Drug targeting by block copolymer micelle having targeting moiety

具有靶向部分的嵌段共聚物胶束的药物靶向

• 批准号: 05455022
• 负责人: KATAOKA Kazunoei
• 金额: $ 2.69万
• 依托单位: Science University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05455022/
• 关键词: poly (ethylene glycol); poly (aspartic acid); block copolymer; adriamycin; polymeric micelle; heterobifunctional oligomer; pharmacokinetics; solid tumor; ヘテロニ官能性オリゴマー; 薬物ターゲティング; 制ガン剤

The polymeric micelles have an important place in the field of drug delivery systems. Indeed, such carriers can be considered to bo close to natural carriers such as viruses because of their small size, apparent stability and capacity for drug solubilization. The polymeric micelles formed by alpha-methoxy PEO/PBLA blck-copolymers already gave interesting results (small diameter, c.a.20nm ; stability ; possibility of anti-cancer drug solubilization, Adriamycin for example). Besides the fact of decreasing the side effects of anti-cancer drugs by entrapment in a carrier, the preparation of intelligent materials which are able to recognize selectively their objective is of interest. For this purpose, the synthesis of micelles having functional groups (such as hydroxy groups) on their outer-shell is necessary. In this project, we conducted the synthesis of heterobifunctional PEO/PBLA block-copolymers as well as the synthesis and chariacterzation of the resulting polymeric micelles.The stabi … More lity of polymeric micelles in blood is strongly correlated with their enhanced accumulation in tumors. Tumor accumulation ratios to normal tissue (muscle) at 24 hours for polymeric micelles (tumor/muscle ratio=40) showed an order of magnitude increase in comparison to free adriamycin (tumor/muscle ratio=1.5). An increase in the tumor accumulation ratio to the heart was also significant for the micelle-forming conjugate, suggesting a low incidence of cardiac toxicity in the conjugate system. Accumulation of the conjugate at tumor sites, possibly throughdirect extravasation, might be due to enhanced vascular permeability and retention effects in a tumor, known as the EPR effect. To achieve this effect at a sufficient level, it will be important to emphasize the core-shell structure of the micelle in order to inhibit nonspecific intertactions of the hydrophobic core of the micelle with the biocomponents (e.g., RES) by covering the core with a hydrated outer shell which will provide higher stability of the micelle structure in blood. Less

聚合物胶束在药物释放系统中占有重要的地位。事实上，这种载体可以被认为是接近天然载体，如病毒，因为它们的小尺寸，明显的稳定性和药物溶解能力。由α-甲氧基PEO/PBLA嵌段共聚物形成的聚合物胶束已经产生了有趣的结果(小直径，约20 nm；稳定性；抗癌药物增溶的可能性，例如阿霉素)。除了通过载体的包埋来减少抗癌药物的副作用之外，能够选择性地识别其目的的智能材料的制备也是令人感兴趣的。为此目的，合成在其外壳上具有官能团(如羟基)的胶束是必要的。在本项目中，我们进行了异双功能聚氧化乙烯/聚对苯二甲酸丁二醇酯嵌段共聚物的合成以及聚合物胶束的合成和表征。稳定的…血液中聚合物胶束的增多与它们在肿瘤中的增强蓄积密切相关。与游离阿霉素(肿瘤/肌肉比=1.5)相比，聚合物胶束(肿瘤/肌肉比=40)在24小时内对正常组织(肌肉)的肿瘤聚集率显示出数量级的增加。胶束形成的结合物对心脏的肿瘤聚集率的增加也是显著的，这表明结合物系统中心脏毒性的发生率很低。结合物可能通过直接外渗在肿瘤部位聚集，可能是由于肿瘤中血管渗透性和滞留效应的增强，即所谓的EPR效应。为了在足够的水平上实现这一效果，重要的是要强调胶束的核-壳结构，以便通过用水合外壳覆盖胶束核来抑制胶束疏水核心与生物成分(例如，RES)的非特异性相互作用，这将提供血液中胶束结构的更高稳定性。较少

项目成果

K.Kataoka: "Design of nanoscopic vehicles for drug targeting based on micellization of amphiphilic block copolymer" J.Macromol.Sci-Pure Appl.Chem.A31 (11). 1759-1769 (1994)

K.Kataoka：“基于两亲性嵌段共聚物胶束化的药物靶向纳米载体的设计”J.Macromol.Sci-Pure Appl.Chem.A31 (11)。

M.Yokoyama, T.Okano, Y.Sakurai, K.Kataoka: "Improved synthesis of adriamycin-conjugated poly (ethylene oxide) -poly (aspartic acid) block copolymer and formation of unimodal micellar structre with controlled amount of physically entrapped adriamycin" J.Co

M.Yokoyama、T.Okano、Y.Sakurai、K.Kataoka：“改进了阿霉素共轭聚（环氧乙烷）-聚（天冬氨酸）嵌段共聚物的合成，并形成了单峰胶束结构，并控制了物理包埋阿霉素的量”

G.S.Kwon: "Physical entrapment of adriamycin in AB block copolymer micelles" Pharmaceutical Research. 12(2). 200-203 (1995)

G.S.Kwon：“AB 嵌段共聚物胶束中阿霉素的物理包埋”药物研究。

Y.J.Kim, Y.Nagasaki, K.Kataoka, M.Kato, M.Yokoyama, T.Okano, Y.Sakurai: "Heterobifuntional poly (ethylene oxide) -One pot synthesis of poly (ethylene oxide) with a primary amino group at one end and a hydroxyl group at the other end" Polymer Bulletin. 33

Y.J.Kim、Y.Nagasaki、K.Kataoka、M.Kato、M.Yokoyama、T.Okano、Y.Sakurai：“异双功能聚环氧乙烷 - 具有伯氨基的聚环氧乙烷的一锅合成

K.Kataoka: "Design of nanoscopic vehicles for drug targeting based on micellization of amphiphilic block copolymers" J.Macromol.Sci.-Pure Appl.Chem.A31(11). 1759-1769 (1994)

K.Kataoka：“基于两亲性嵌段共聚物胶束化的药物靶向纳米载体的设计”J.Macromol.Sci.-Pure Appl.Chem.A31(11)。