Sterically stabilized liposomes targeting P21 (RAC1) activated kinase‑1 and secreted phospholipase A<sub>2</sub> suppress prostate cancer growth and metastasis

Verma,Arti; Najahi‑Missaoui,Wided; Cummings,Brian S.; Somanath,Payaningal R.

doi:10.3892/ol.2020.12040

Sterically stabilized liposomes targeting P21 (RAC1) activated kinase‑1 and secreted phospholipase A₂ suppress prostate cancer growth and metastasis

Authors:
- Arti Verma
- Wided Najahi‑Missaoui
- Brian S. Cummings
- Payaningal R. Somanath
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Affiliations: Program in Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA 30912, USA, Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA
Published online on: August 31, 2020 https://doi.org/10.3892/ol.2020.12040
Article Number: 179
Copyright: © Verma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Metastatic prostate cancer (PCa) has a very high mortality rate in men, in Western countries and lacks reliable treatment. The advanced‑stage PCa cells overexpress P21 (RAC1) activated kinase‑1 (PAK1) and secreted phospholipase A₂ (sPLA₂) suggesting the potential utility of pharmacologically targeting these molecules to treat metastatic PCa. The small molecule, inhibitor targeting PAK1 activation‑3 (IPA3) is a highly specific allosteric inhibitor of PAK1; however, it is metabolically unstable once in the plasma thus, limiting its utility as a chemotherapeutic agent. In the present study, the efficacy and specificity of IPA3 were combined with the stability and the sPLA₂‑targeted delivery method of two sterically stabilized liposomes [sterically stabilized long‑circulating liposomes (SSL)‑IPA3 and sPLA₂ responsive liposomes (SPRL)‑IPA3, respectively] to inhibit PCa growth and metastasis. It was found that twice‑a‑week administration of either SSL‑IPA3 or SPRL‑IPA3 for 3 weeks effectively suppressed the growth of PC‑3 cell tumor xenografts implanted in athymic nude mice. Both drug formulations also inhibited the metastasis of intravenously administered murine RM1 PCa cells to the lungs of C57BL/6 mice. Whereas the twice‑a‑week administration of SSL‑IPA3 significantly inhibited the spontaneous PCa metastasis to the lungs in Transgenic Adenocarcinoma of the Mouse Prostate mice, the administration of free IPA3 had no significant therapeutic benefit. The results present two novel IPA3 encapsulated liposomes to treat metastatic PCa.

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