Efficient Delivery of Oncolytic Peptide LTX-315 by ZIF-8: pH-Responsive Release, Improved Stability, and Reduced Hemolysis

The first-in-class oncolytic peptide LTX-315 has exhibited positive anticancer responses in multiple phase I/II clinical trials. Nevertheless, the linear peptide LTX-315 suffers from poor proteolytic stability and undesired toxicity, especially hemolysis, which may limit its widespread applications. Except for the direct structural modifications, drug delivery systems (DDSs) are expected to protect LTX-315 from degradation and shield its hemolytic properties. Therefore, the LTX-315 and zeolitic imidazolate framework (ZIF-8)-based nanoparticles (NPs) were constructed with a high LTX-315 encapsulation rate of 59.9%, utilizing the biomineralized "one-pot method" in an aqueous system. The release of LTX-315, in vitro anticancer potency, serum stability, anticancer durability, antimigration activity, hemolysis effect, subcellular localization, and the membrane disruption/permeation effects of LTX-315@ZIF-8 NPs were investigated. LTX-315@ZIF-8 NPs exhibited potent cytotoxicity against cancer cells. The serum stability experiment and time-inhibition curve assay indicated that ZIF-8 NPs could effectively improve the stability of LTX-315, prolong the duration of anticancer action, and enhance the cytostatic potency. Especially, the LTX-315@ZIF-8 NPs not only effectively attenuated the hemolytic toxicity of LTX-315 but also achieved the pH-responsive release of LTX-315. The mechanism investigation indicated that LTX-315@ZIF-8 NPs possessed potent membranolytic activity and reduced the mitochondrial membrane potential to trigger cell death. Collectively, this paper not only established a robust strategy to improve the stability and reduce the hemolytic properties of LTX-315 but also provided a reliable reference for the future delivery of oncolytic peptides.