DNA， RNA，小分子药）耦合体 高分子治疗体系 高分子药物缓释体
高分子药物
1.3 低分子药物与高分子的结合方式模型
高分子-药物耦合体
Hosting polymer : water-soluble, nontoxic, and nonimmunogenic, as well as degraded and/or eliminated from the organism
小分子 药物：新陈代谢速度快，半衰期短，易排泄，非选择性，毒副作用
2
1.2 高分子药物体系类型
Generally, these can be classified as nanoparticulate drugdelivery systems or as drug–polymer conjugates. Particulate delivery systems in which the drugs are physically incorporated into nanoparticles include emulsions, liposomes, and noncovalent polymeric carrier systems. In drug–polymer conjugates, however, a drug is covalently linked to polymers such as proteins, polysaccharides, or synthetic polymers.
第七章 药用高分子
1 概述
1.1 为什么要研究高分子药物
Today, the vast majority of clinically used drugs are low molecularweight compounds (typically under 500 gmol-1) that exhibit a short halflife in the blood stream and a high overall clearance rate. These smallmolecule drugs typically interact through a multiple but monovalent （单 一键合） binding with a given receptor. Furthermore, they diffuse rapidly into healthy tissues and are distributed evenly within the body. As a consequence, relatively small amounts of the drug reach the target site, and therapy is associated with side effects. These disadvantages are especially pronounced with drugs that exhibit a narrow therapeutic index, such as anticancer, antirheumatic, and immunosuppressive agents. Frequent side effects associated with these drugs are nephrotoxicity (肾中毒), bonemarrow （骨髓）toxicity, neurotoxicity （神 经毒性）, cardiotoxicity （心血管毒性）, mucositis（黏膜炎）, and gastrointestinal （胃肠毒性）toxicity, which are dose-limiting and thusprevent effective treatment.
1.4.2. Cellular Uptake of Polymers, Site-Specific Drug Release, and Implications for Drug Design 定点性药物释放
高分子药 物进入细 胞的方式
In general, macromolecules are taken up by the cell through receptor-mediated endocytosis, adsorptive endocytosis, or fluid-phase endocytosis (Figure 4).[39] During endocytosis a significant drop in the pH value takes place from the physiological value (7.2–7.4) in the extracellular space to pH 6.5–5.0 in the endosomes （核内体）and to around pH 4.0 in primary and secondary lysosomes（溶酶体）. A great number of lysosomal enzymes become active in the acidic environment of these vesicles, for example, phosphatases, nucleases, proteases, esterases, and ulation of macromolecules and other nanoparticles in solid tumors is a phenomenon which was probably overlooked for several years as a potential biological target for tumor-selective drug delivery. The rationale for using macromolecules as efficient carriers for the delivery of antitumor agents, even if they are not targeted towards an antigen or receptor on the surface of the tumor cell, is based on the pioneering work of Maeda and co-workers[29, 30] as well as Jain et al.[31, 32] The results of these studies gave detailed insight into the pathophysiology （病理学）of tumor tissue that is characteristic of angiogenesis（再生血管）, hypervasculature （高密 度血管分布）, a defective vascular architecture （血管缺陷）, and an impaired lymphatic drainage（受损的淋巴通道）. Differences in the biochemical and physiological characteristics of healthy and malignant （恶劣的，恶性的） tissue are responsible for the passive accumulation of macromolecules in tumors. This feature has been termed “enhanced permeability and retention” (EPR effect)[30, 33] and is depicted schematically in Figure 3.