Abstract 4649: Targeting the cancer cell lysosome with transformable self-assembling peptide nanoparticles

Abstract

Abstract Lysosome-mediated cell death has recently become of great interest to the cancer community as several compounds have been shown to preferentially induce cancer cell death via lysosomal membrane permeabilization (LMP) (e.g., oleocanthal, salinomycin, and TiO2 nanoparticles). Further, many cancer cell lines that are resistant to traditional cancer therapeutics are highly susceptible to lysosome-mediated cell death. Here, we develop transformable peptide nanoparticles (NP) designed to traffic to cancer cell lysosomes, form aggregates, and induce LMP. The peptide consists of three motifs: 1) a hydrophilic, cell penetrating, and pH-responsive poly-d-Arg motif, 2) a hydrogen-bonding motif derived from beta amyloid (KLVFF); and 3) hydrophobic bis(pyrene) that fluoresces upon aggregation. The peptides initially self-assemble into NPs (50nm via TEM) in PBS, but when exposed to a lysosomal pH of 4.5, form much larger aggregates. We show that these nanoaggregates colocalize with the lysosome, leading to cell death, suggesting the induction of LMP. Moreover, utilizing bis(pyrene) we show that while these aggregates form in the lung carcinoma cell line, A549, they do not form in 3T3 fibroblasts. Additionally, we demonstrate that these nanoaggregates are highly toxic to A549 cells with IC50 in the low micromolar range (~2μM). This offers a novel organelle-specific strategy to preferentially target and kill cancer cells. Citation Format: Christopher M. Baehr, Lei Wang, Kit S. Lam. Targeting the cancer cell lysosome with transformable self-assembling peptide nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4649.