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.
Studies proposed in this application examine the ability of an enzyme and its receptor expressed in many cancers to increase targeted drug delivery of nano drug carriers. This will determine the role and importance of these proteins on degradation, release, uptake, and drug delivery of molecularly-targeted drug carriers. We hypothesize this will increase the therapeutic index and decrease toxicity of these nanocarriers to healthy tissues.
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