Polyplexes targeted

Moffatt S, Wiehle S, Cristiano RJ (2005) Tumor-specific gene delivery mediated by a novel peptide-polyethylenimine-DNA polyplex targeting aminopeptidase N/CD13. Hum Gene Ther 16 57-67... 

Shielded polyplexes with improved blood circulating properties are interesting tools for systemic cancer therapy (see Sect. 4.2). Nanoparticles can take advantage of the enhanced permeability and retention (EPR effect) [89] for passive tumor targeting. The EPR effect is based on the leakiness of tumor vasculature, due to neovascularization in growing tumors, combined with an inadequate lymphatic drainage. Nanoparticles with an elongated plasma circulation time can extravasate and passively accumulate at the tumor site. 

The neoangiogenic tumor vasculature overexpresses certain integrins and other surface markers, which can also be used for targeting of polyplexes. The RGD peptide motif has been successfully applied for integrin-targeted pDNA [125-128] and siRNA [129, 130] delivery. In many cases, the PEG motif-containing peptide was attached to the polycation via a PEG spacer. For RGD-PEG-PEI/pDNA polyplexes, an optimum grafting with RGD-PEG was required because transfection... 

A highly stable and shielded polyplex should circulate in the blood stream without undesired interactions until it reaches the target cell. At that location, specific interactions with the cell surface should trigger intracellular uptake. While lipid membrane interaction is undesired at the cell surface, it should happen subsequently within the endosomal vesicle and mediate polyplex delivery into the cytosol. During or after intracellular transport to the site of action, the polyplex stability should be weakened to an extent that the nucleic acid is accessible to exert its function. 

Since the design of the first targeted polyplexes more than 20 years ago [97, 134], numerous efforts have been made to develop polyplexes for use in medical products, both in pharmacological animal studies and in human studies. Therapeutic modalities include ex vivo treatment of isolated human patient cells, localized in vivo treatments, and - currently the most challenging delivery scenario - in vivo targeted intravenous 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. 

Various researchers have applied the receptor-targeted strategy in pharmacological models for tumor-targeted delivery of pDNA expressing tumor necrosis factor alpha (TNFa). For example, Tf- or Tf-PEG-shielded PEI polyplexes have been used... 

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]. 

Ogris M, Wagner E (2002) Tumor-targeted gene transfer with DNA polyplexes. Somat Cell Mol Genet 27 85-95... 

Wagner E, Culmsee C, Boeckle S (2005) Targeting of polyplexes toward synthetic virus... 

Nie Y, Schaffert D, Roedl W, Ogris M, Wagner E, Guenther M (2011) Dual-targeted polyplexes one step towards a synthetic virus for cancer gene therapy. J Control Release 152 127-134. doi 10.1016/j.jconrel.2011.02.028... 

Boeckle S, Fahrmeir J, Roedl W, Ogris M, Wagner E (2006) Melittin analogs with high lytic activity at endosomal pH enhance transfection with purified targeted PEI polyplexes. J Control Release 112 240-248... 

Figuer 9.1 Schematic illustration of various polycation structures used for preparation of polyplexes (A) linear (PEI) (B) randomly branched (PEI) (C) dendrimer (PAMAM) (D) block and graft copolymers (Pluronic-g-PEI and PEO-g-PEI modified with a targeting moiety by one PEO end) (E) nanoscale cross-linked network (PEO-c7-PEI). 

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