Progress in developing cationic vectors for non-viral systemic gene therapy against cancer

Abstract

Initially, gene therapy was viewed as an approach for treating hereditary diseases, but its potential role in the treatment of acquired diseases such as cancer is now widely recognized. The understanding of the molecular mechanisms involved in cancer and the development of nucleic acid delivery systems are two concepts that have led to this development. Systemic gene delivery systems are needed for therapeutic application to cells inaccessible by percutaneous injection and for multi-located tumor sites, i.e. metastases. Non-viral vectors based on the use of cationic lipids or polymers appear to have promising potential, given the problems of safety encountered with viral vectors. Using these non-viral vectors, the current challenge is to obtain a similarly effective transfection to viral ones. Based on the advantages and disadvantages of existing vectors and on the hurdles encountered with these carriers, the aim of this review is to describe the "perfect vector" for systemic gene therapy against cancer.

Different strategies of gene delivery for treatment of cancer and other disorders

“…The studies showed that the transfection efficiency by high generation dendrimers is higher than low generation dendrimers. [35] Polyamidoamine (PAMAM) dendrimers, the hydrophilic branched spherical polymers, have produced very stable and highly soluble DNA complexes. [5,29] The efficiency of this gene delivery could be enhanced by dendrimer flexibility using a triethanolamine core.…”

“…[5] For improving transfection efficiency, cationic lipids are often mixed with helper lipids such as cholesterol or DOPE (1, 2-dioleyl-sn-glycerol-3-phosphoethanolamine) potentially promoting conversion of the lamellar lipoplex phase into a hexagonal structure. [35] The lipoplexes enter cells via the endocytotic pathway and effectively protect the foreign DNA from the degradation within cells. Targeted transfection can be increased by the addition of tissue-specific target ligand and the applications of proteoglycans in this process.…”

A review of RGD-functionalized nonviral gene delivery vectors for cancer therapy

“…In particular, cationic lipids and cationic polymers have gained great interest for their abilities to form a complex with negatively-charged therapeutic genes, to protect genes, and to achieve effective cell entry. [25][26][27][28] Furthermore, the integration of inorganic nanomaterials with cationic polymers creates hybrid vectors that allow not only easy incorporation of genetic materials through electrostatic interactions but also further modifications to be upgraded for image-guided gene delivery with enhanced transgene efficiencies. [29][30][31] Nonetheless, the transfection efficiency of nonviral vectors is significantly lower than that of viral vectors.…”

Incorporation of a Nuclear Localization Signal in pH Responsive LAH4-L1 Peptide Enhances Transfection and Nuclear Uptake of Plasmid DNA

“…1,3,4 Upon cell entry, non-viral delivery systems usually face two major intracellular barriers: (i) endosomal/lysosomal degradation; and (ii) poor nuclear entry. Therefore, the efficiency of a non-viral vector highly depends on its ability to promote endosomal/lysosomal escape and nuclear uptake.…”

“…The β-subunit mediates the interaction with the NPC to facilitate the translocation of the trimeric complex into the nucleus. 3,6,[12][13][14] Other classical NLSs include the nucleoplasmin targeting signal, which is a representative of bipartite NLSs and contains two interdependent basic amino acid clusters separated by 10 intervening neutral amino acids. Similar to SV40 derived NLS, the nucleoplasmin targeting signal also facilitates the nuclear entry of macromolecules by the importin α/β heterodimer.…”