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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB016100-02
Application #
8601531
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Tucker, Jessica
Project Start
2013-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$300,128
Indirect Cost
$56,088
Name
Auburn University at Auburn
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
066470972
City
Auburn University
State
AL
Country
United States
Zip Code
36849
Pati, Sumitra; Ingram, Lishann M; Sun, Min K et al. (2018) Localization and expression of CTP: Phosphocholine cytidylyltransferase in rat brain following cocaine exposure. J Chem Neuroanat 96:1-6
Brannen, Andrew; Eggert, Matthew; Nahrendorf, Matthias et al. (2018) Correlation of 360-degree Surface Mapping In Vivo Bioluminescence with Multi-Spectral Optoacoustic Tomography in Human Xenograft Tumor Models. Sci Rep 8:3321
Pradhan, Shantanu; Smith, Ashley M; Garson, Charles J et al. (2018) A Microvascularized Tumor-mimetic Platform for Assessing Anti-cancer Drug Efficacy. Sci Rep 8:3171
Huang, Jiansheng; Milton, Amber; Arnold, Robert D et al. (2016) Methods for measuring myeloperoxidase activity toward assessing inhibitor efficacy in living systems. J Leukoc Biol 99:541-8
Scholpa, N E; Kolli, R T; Moore, M et al. (2016) Nephrotoxicity of epigenetic inhibitors used for the treatment of cancer. Chem Biol Interact 258:21-9
Kephart, Wesley C; Wachs, Taylor D; Thompson, R Mac et al. (2016) Ten weeks of branched-chain amino acid supplementation improves select performance and immunological variables in trained cyclists. Amino Acids 48:779-789
Kaye, Sarrah; Johnson, Shawn; Arnold, Robert D et al. (2016) PHARMACOKINETIC STUDY OF ORAL ?-AMINOCAPROIC ACID IN THE NORTHERN ELEPHANT SEAL (MIROUNGA ANGUSTIROSTRIS). J Zoo Wildl Med 47:438-46
Pati, Sumitra; Nie, Ben; Arnold, Robert D et al. (2016) Extraction, chromatographic and mass spectrometric methods for lipid analysis. Biomed Chromatogr 30:695-709
Al-Azayzih, Ahmad; Missaoui, Wided N; Cummings, Brian S et al. (2016) Liposome-mediated delivery of the p21 activated kinase-1 (PAK-1) inhibitor IPA-3 limits prostate tumor growth in vivo. Nanomedicine 12:1231-1239
Boozer, Lindsay B; Platt, Simon R; Haley, Allison C et al. (2015) Pharmacokinetic evaluation of immediate- and extended-release formulations of levetiracetam in dogs. Am J Vet Res 76:719-23

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