Liposome-mediated delivery of the p21 activated kinase-1 (PAK-1) inhibitor IPA-3 limits prostate tumor growth in vivo

P21 activated kinases-1 (PAK-1) is implicated in various diseases. It is inhibited by the small molecule ‘inhibitor targeting PAK1 activation-3’ (IPA-3), which is highly specific but metabolically unstable. To address this limitation we encapsulated IPA-3 in sterically stabilized liposomes (SSL). SSL-IPA-3 averaged 139 nm in diameter, polydispersity index (PDI) of 0.05, and a zeta potential of − 28.1, neither of which changed over 14 days; however, the PDI increased to 0.139. Analysis of liposomal IPA-3 levels demonstrated good stability, with 70% of IPA-3 remaining after 7 days. SSL-IPA-3 inhibited prostate cancer cell growth in vitro with comparable efficacy to free IPA-3. Excitingly, only a 2 day/week dose of SSL-IPA-3 was needed to inhibit the growth of prostate xenografts in vivo, while a similar dose of free IPA-3 was ineffective. These data demonstrate the development and clinical utility of a novel liposomal formulation for the treatment of prostate cancer.

The small molecule ‘inhibitor targeting P21-activated kinase-1 (PAK1) activation-3’ (IPA-3) has potential anti-cancer effects, but is metabolically unstable. We encapsulated IPA-3 in sterically stabilized liposomes (SSL) that averaged 139 nm in diameter, polydispersity index (PDI) of 0.05, and a zeta potential of − 28.1, which was stable for over 14 days with 70 % of IPA-3 remaining even after 7 days. A 2 day/week administration of 5 mg/kg dose of SSL-IPA-3 significantly inhibited the growth of prostate xenografts in vivo as compared to similar dose of free IPA-3, demonstrating the potential benefits of SSL-IPA-3 for the management of prostate cancer.Figure optionsDownload high-quality image (208 K)Download as PowerPoint slide