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Dual-targeting pro-apoptotic peptide for programmed cancer cell death via specific mitochondria damage.

ABSTRACT: Mitochondria are vital organelles to eukaryotic cells. Damage to mitochondria will cause irreversible cell death or apoptosis. In this report, we aim at programmed cancer cell death via specific mitochondrial damage. Herein, a functionalized pro-apoptotic peptide demonstrates a dual-targeting capability using folic acid (FA) (targeting agent I) and triphenylphosphonium (TPP) cation (targeting agent II). FA is a cancer-targeting agent, which can increase the cellular uptake of the pro-apoptotic peptide via receptor-mediated endocytosis. And the TPP cation is the mitochondrial targeting agent, which specifically delivers the pro-apoptotic peptide to its particular subcellular mitochondria after internalized by cancer cells. Then the pro-apoptotic peptide accumulates in mitochondria and causes its serious damage. This dual-targeting strategy has the potential to effectively transport the pro-apoptotic peptide to targeted cancer cell mitochondria, inducing mitochondrial dysfunction and triggering the mitochondria-dependent apoptosis to efficiently eliminate cancer cells.

SUBMITTER: Chen WH

PROVIDER: S-EPMC3863817 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Dual-targeting pro-apoptotic peptide for programmed cancer cell death via specific mitochondria damage.

Chen Wei-Hai WH Xu Xiao-Ding XD Luo Guo-Feng GF Jia Hui-Zhen HZ Lei Qi Q Cheng Si-Xue SX Zhuo Ren-Xi RX Zhang Xian-Zheng XZ

Scientific reports 20131216

Mitochondria are vital organelles to eukaryotic cells. Damage to mitochondria will cause irreversible cell death or apoptosis. In this report, we aim at programmed cancer cell death via specific mitochondrial damage. Herein, a functionalized pro-apoptotic peptide demonstrates a dual-targeting capability using folic acid (FA) (targeting agent I) and triphenylphosphonium (TPP) cation (targeting agent II). FA is a cancer-targeting agent, which can increase the cellular uptake of the pro-apoptotic p ...[more]

PMID: 24336626

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Project description:Gastrointestinal and gynecological malignancies disseminate in the peritoneal cavity - a condition known as peritoneal carcinomatosis (PC). Intraperitoneal (IP) administration can be used to improve therapeutic index of anticancer drugs used for PC treatment. Activity of IP anticancer drugs can be further potentiated by encapsulation in nanocarriers and/or affinity targeting with tumor-specific affinity ligands, such as tumor homing peptides. Here we evaluated a novel tumor penetrating peptide, linTT1 (AKRGARSTA), as a PC targeting ligand for nanoparticles. We first demonstrated that the primary homing receptor for linTT1, p32 (or gC1qR), is expressed on the cell surface of peritoneal carcinoma cell lines of gastric (MKN-45P), ovarian (SKOV-3), and colon (CT-26) origin, and that peritoneal tumors in mice and clinical peritoneal carcinoma explants express p32 protein accessible from the IP space. Iron oxide nanoworms (NWs) functionalized with the linTT1 peptide were taken up and routed to mitochondria in cultured PC cells. NWs functionalized with linTT1 peptide in tandem with a pro-apoptotic [D(KLAKLAK)2] peptide showed p32-dependent cytotoxicity in MKN-45P, SKOV-3, and CT-26 cells. Upon IP administration in mice bearing MKN-45P, SKOV-3, and CT-26 tumors, linTT1-functionalized NWs showed robust homing and penetration into malignant lesions, whereas only a background accumulation was seen in control tissues. In tumors, the linTT1-NW accumulation was seen predominantly in CD31-positive blood vessels, in LYVE-1-positive lymphatic structures, and in CD11b-positive tumor macrophages. Experimental therapy of mice bearing peritoneal MKN-45P xenografts and CT-26 syngeneic tumors with IP linTT1-D(KLAKLAK)2-NWs resulted in significant reduction of weight of peritoneal tumors and significant decrease in the number of metastatic tumor nodules, whereas treatment with untargeted D(KLAKLAK)2-NWs had no effect. Our data show that targeting of p32 with linTT1 tumor-penetrating peptide improves tumor selectivity and antitumor efficacy of IP pro-apoptotic NWs. P32-directed intraperitoneal targeting of other anticancer agents and nanoparticles using peptides and other affinity ligands may represent a general strategy to increase their therapeutic index.

Dataset Information

Dual-targeting pro-apoptotic peptide for programmed cancer cell death via specific mitochondria damage.

Publications

Dual-targeting pro-apoptotic peptide for programmed cancer cell death via specific mitochondria damage.

Similar Datasets

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