Secretory Phospholipases sPLA2 and their Receptors for Delivering Nanoparticles

说明(申请人提供)：纳米粒制剂，如聚乙二醇化长循环脂质体，可以稳定地包埋药物，改变药物处置，提高抗肿瘤活性，并将毒性降至最低。然而，对它们的药物释放动力学的控制限制了它们的临床潜力。分泌型磷脂酶A2(SPLA2)在多种肿瘤中分泌和过度表达，例如在前列腺癌中高达22倍。这些酶优先在sn-2酯位置降解磷脂，并被假设为控制脂基纳米粒(如脂质体)药物释放的靶点。我们开发了一个平台来定量sPLA2响应性脂质体(SPRL)的降解和释放动力学。不幸的是，类似制剂的临床表现一直受到限制。最近，我们发现在前列腺癌中存在PLA2受体(PLA2R)。SPLA2与PLA2R的结合通常会导致两种蛋白质的内化和sPLA2的失活。目前尚不清楚这种负调控是否发生在所有的sPLA2中。据报道，除了sPLA2失活外，sPLA2与PLA2R结合还可以改变细胞的侵袭、增殖和MAPK激活。研究还表明，脂质代谢的改变和脂质信号的增加。几乎没有数据表明sPLA2和PLA2R之间的相互作用介导了脂基纳米粒的传递。这项授权测试了sPLA2和PLA2R控制脂质体的降解、细胞摄取、有效性和非靶向性毒性的假设。这一假说将通过追求四个目标来验证：目的1.确定PLA2R在前列腺癌细胞靶向递送中的作用和SPRL的有效性；目的2.描述sPLA2亚型在前列腺癌细胞靶向递送和SPRL有效性中的作用；目的3.寻找新的基于sPLA2的多肽，靶向摄取PLA2R的脂质体；以及目的4.在人前列腺癌小鼠移植瘤模型中确定SPR1对PLA2R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.