Secretory phospholipase A2 as a tumor-specific trigger for targeted delivery of a novel class of liposomal prodrug anticancer etherlipids

Abstract

The use of many common clinically relevant chemotherapeutics is often limited due to insufficient delivery to the tumor and dose-limiting systemic toxicities. Therefore, therapeutics that specifically target tumor cells and are nontoxic to normal cells are required. Here, we report the development of a novel class of liposomes composed of lipid prodrugs, which use the increased secretory phospholipase A2 type IIA (sPLA2) activity of the tumor microenvironment as a trigger for the release of anticancer etherlipids (AEL). Treatment of sPLA2-secreting tumor cells in vitro with liposomes consisting of proAELs resulted in growth inhibition comparable with addition of the AELs alone. Using a specific sPLA2 inhibitor, we showed the low cytotoxicity of the nonhydrolyzed proAEL liposomes and have proven the sPLA2 dependency of the activation of proAELs to cytotoxic AELs. In addition, we showed that our proAEL liposomes circumvent the inherent hemolytic toxicities associated with the use of etherlipids, thereby allowing i.v. administration of such therapeutics as nontoxic prodrug liposomes. Furthermore, using a sPLA2-secreting human colon cancer xenograft model, we showed that the proAEL liposomes are capable of inducing a tumor growth delay in vivo. Taken together, these data support the validity of this novel tumor-selective liposomal prodrug delivery strategy. This new approach also provides a promising system for tumor-selective delivery and release of conventional chemotherapeutics encapsulated in the sPLA2-degradable prodrug liposomes.

19F MRI Nanoprobes for the Turn-On Detection of Phospholipase A2 with a Low Background

“…Then, we chose the Colo205 xenograft tumor model to test the feasibility of the nanoprobes for the detection of endogenous PLA2. Previous studies suggested that PLA2 was overexpressed in the Colo205 xenograft tumor model. − As shown in Figure a, 1 h postinjection, the 19 F MRI signal could be observed with low intensity, which became much stronger 3 h postinjection. Meanwhile, similar experiments were carried out with a healthy mouse.…”

Enzyme-Responsive Liposomes for the Delivery of Anticancer Drugs

“…AELs exhibit cytotoxicity and inhibit cell growth. , However, the toxicity of AELs is limited to the target site because a high concentration of sPLA 2 (enough for degradation of liposomes) is found only in the tumor site. It has also been demonstrated that proAEL liposomes lacked hemolytic effect and systemic toxicity compared to a potent AEL (ET-18-OCH 3 ) in vivo and in vitro. , …”

“…It has also been demonstrated that proAEL liposomes lacked hemolytic effect and systemic toxicity compared to a potent AEL (ET-18-OCH 3 ) in vivo and in vitro. 75,76 Overall, liposomes are good carriers for targeted delivery of lipid-based prodrugs to tumor sites. Prodrugs are converted into active drug at the tumor site by sPLA 2 .…”

The Role of Nanomaterials in Translational Medicine

“…To address this issue, liposomes were fabricated with an enzymatically degradable unit sensitive to phospholipase A 2 , which exists in high concentrations around tumors . The concept behind delivery of an enzymatically targeted system is intriguing, and preclinical work showed reduction in tumors with minimal side effects noted beyond weight loss (5% in the liposomal group versus 3% in the control on day 1) .…”