Antiangiogenic gene therapy with systemically administered sFlt-1 plasmid DNA in engineered gelatin-based nanovectors

Abstract

This study examined the potential of engineered gelatin-based nanoparticulate vectors for systemic delivery of therapeutic genes to human solid tumor xenografts in vivo. Plasmid DNA encoding for the soluble form of the extracellular domain of vascular endothelial growth factor receptor-1 (VEGF-R1 or sFlt-1) was encapsulated in the control and poly(ethylene glycol) (PEG)-modified gelatin-based nanoparticles. When the plasmid DNA was delivered in PEG-modified thiolated gelatin nanoparticles, highest levels of sFlt-1 expression was observed in vitro in MDA-MB-435 human breast adenocarcinoma cell line. In addition, upon intravenous administration in female Nu/Nu mice bearing orthotopic MDA-MB-435 breast adenocarcinoma xenografts, efficient in vivo expression of sFlt-1 plasmid DNA was confirmed quantitatively by enzyme-linked immunosorbent assay and qualitatively by Western blot analysis. The expressed sFlt-1 was therapeutically active as shown by suppression of tumor growth and microvessel density measurements. The results of this study show that PEG-modified gelatin-based nanovectors can serve as a safe and effective systemically administered gene delivery vehicle for solid tumor.

Oral IL-10 gene delivery in a microsphere-based formulation for local transfection and therapeutic efficacy in inflammatory bowel disease

“…26,27 To illustrate the utility of type B gelatin nanoparticles for systemic gene therapy, we have administered reporter and therapeutic (sFlt-1 expressing) plasmid DNA in poly (ethylene glycol)-modified nanoparticles for efficient and sustained transgene expression and antiangiogenic therapeutic efficacy in solid tumor models. 19,[28][29][30] To further evaluate the potential of NiMOS in oral therapeutic gene therapy, in this study, we show local transfection of IL-10 and therapeutic efficacy in TNBSinduced acute colitis model developed in Balb/c mice. Figure 1 shows the cross-sectional schematic of NiMOS and the scanning electron microscopy (SEM) images obtained for gelatin nanoparticles.…”

Experimental therapeutic approaches to peripheral nerve tumors

“…120 Alternatively, gene-based approaches to inhibit VEGF have recently demonstrated promise. 71,172 One such approach utilized an adenovirus-mediated delivery strategy to simultaneously achieve tumor cell oncolysis and inhibition of VEGF signaling. 172 Inhibition of individual angiogenic factors may be overcome through alteration in the balance of tumor cell receptor expression and possibly through the use of alternate signaling pathways.…”

Synthesis of a novel PEGDGA-coated hPAMAM complex as an efficient and biocompatible gene delivery vector: an in vitro and in vivo study

“…Using direct administration into the body (in vivo) or transformation (ex vivo), gene therapy strategies can be successfully applied to a variety of solid tumors for various purposes, including cell growth control, allergy medication, tumor immunity induction and angiogenesis inhibition (Crystal, 1995;Kommareddy & Amiji, 2007). The major problem in systemic gene delivery is to develop a safe and effective vector system.…”