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

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• 作者：Ahmad Al-Azayzih ; PharmD ; PhD ; BCOP^a ; ^b ; ¹ ; Wided N. Missaoui ; PharmD ; MS^c ; ¹ ; Brian S. Cummings ; PhD^c ; ^d ; ^{briansc@uga.edu" class="auth_mail" title="E-mail the corresponding author} ; Payaningal R. Somanath ; PhD ; FAHA^a ; ^e ; ^{sshenoy@gru.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：PAK-1 ; P21 activated kinase-1 ; SSL ; sterically stabilized liposomes ; IPA-3 ; inhibitor targeting PAK1 activation-3 ; PDI ; polydispersity index.
• 刊名：Nanomedicine: Nanotechnology, Biology and Medicine
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：12
• 期：5
• 页码：1231-1239
• 全文大小：1198 K

文摘

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.