Polymer-based nonviral vectors

Lipid- and polymer-based nonviral vectors for systemic siRNA and DNA delivery... 

Table 14.1 Current clinical trials using lipid- and polymer-based nonviral vectors containing siRNA (identification numbers of tbe clinical trial from bt s //clinicaltrials.gov/)... 

Despite the recent advances in the development of polymer-based nonviral vectors for siRNA or DNA delivery, the number of formulations that entered clinical trials has been substantially lower than lipid-based nonviral vectors. In this respect, the first-inhuman trial for siRNA delivery was a transferrin-targeted cyclodextrin, CALAA-01 (Fonseca et al., 2014). In 2008, Calando Pharmaceuticals (now part of Arrowhead Research Corporation) started a phase 1 clinical trial with CALAA-01 for the treatment of melanoma (Zuckerman et al., 2014). The rationale relied on the dowmegula-tion of ribonuclease reductase (RRM2) upon transferrin-mediated endocytosis of the siRNA-containing nanoparticle (Zuckerman et al., 2014). However, this nanoparticle was further withdrawn (Fonseca et al., 2014). 

Nonviral vector systems are usually either composed of a plasmid based expression cassette alone ( naked DNA), or are prepared with a synthetic amphipathic DNA-complexing agent (84, 88). Gene delivery systems based on nonviral vectors mainly comprise cationic liposomes, DNA-polymer-protein complexes, and mechanic administration of naked DNA. An idealized/optimized multifunctional nonviral gene delivery system is depicted in Figure 13.4. 

This section will focus primarily on the development of nonviral vectors that are based on surfactants, phospholipids, and natural or synthetic polymers for their application to the delivery of macromolecules, mainly of genetic materials such as DNA or RNA. Development of safe and efficient vectors will expedite the success of human gene therapy, which has captured the attention recently of the public and the biomedical research community. Even though more and more new delivery vectors are being introduced into the scientific milieu with enhanced efficiency, it should be emphasized that safety always goes first, especially after the tragedy of J. Gelsinger in 1999. 

PLL and its derivatives have not been as extensively used in vivo as other cationic polymers to deliver therapeutically relevant genes however, they have found some success in systemic delivery to the liver [141] and matrix-based delivery to enhance angiogenesis [120]. Tables 7.3-5,7.3-6 (systemic), and 7.3-7 (matrix) summarize the in vivo studies involving nonviral vectors and their therapeutic outcome. 

Among the several types of nonviral or synthetic vectors in use, cationic lipids have perhaps been the most widely studied to date. The reader is referred to recent reviews for additional information (5,6). Other cationic systems such as those based on cationic polymers, for example, poly-L-lysine and polyethyleneimine (PEI), share many of the properties of the cationic lipid systems, but they will not be described here. The reader is referred to recent reviews on... 

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