Development of Novel Anticancer Drug-Carriers Targetable to Tumor Blood Vessels.

加强肿瘤药物在肿瘤血管床中的分布和有效药物的控释是提高抗肿瘤药物疗效的最有效途径。这可以通过使用药物载体配合物来实现。虽然已经提出了多种载体，但没有一种载体在药物装载率、粒径、药物释放率和/或储存稳定性方面满足实际使用。本研究旨在改善这些问题的药物载体。乙基纤维素微胶囊。这种载体的优点是；1)基于凝聚原理的制备工艺简单，2)水溶性药物可广泛利用，3)载药率高达80%，4)药物释放速度可控，5)室温下储存稳定。然而，不可避免的缺点是难以产生小于100微米的颗粒尺寸。为了克服这个问题，我们开发了一种新的方法来获得大量的小微胶囊（<100um）。有了这个新产品，小的肿瘤供血动脉成为微胶囊化疗栓塞的目标。聚丙醇微球聚乳酸纤维。采用水内干燥乳化液法制备了乳酸/乙醇酸共聚微球。该微球能有效结合油溶性药物。一种抗血管生成药物TNP-470（富马青霉素衍生物）被证明制备成聚乳酸微球，并对兔VX2肿瘤发挥抗肿瘤作用。甘油三酯（油载体）。TNP-470溶解于甘油三酯溶液（MIGLYOL）中，由于其释放时间长，稳定性好，与传统的油载体（如豆油和脂醇）相比，具有更强的抗肿瘤作用。MIGLYOL是一种新型的油性药物载体。二乙酰血卟啉（diAc-Hp）。diAc-Hp在肿瘤组织中积累，并对超声有反应。diAc-Hp-丝裂霉素C偶联物在超声照射下增强了母体药物的细胞毒作用，表明diAc-Hp作为药物载体的应用价值。少

The most effective approach to enhance the anticancer drugs is the restrive distribution in the tumor vascular beds and the controlled release of the available drugs. This can be achieved by using drug-carrier complexes. Though a variety carriers have been proposed, none of them saticefy the practical use in respect to drug loading rate, particle size, drug release rate and/or stability in storage. This research was designed to improve these problems of drug carriers.Ethylcellulose microcapsule. The advantage of this carrier is ; 1) simple processes for preparation based on the principle of coacervation, 2) wide availability for water-soluble drugs, 3) high drug loading rate upto 80%, 4) controlability of drug release rate, and 5) stability in storage at room temparature. While, the inevitable disadvantage is the difficulty to produce a particle size of smaller than 100 um. To overcome this problem, we developed a new method to obtain a large quantity of small microcapsules (<100um) . … More With this new product, small tumorfeeding arteries become the target of microcapsule chemoembolization.Polylactic microsphere. Preparation of microspheres with copoly (DL-lactic /glycolic acid was developed using an in-water drying emulsion method. This microsphere effectively conjugate oil-soluble drugs. An antiangiogenetic drug, TNP-470 (a derivative of fumagillin) , proved to be prepared as polylactic microspheres and exert an antitumor effect on VX2 tumors in rabbits.Triqlyceride (oily carrier) . TNP-470 dissolved in triglyceride solution (MIGLYOL) exerted an enchanced antitumor effect due to the prolonged drug-release as well as the stability as compared with the conventional oily carriers such as sexame oil and lipiodol. MIGLYOL may be used a novel oily drug-carrier.Diacetylhematoporphyrin (diAc-Hp) . diAc-Hp accumulates in tumor tissues and responds to ultrasound. The diAc-Hp-mitomycin C conjugate enhanced the cytotoxic effect of the parent drugs under ultrasonic irradiation, indicating the aplicability of diAc-Hp as a drug-carrier. Less