DESIGN OF PH SENSITIVE LIPOSOMES CONTAINING ACID LABILE POLYETHYLENE CONJUGATES

脂质体介导的抗肿瘤药物的递送， 已经显示阿霉素通过以下方式增加它们的治疗功效： 改变药物的药代动力学。 脂质体研究进展 技术导致了小的刚性聚乙二醇的发展 （PEG）-包被的脂质体，其在体内具有相对长的半衰期。 循环和有限的组织分布。 这些脂质体 由于增加了肿瘤的生长， 由于可渗透的微血管系统导致的外渗。 的发展 靶向HER 2的新型Fab '连接免疫脂质体 抗原的特异性结合和内化， 脂质体载体对乳腺癌细胞的体外作用。 临床前试验 在裸鼠中HER 2过表达肿瘤异种移植模型显示， 抗HER 2免疫脂质体优先积累， 保留在肿瘤组织中。 抗HER 2免疫脂质体也被 在肿瘤异种移植细胞的细胞内定位中发现 表明载体的内吞作用。 的一个障碍 脂质体介导的药物递送是载体 在到达目标组织时释放其内容物。 的目的 建议的工作是设计可逆稳定的脂质体， 并且在暴露于酸性管腔时可以释放药物， 内体 这将导致增加反应， 靶点和治疗指数的总体增加 药 用于膜的酸敏感性邻柠康基保护基团 不稳定脂质和酸敏感缩酮和马来酰基交联 用于释放融合抑制聚合物的试剂将 用于制备在中性pH下稳定的脂质体， 但在酸性细胞器中变得不稳定， 核内体 靶部位的药物释放增加， 这些策略将导致优化的脂质体制剂， 联合抗HER 2靶向和增加循环 PEG提供的寿命将导致更大的临床 阿霉素脂质体治疗乳腺癌的疗效观察 癌 将利用质谱法表征 脂质聚合物缀合物以及合成中的任何中间体 这些共轭物。 加州大学旧金山分校的质谱仪将帮助我们 获取这些数据。

Liposome-mediated delivery of anti-neoplastic drugs such as doxorubicin has been shown to increase their therapeutic efficacy by altering the pharmacokinetics of the drug. Advances in liposome technology led to the development of small rigid polyethylene glycol (PEG)-coated liposomes that have a relatively long half-life in the circulation and a limited tissue distribution. These liposomes localize preferentially in tumors as a result of increased extravasation due to a permeable microvasculature. The development of novel Fab'-linked immunoliposomes that are targeted to the HER2 antigen resulted in specific binding and internalization of the liposomal carrier by breast cancer cells in vitro. Preclinical trials with an HER2 overexpressing tumor xenograft model in nude mice showed that anti-HER2 immunoliposomes preferentially accumulated and were retained in the tumor tissue. Anti-HER2 immunoliposomes were also found in an intracellular localization in tumor-xenograft cells suggesting endocytosis of the carrier. One barrier to liposome-mediated drug delivery is the efficiency at which the carrier releases its contents upon reaching the target tissue. The aim of the proposed work is to design liposomes that are reversibly stabilized and that can release their drug upon exposure to the acidic lumen of the endosome. This would result in an increased response at the target site and overall increase in the therapeutic index for the drug. Acid-sensitive o-citraconyl protecting groups for membrane destabilizing lipids and acid-sensitive ketal and maleyl crosslinking reagents for the release of fusion-inhibiting polymers will be utilized to prepare liposomes that are stable at neutral pH and in the presence of plasma but become destabilized in acidic organelles such endosomes. Increased drug release at the target site as a result of these strategies will result in an optimized liposome formulation that in combination with anti-HER2 targeting and incresased circulatory lifetimes afforded by PEG will result in a greater clinical effectiveness of liposomal doxorubicin in the treatment of breast cancer. Mass spectrometry will be utilized to characterize the lipidpolymer conjugates as well as any intermediates in the synthesis of these conjugates. The UCSF Mass Spectrometry Facility will aid us in obtaining this data.