Secretory Phospholipase A2-Responsive Liposomal Delivery of IPA-3 for Prostate Cancer Therapy
Abstract
Treating advanced metastatic prostate cancer (PCa) is a challenge due to the uncertainties in the molecular mechanism regulating metastasis and the serious side effects of chemotherapy. Drug toxicities also arise as a result of off-target effects and undesired effects on the normal organs. Our recent studies demonstrated that a protein called p21 activated kinase-1 (Pak1), which is usually absent in normal human prostate and benign prostatic hyperplasia tissues, is highly expressed in metastatic PCa cells. Further, this protein is highly expressed in human prostate tumors and lung metastatic lesions. Our subsequent studies revealed that Pak1 is needed for PCa epithelial-to-mesenchymal transition (EMT) in vitro, a step believed to be needed for these cells to metastasize. A small molecule inhibitor of Pak1 called IPA-3 (inhibitor targeting Pak1 activation-3) was identified through high-throughput screening and shown to have the advantage of high specificity for Pak1 inhibition. Unfortunately, like many potential drugs, the poor stability of IPA-3 is a major bottleneck in its therapeutic use. For example, while we showed that IPA-3 inhibited PCa growth, this required daily intravenous administration. This raises toxicity concerns due to the integral role of Pak1 in physiology, and we cannot rule out any adverse side effects of IPA-3. What is needed to overcome these barriers is a reliable approach to specifically deliver IPA-3 to PCa cells in vivo to improve the stability and efficacy, to minimize the frequency of drug administration, and to reduce any potential side effects. This can be achieved using nanoparticle technology, specifically by using tissue-guided liposomes for drug delivery. Secretory phospholipase A2 (sPLA2) are esterases whose expression is increased in inflammatory diseases. Select sPLA2 are overexpressed ~10- to 20-fold in PCa, and higher expression correlates with poor clinical prognosis, including decreased 5 years survival. These findings led us to design of sPLA2-targeted lipid-based nanoparticles called SPRL. The Partnering Principal Investigator s (Dr. Brian Cummings) group has demonstrated that SPRLs were susceptible to sPLA2-mediated degradation and efficient at delivery drugs to PCa cells in vitro. He also demonstrated that SPRL were twice as effective as the clinically used SSL formulation containing doxorubicin (DOXIL®) at inhibiting tumor growth in vivo. While these studies are encouraging, doxorubicin is not typically used for treatment of PCa, and studies are needed with more relevant drugs. Further, these nanoparticles were not tested in metastatic model of PCa. This proposal combines two unique aspects of PCa to design more effective therapeutics, the overexpression of the protein kinase Pak1 and the overexpression of the phospholipase sPLA2. The overall objective is to make use of this unique tumor pathophysiology to design and determine the effectiveness of "sPLA2-liposomal encapsulated IPA 3" (SPRL-IPA-3) in limiting PCa growth, metastasis, and bone remodeling. Such a combination will create a novel, innovative, and effective treatment for metastatic PCa. The major objective of our proposal is to engineer and identify the biophysical properties of SPRL-IPA-3, determine their targeting ability and mechanism of action, and test their efficacy on PCa in vivo. We hypothesize that SPRL-IPA-3 will significantly inhibit the growth of prostate tumors, metastasis, and remodeling of the tumor microenvironment. Our specific aims are to (1) engineer, characterize, and test the sPLA2 sensitivity of IPA-3 SPRL in multiple prostate cancer cell models and (2) test the hypotheses that IPA-3 SPRL administration will (a) inhibit PCa growth in mice, (b) inhibit PCa metastasis to lungs, and (c) inhibit PCa-induced bone remodeling. Most laboratory-based research with human PCa cells does not reach the clinic due to issues relating to dose, frequency of administration, toxicity, and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610612
Entities
People
- Brian S Cummings
Organizations
- United States Army
- University of Georgia