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

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 A 2 (sPLA 2) 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 sPLA 2-targeted delivery method of two sterically stabilized liposomes [sterically stabilized long-circulating liposomes (SSL)-IPA3 and sPLA 2 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.

Liposomes Targeting P21 Activated Kinase-1 (PAK-1) and Selective for Secretory Phospholipase A2 (sPLA2) Decrease Cell Viability and Induce Apoptosis in Metastatic Triple-Negative Breast Cancer Cells

“…In addition, SSLs are known to alter the pharmacokinetic profile of encapsulated drugs and improve their pharmacological activities [ 29 , 30 , 31 ]. Our studies showed that SSL-IPA-3 improved the stability of IPA-3 and improved its efficacy with regard to inhibiting prostate cancer growth both in vitro and in vivo [ 32 , 33 , 34 ]. While these studies focused on prostate cancer, we have also previously shown that the ability of SSL-IPA-3 to decrease cell growth was dependent on the expression of PAK-1 in a diverse set of breast cancer cells.…”

“…This resulted in a novel formulation containing an increased level of 1,2-distearoyl- sn -glycero-3-phosphoethanolamine (DSPE). This formulation called secretory phospholipase responsive liposomes, or SPRL, was demonstrated to have increased efficacy in vitro and in vivo [ 34 , 35 ]. We further demonstrated that the increased efficacy was due, in part, to the increased selectivity for sPLA 2 [ 34 ], which was conferred by the inclusion of the anionic DSPE ( Table 1 ) [ 36 ].…”

“…This formulation called secretory phospholipase responsive liposomes, or SPRL, was demonstrated to have increased efficacy in vitro and in vivo [ 34 , 35 ]. We further demonstrated that the increased efficacy was due, in part, to the increased selectivity for sPLA 2 [ 34 ], which was conferred by the inclusion of the anionic DSPE ( Table 1 ) [ 36 ]. The effect of these molecular differences between SSL and SPRL was tested in vitro and in vivo where SPRL had a greater effect on limiting the growth of prostate cancer xenografts compared to the conventional SSL [ 34 , 35 ].…”

The Use of Nanomedicine to Target Signaling by the PAK Kinases for Disease Treatment

“…PAK1 has in fact been shown to be essential for the growth of prostate cancer cells in a xenograft mouse model [ 86 , 89 ]. PAK1 contributes to prostate cancer cell growth and metastasis, due to its role in cell proliferation, survival, motility, invasion, and epithelial–mesenchymal transition (EMT) [ 90 , 91 , 92 , 93 ]. Inhibition of PAK1 is therefore promising for the treatment of this disease.…”

“…Both SSL- and SPRL-IPA3 have markedly anti-proliferative effects on murine prostate cells (RM-1 cells). However, the free IPA3 had no significant therapeutic efficacy in the transgenic adenocarcinoma of the mouse prostate mice [ 90 ]. The authors found that this nanoparticle delivery system resulted in strong efficiency both in vitro and in vivo in the prostate cancer model, and that the drug showed strong specificity.…”