Enhancing in vivo circulation and siRNA delivery with biodegradable polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol) copolymers.
ABSTRACT The purpose of this study was to enhance the in vivo blood circulation time and siRNA delivery efficiency of biodegradable copolymers polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol) (hy-PEI-g-PCL-b-PEG) by introducing high graft densities of PCL-PEG chains. SYBR(®) Gold and heparin assays indicated improved stability of siRNA/copolymer-complexes with a graft density of 5. At N/P 1, only 40% siRNA condensation was achieved with non-grafted polymer, but 95% siRNA was condensed with copolymer PEI25k-(PCL570-PEG5k)(5). Intracellular uptake studies with confocal laser scanning microscopy and flow cytometry showed that the cellular uptake was increased with graft density, and copolymer PEI25k-(PCL570-PEG5k)(5) was able to deliver siRNA much more efficiently into the cytosol than into the nucleus. The in vitro knockdown effect of siRNA/hyPEI-g-PCL-b-PEG was also significantly improved with increasing graft density, and the most potent copolymer PEI25k-(PCL570-PEG5k)(5) knocked down 84.43% of the GAPDH expression. Complexes of both the copolymers with graft density 3 and 5 circulated much longer than unmodified PEI25 kDa and free siRNA, leading to a longer elimination half-life, a slower clearance and a three- or fourfold increase of the AUC compared to free siRNA, respectively. We demonstrated that the graft density of the amphiphilic chains can enhance the siRNA delivery efficiency and blood circulation, which highlights the development of safe and efficient non-viral polymeric siRNA nanocarriers that are especially stable and provide longer circulation in vivo.
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ABSTRACT: Small-interfering RNA (siRNA) is both a powerful tool in research and a promising therapeutic platform to modulate expression of disease-related genes. Malignant tumors are attractive disease targets for nucleic acid-based therapies. siRNA directed against oncogenes, and genes driving metastases or angiogenesis have been evaluated in animal models and in some cases, in humans. The outcomes of these studies indicate that drug delivery is a significant limiting factor. This review provides perspectives on in vivo validated nanoparticle-based siRNA delivery systems. Results of recent advances in liposomes and polymeric and inorganic formulations illustrate the need for mutually optimized attributes for performance in systemic circulation, tumor interstitial space, plasma membrane, and endosomes. Physiochemical properties conducive to efficient siRNA delivery are summarized and directions for future research are discussed.Journal of Pharmaceutical Innovation 06/2014; 9(2):158-173. · 1.44 Impact Factor
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ABSTRACT: RNA interference (RNAi) has been thought of as the general answer to many unmet medical needs. After the first success stories, it soon became obvious that short interfering RNA (siRNA) is not suitable for systemic administration due to its poor pharmacokinetics. Therefore local administration routes have been adopted for more successful in vivo RNAi. This paper reviews nucleic acid modifications, nanocarrier chemistry, animal models used in successful pulmonary siRNA delivery, as well as clinical translation approaches. We summarize what has been published recently and conclude with the potential problems that may still hamper the efficient clinical application of RNAi in the lung.Advanced Drug Delivery Reviews 06/2014; · 12.89 Impact Factor
Article: Quo vadis polyplex?[Show abstract] [Hide abstract]
ABSTRACT: Polymeric siRNA delivery has been an important field for the Journal of Controlled Release since the early 2000s. With currently about 1600 publications on this topic that can be found in Scopus, we have to ask ourselves why the clinical translation has been so slow. In this review we address the importance of in vivo studies, the problem of biocompatibility of the carrier systems, intracellular entrapment and endosomal release, as well as stability issues in presence of serum. Most of all, we ask the question: Quo vadis? Where do polymeric carriers go inside the cell and inside the body and how does this affect repeated administration? We show that the gap of knowledge on polymer biodistribution and excretion has not been closed yet and needs to be addressed to develop safe RNAi therapeutics.Journal of controlled release : official journal of the Controlled Release Society. 06/2014;