Nanoparticle-based targeted gene therapy for lung cancer

Abstract

Despite striking insights on lung cancer progression, and cutting-edge therapeutic approaches the survival of patients with lung cancer, remains poor. In recent years, targeted gene therapy with nanoparticles is one of the most rapidly evolving and extensive areas of research for lung cancer. The major goal of targeted gene therapy is to bring forward a safe and efficient treatment to cancer patients via specifically targeting and deterring cancer cells in the body. To achieve high therapeutic efficacy of gene delivery, various carriers have been engineered and developed to provide protection to the genetic materials and efficient delivery to targeted cancer cells. Nanoparticles play an important role in the area of drug delivery and have been widely applied in cancer treatments for the purposes of controlled release and cancer cell targeting. Nanoparticles composed of artificial polymers, proteins, polysaccharides and lipids have been developed for the delivery of therapeutic deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) sequences to target cancer. In addition, the effectiveness of cancer targeting has been enhanced by surface modification or conjugation with biomolecules on the surface of nanoparticles. In this review article we provide an overview on the latest developments in nanoparticle-based targeted gene therapy for lung cancers. Firstly, we outline the conventional therapies and discuss strategies for targeted gene therapy using nanoparticles. Secondly, we provide the most representative and recent researches in lung cancers including malignant pleural mesothelioma, mainly focusing on the application of Polymeric, Lipid-based, and Metal-based nanoparticles. Finally, we discuss current achievements and future challenges.

Keywords: EphA2; EphrinA1; Lung cancer; malignant mesothelioma; nanoparticles; targeted gene therapy.

Figure 1

Nanoparticle targeting mechanisms. A. Nanoparticles perform nonspecific passive targeting by diffusing and aggregating through leaky vessel in solid tumors via EPR effect. B. Nanoparticles modified with targeting agents perform active targeting on tumor cells expressing specific receptors. Nanoparticles specifically target on metastatic cancer cells. C. Fate of nanoparticles in non-specific gene delivery: phagocytosis, decomposition of nanoparticles outside of cells, and for the lipid or surfactant-based nanoparticles, the nanoparticles infuse into the cell membrane bilayers for drug release. D. Nanoparticles modified with targeting ligands specifically bind onto the membrane receptor and induce endocytosis. Higher proportion of gene molecules may eventually enter into nucleus.

Figure 2

Gene molecules carried by nanoparticles in three different forms: Gene molecules are (A) encapsulated inside nanoparticles, (B) forming complexes through ionic interactions with nanoparticles, and (C) loaded on the surface via conjugation or modified-polymer trapping.

Figure 3

Schematic presentation of Combination therapy of ligand protein and miRNA using nanoliposomes for NSCLC and MPM over-expressing EphA2. A. The ligand proteins, ephrin-A1, were conjugated with miR-Let-7a encapsulated nanoliposomes via the reaction between amines on proteins and cyanuric chlorides on PEGylated lipids. The ephrin-A1, ligand of EphA2 receptor acts as targeting and therapeutic agents in the complex system. B. The miR-Let-7a/liposome/ephrinA1 complex system suppresses tumor growth through ephrin-A1/EphA2 binding and intracellular release of miR-Let-7a. The binding of ephrin-A1 leads to phosphorylation of EphA2 and inhibits the RAS pathway. In one of the signaling pathways, the activation of EphA2 induces miR-Let-7a which inhibits RAS signaling. Combined with ligand proteins, the extrinsic miR-Let-7a were delivered intracellularly majorly through endocytosis of nanoliposomes to enhance therapeutic effectiveness. BBS= borate buffered saline; TK= tyrosine kinase domain; PDZ= PDZ-binding motif; P= phosphorylation; ┴= inhibition [1-3].