RNA interference in the mouse vascular endothelium by systemic administration of siRNA-lipoplexes for cancer therapy

Abstract

RNA interference (RNAi) entails the potential for novel therapeutic strategies through the silencing of disease-causing genes in vivo. However, recent studies have raised an issue regarding applicable routes of administration for small interfering RNA (siRNA) molecules as therapeutics. In this study, we demonstrate that liposomally formulated siRNA molecules, the so-called siRNA-lipoplexes, but not naked siRNAs, are delivered to the tumor endothelial cells in vivo by microscopy. In addition, functional intracellular delivery of formulated siRNA targeting the tumor suppressor PTEN is shown in endothelial cells of the liver and tumor. Finally, the therapeutic potential of systemically administered siRNA CD31 -lipoplexes is established by inhibition of tumor growth in two different xenograft mouse models. Our findings corroborate the applicability of this liposomal siRNA delivery technology for inducing RNAi to modulate gene expression levels in angiogenesis-dependent processes. In addition, our results advocate CD31 as a promising therapeutic target for antiangiogenic intervention. Therefore, our study provides a basis for the development of antiangiogenic cancer therapies based on RNAi.

The Business of RNAi Therapeutics

“…This multilamellar, positively charged, lipid-based formulation has proven useful for knocking down genes in the vascular endothelium in small and large animal models. 19 The pharmacokinetic and safety data that emerges from the ongoing Atu027 trial (e.g., ASCO 2011 poster presentation) indicate this also likely to be the case in humans. With applications particularly in oncology (antiangiogenesis) and acute inflammatory conditions (the vascular endothelium as a barrier to inflammatory cell infiltration), this technology has garnered increased partnership interest.…”

Systemic delivery of siRNA specific to tumor mediated by atelocollagen: Combined therapy using siRNA targeting Bcl‐xL and cisplatin against prostate cancer

“…4 The other obstacles to the delivery of siRNAs in vivo, such as degradation by nuclease(s) in blood and interaction with blood components, indeed exist. 5 To overcome these obstacles, many delivery systems, such as hydrodynamic approaches 6 and bioconjugating approaches including cationic liposomes, 7 cationic polymers, 8 and cell penetrating peptides, 9 have been developed. However, thus far there is little conclusive method.…”

RNAi-based Cancer Therapeutics: Are we there yet?

“…Various promising nanoparticles (NPs) strategies that have been successful in depicting in vitro gene silencing and tumor reduction efficacy in animal models, safety in non-human primates and in few cases, have undergone clinical trial testing include, (A) Lipid based NPs: liposomes [16], lipoplexes [17,18], stable nucleic acid lipid nanoparticles (SNALP) [19,20] & lipidoid [21], polycation liposomes [22,23], (B) Polymeric NPs: both natural and synthetic, includes cyclodextrin [24], chitosan [25], PLGA [26], polymeric micelles [27], PEI [28] & dendrimers [29], (C) Inorganic NPs: calcium phosphate CaP [30], (D) Carbon-based materials, carbon nanotubes (SWNTs, MWNTs) [31,32], (E) Metal nanoparticles -Gold (Au) [33], Quantum dots (QDs) [34], silicon-based nanoparticles (MSNPs) [35] & super paramagnetic iron oxide nanoparticles (SPIONs) [36] etc. In addition to this, atelocollagen-based delivery strategy also proved to be successful in few cases [37,38].…”