Novel Ran-RCC1 Inhibitory Peptide-Loaded Nanoparticles Have Anti-Cancer Efficacy In Vitro and In Vivo.

Yusuf Haggag,Mohammad Isreb,Paul Mccarron,Mohamed El-Tanani,Jason Jones,Robert Falconer,Ahmed Faheem,Kyle Matchett

doi:10.3390/cancers11020222

Abstract

The delivery of anticancer agents to their subcellular sites of action is a significant challenge for effective cancer therapy. Peptides, which are integral to several oncogenic pathways, have significant potential to be utilised as cancer therapeutics due to their selectivity, high potency and lack of normal cell toxicity. Novel Ras protein-Regulator of chromosome condensation 1 (Ran-RCC1) inhibitory peptides designed to interact with Ran, a novel therapeutic target in breast cancer, were delivered by entrapment into polyethylene glycol-poly (lactic-co-glycolic acid) PEG-PLGA polymeric nanoparticles (NPs). A modified double emulsion solvent evaporation technique was used to optimise the physicochemical properties of these peptide-loaded biodegradable NPs. The anti-cancer activity of peptide-loaded NPs was studied in vitro using Ran-expressing metastatic breast (MDA-MB-231) and lung cancer (A549) cell lines, and in vivo using Solid Ehrlich Carcinoma-bearing mice. The anti-metastatic activity of peptide-loaded NPs was investigated using migration, invasion and colony formation assays in vitro. A PEG-PLGA-nanoparticle encapsulating N-terminal peptide showed a pronounced antitumor and anti-metastatic action in lung and breast cancer cells in vitro and caused a significant reduction of tumor volume and associated tumor growth inhibition of breast cancer model in vivo. These findings suggest that the novel inhibitory peptides encapsulated into PEGylated PLGA NPs are delivered effectively to interact and deactivate Ran. This novel Ran-targeting peptide construct shows significant potential for therapy of breast cancer and other cancers mediated by Ran overexpression.

Highlights

Metastasis is the major cause of cancer-related morbidity and mortality
The involvement of Ran in the development and progression of breast cancer has been described to be due to its complex mechanisms enabling tumorigenesis and metastasis
An optimized nanoparticle formulation has shown significant cytotoxic effects in metastatic cancer (MDA-MB-231 and A549) cells compared to free peptide

Summary

Introduction

Metastasis is the major cause of cancer-related morbidity and mortality. Approximately 7 million people die from cancer-related cases per year and it is predicted that there will be more than 16 million new cancer patients every year by 2020 [1].The eukaryotic cell Ran is a small GTPase of the Ras superfamily, which has been shown to be essential for directing nucleocytoplasmic transport, mitotic spindle fiber assembly and post-mitotic nuclear envelope dynamics [2]. Metastasis is the major cause of cancer-related morbidity and mortality. Ran in fibroblasts induces cellular transformation and tumor formation in mice [3]. Ran has been reported to be overexpressed in a wide range of human tumor types and cancer cell lines [4]. Overexpression of Ran was shown to stimulate anchorage-independent growth in a non-invasive mammary cell line, cell attachment and invasion through Matrigel® in vitro, and metastasis in syngeneic rats in vivo. Ran functions as a novel effector of osteopontin-mediated malignant transformation. RAN GTPase (RAN) is one of the genes whose expression is substantially increased in relation to overexpression of osteopontin [5,6]. Ran has been shown to be a potential therapeutic target for cancer treatment [7]

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