Tumor-targeted siRNA systemic delivery

Systemic targeting of pDNA and siRNA polyplexes has been demonstrated in several animal models. In continuation of the work with localized antiproliferative and immunostimulatory poly(I C) RNA, intravenous systemic delivery of EGER-targeted PEG-modified polyplexes were successfully used for human carcinoma treatment in mice [225]. The therapeutic effect was most pronounced when intravenous delivery of poly(I C) polyplexes was followed by intraperitoneal injection of peripheral blood mononuclear cells [226]. This induced the complete cure of SCID mice with pre-established disseminated EGFR-overexpressing tumors, without adverse toxic effects. Due to the chemokines produced by the internalized poly (I C) in the tumor cells, the immune cells home to the tumors of the treated animal and contribute to the tumor destruction. 

Tf-containing PEG-shielded polyplexes have also been applied for systemic tumor-targeted delivery of siRNA [106-108]. Systemic treatment of Neuro 2A tumorbearing mice using Tf-PEG-shielded crosslinked oligoethylenimines for delivery of siRNA against Ras-related nuclear protein (Ran) led to >80% reduced Ran protein expression, associated with tumor apoptosis and reduced tumor growth [108]. 

Wang XL, XuR, Wu X, Gillespie D, Jensen R, Lu ZR (2009) Targeted systemic delivery of a therapeutic siRNA with a multifunctional carrier controls tumor proliferation in mice. Mol Pharmaceutics 6 738-746... 

The choice between local and systemic delivery depends on what tissues and cell types are targeted. For example, skin and muscle can be better accessed using local siRNA delivery, while lung and tumor can be reached efficiently by both local and systemic siRNA deliveries. There is increasing evidence supporting that siRNA can be efficiently delivered to various tissue types, using different approaches (Fig. 3.2). 

Oe Y et al (2014) Actively-targeted polyion complex micelles stabilized by cholesterol and disulfide cross-linking for systemic delivery of siRNA to solid tumors. Biomaterials 35 7887-7895. doi 10.1016/j.biomaterials.2014.05.041... 

Transferrin-containing CD polymer-based nanoparticles were studied as nucleic acid delivery system that can be modified for targeted delivery of small interfering ribonucleic acid (siRNA) to cancer cells. Molecular studies showed that the siRNA CD nanoparticles reduced levels of Ewing s transcript by 80% and inhibited growth of cultured Ewing s tumor cell line. It was also reported that this delivery system indicated a lack of toxicity [39],... 

Fig. 5 Schematic diagram of the siRNA delivery system. A cationic group is universal in all siRNA delivery systems to condense siRNA into nanosized complex. To release the siRNA from the endosome after endocytosis, an endosomal disrupting agent is also essential. PEG modification is also important to improve the pharmacokinetic profile of the complex, as well as to avoid the nonspecific uptake by RES. To achieve the targeted delivery to tumor cells, various ligands including antibody, antibody fragments, peptides, small molecules should be modified to the complex directly or via PEG as a linker...

To develop an efficient siRNA cancer therapy, targeted delivery of siRNA to tumor cells is the primary requisite to overcome nonspecific side effects, as well as increase the therapeutic effect. Most cancer cells express unique or overexpressed receptors/antigens on their cell surface which can bind various ligands including antibodies, antibody fragments, small molecules, peptides, and aptamers. A number of tumor-specific ligands have been modified to the siRNA delivery system to enhance the specific cellular uptake in tumor cells. The most commonly used ligands are described below. 

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