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

提高抗癌药物最有效的途径是重新争取肿瘤血管床的分布和现有药物的控释。这可以通过使用药物载体复合体来实现。虽然已经提出了多种载体，但没有一种载体在载药率、粒径、药物释放速率和/或储存稳定性方面具有实际应用价值。本研究旨在改善药物载体的这些问题。乙基纤维素微胶囊。该载体的优点是：1)基于凝聚原理的制备工艺简单；2)水溶性药物的利用率高；3)载药率高达80%；4)药物释放速度可控；5)室温储存稳定。然而，不可避免的缺点是难以生产出小于100微米的颗粒。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胶囊(~lt；100um)。…随着这一新产品的推出，小的肿瘤供血动脉成为微囊化疗栓塞的靶点。采用水中干燥乳化法制备了乳酸/乙醇酸共聚物微球。这种微球有效地结合了油溶药物。抗血管生成药物TNP-470(伏马西林的衍生物)被证实制备成聚乳酸微球，并对兔VX2肿瘤起到抗肿瘤作用。TNP-470溶于甘油三酯溶液(MIGLYOL)，与传统的油性载体如性油和碘油相比，由于药物释放时间长和稳定性好，具有更强的抗肿瘤作用。MIGLYOL可能是一种新型的油性药物载体--双乙酰血卟啉(DIAC-HP)。DIAC-HP积聚在肿瘤组织中，对超声波有反应。DIAC-HP-丝裂霉素C结合物在超声辐射下增强了母体药物的细胞毒作用，表明DIAC-HP作为药物载体的可行性。较少

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