LIPOSOME TARGETING TO TUMOR CELLS IN VIVO

我们建议优化抗体导向的脂体作为体内抗肿瘤药物 选定的动物模型系统中的肿瘤药物载体。我们的方法需要INT 考虑到针对任何颗粒物的两个主要问题，即， 内皮屏障与网状内皮系统的摄取 (分辨率)。因此，我们建议开发新的方法来最小化 白藜芦醇对循环脂质体的摄取及其靶向性研究 脂质体定位于可访问的解剖隔间内的肿瘤细胞 到脂质体。 1.减少可再生能源吸收的新方法。在过去几年中， 我们对清除抗体偶联脂质体进行了广泛的研究。 发行量。从本质上讲，快速清除表明 肝脏Res对脂质体吸收的贡献。因此，一名少校 目标是战略的设计 从而导致脂质体的清除较慢，从而增加了LikeLio 肿瘤细胞对靶向脂质体的摄取。我们对此的中心方法 目标是设计具有组成和生物物理性质的脂质体 这将降低他们对RE的亲和力，并增加他们的稳定性 (无内容物泄漏)在延长的流通时间内。在……里面 此外，我们还提出了可逆性RES失活的佐剂方法。 2.靶向肿瘤细胞。我们选择了几种小鼠肿瘤模型： 局部种植的SC肿瘤；系统性播散性白血病和淋巴瘤 模型；以及肝转移模型。我们还计划使用人类结肠 生长时具有肝转移能力的肿瘤细胞系 裸鼠。所有这些肿瘤细胞系都显示有靶向性的表面标记。 靶向将用脂质体包裹的放射性示踪剂和 我们实验室在原发肿瘤部位和 在转移的地方，肝脏。这一战略的一个补充方面 就是增加内皮细胞屏障的渗透性 脂质体。我们计划检查低血压是否会对内皮细胞造成损害 放射治疗的剂量将增加，靶向获取将增加 靶向脂质体进入肿瘤细胞附近。跟随 靶向系统的优化，治疗实验将 进行抗肿瘤药物包埋后的疗效评价 靶向脂质体治疗肝转移和全身疾病。

We are proposing to optimize antibody-directed lipsomes as an in vivo anti- tumor drug-carrier in selected animal model systems. Our approach takes int account the two major problems of targeting any particulate matter, i.e., the endothelial barrier and the uptake by the reticuloendothelial system (RES). We are therefore proposing to develop new methods for minimizing uptake of circulating liposomes by the RES and to apply targeting of liposomes to tumor cells localized within anatomic compartments accessible to liposomes. 1. New methods for minimizing uptake by the RES. During the past few years, we have studied extensively the clearance antibody-conjugated liposomes fro the circulation. Essentially, a fast clearance indicates a predominant contribution of the liver RES in the uptake of liposomes. Thus, a major objective is the design of strategies resulting in slower clearance of liposomes, thereby increasing the liklihoo of uptake of targeted liposomes by tumor cells. Our central approach to thi goal is the design of liposomes with composition and biophysical properties that would reduce their affinity for the RES and increase their stability (absence of leakage of contents) during prolonged circulation times. In addition, we have proposed adjuvant methods of reversible RES inactivation. 2.Targeting to tumor cells. We have selected several murine tumor models: locally implanted SC tumors; systemically disseminated leukemia and lymphom models; and liver metastases models. We plan also to use a human colon carcinoma derived cell line with liver-metastasizing ability when grown in nude mice. All these tumor cell lines display targetable surface markers. Targeting will be assessed with liposome-encapsulated radiotracers and fluorofores developed in our laboratory both at the primary tumor site and at the metastatic site, the liver. A complementary aspect of this strategy would be to increase the permeability of the endothelial barrier to liposomes. We plan to examine whether the endothelial damage caused by low dose radiation therapy will increase the access of targeted will increase the access of targeted liposomes to the vicinity of tumor cells. Following optimization of the targeting system, therapeutic experiments will be performed to evaluate the efficacy of anti-tumor drugs encapsulated in targeted liposomes on liver metastases and on systemic disease.