Secretory Phospholipases sPLA2 and their Receptors for Delivering Nanoparticles

描述（由申请人提供）：纳米颗粒制剂，如聚乙二醇化长循环脂质体，可以稳定地捕获药物，改变药物分布，提高抗肿瘤活性并使毒性最小化。然而，其药物释放动力学的控制限制了其临床潜力。分泌型磷脂酶A2（sPLA 2）在多种肿瘤中分泌和过表达，例如，在前列腺中高达22倍。这些酶优先在sn-2酯位置降解磷脂，并被假设为控制药物从基于脂质的纳米颗粒（如脂质体）释放的靶标。我们开发了一个平台来定量sPLA 2-介导的降解和sPLA 2响应性脂质体（SPRL）的释放动力学。不幸的是，类似制剂的临床性能有限。最近，我们确定了PLA 2受体（PLA 2 R）在前列腺癌中的存在。sPLA 2与PLA 2 R的结合通常会导致两种蛋白质的内化和sPLA 2的失活。尚不清楚是否所有sPLA 2都发生这种负调节。除了sPLA 2失活之外，据报道sPLA 2与PLA 2 R的结合改变细胞侵袭、增殖和MAPK活化。研究还表明脂质代谢的改变和脂质信号的增加。很少有数据表明sPLA 2和PLA 2 R之间的相互作用介导脂质基纳米颗粒的递送。该授权测试了sPLA 2和PLA 2 R控制脂质体的降解、细胞摄取、功效和非靶向毒性的假设。这一假设将通过追求四个目标来检验：目标1。鉴定PLA 2 R在前列腺癌细胞中靶向递送SPRL和SPRL功效中的作用;目的2.阐明sPLA 2亚型对前列腺癌细胞中SPRL的靶向递送和功效的作用;目的3.鉴定新的基于sPLA 2的肽以靶向PLA 2 R对脂质体的摄取;和目的4.在人前列腺癌的小鼠异种移植模型中测定SPRL对PLA 2 R的特异性和抗肿瘤活性。

DESCRIPTION (provided by applicant): Nanoparticle formulations, such as pegylated long-circulating liposomes, can stably entrap drug, alter drug disposition, improve antitumor activity and minimize toxicity. However, control of their drug-release kinetics has limited their clinical potential. Secretory phospholipases A2 (sPLA2) are excreted and over expressed in a variety of tumors, e.g., up to 22-fold in prostate. These enzymes degrade phospholipids preferentially at the sn-2 ester position and have been hypothesized as targets to control drug release from lipid-based nanoparticles, such as liposomes. We developed a platform to quantify sPLA2-meidated degradation and release kinetics of sPLA2 responsive liposomes (SPRL). Unfortunately, the clinical performance of similar formulations has been limited. Recently we identified the presence of PLA2 receptors (PLA2R), in prostate cancer. Binding of sPLA2 to PLA2R typically results in internalization of both proteins and inactivation of sPLA2. It is not known if this negative regulation occurs with all sPLA2. In addition to sPLA2 inactivation, sPLA2 binding to PLA2R is reported to alter cell invasion, proliferation and MAPK activation. Studies also suggest alterations in lipid metabolism and increases in lipid signaling. Little data exists identifying ho interactions between sPLA2 and PLA2R mediate the delivery of lipid-based nanoparticles. This grant tests the hypothesis that sPLA2 and PLA2R control degradation, cell uptake, efficacy, and non-targeted toxicity of liposomes. This hypothesis will be tested by pursuing four aims: Aim 1. Identify the role of PLA2R in the targeted delivery and efficacy of SPRL in prostate cancer cells; Aim 2. Delineate the role of sPLA2 isoforms on the targeted delivery and efficacy of SPRL in prostate cancer cells; Aim 3. Identify novel sPLA2-based peptides to target uptake of liposomes by PLA2R; and Aim 4. Determine the specificity and antitumor activity of SPRL for PLA2R in a mouse xenograft model of human prostate cancer.