In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight

Abstract

Dysfunctional endothelium contributes to more disease than any other tissue in the body. Small interfering RNAs (siRNAs) have the potential to help study and treat endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here we show that polymeric nanoparticles made of low molecular weight polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo. Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. It mediates the most durable non-liver silencing reported to date, and facilitates the delivery of siRNAs that modify endothelial function in mouse models of vascular permeability, emphysema, primary tumour growth, and metastasis. We believe these nanoparticles improve the ability to study endothelial gene function in vivo, and may be used to treat diseases caused by vascular dysfunction.

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

“…Instead of using transfection reagents, LPNPs serve as the packaging and delivery vehicle by shielding the negative charge of the siRNA duplex while offering the benefits of low toxicity and decreased liver targeting and kidney clearance when given systemically in the blood stream (23). To examine the feasibility of using LPNPs to deliver RNAi to BTICs and potentially to a tumor-associated microenvironment such as tumor-associated blood vessels, in vitro knockdown of the four master TF mRNAs was performed using 7C1 LPNPs formulated with a combination of siRNAs.…”

“…conjugating epoxide-terminated lipids to low-molecular-weight polyamines with an epoxide ring-opening reaction (23). The resultant nano constructs then were evaluated for their ability to complex with siRNA and knock down gene expression in vitro.…”

“…The most effective candidates were selected after in vivo assessment. One compound, named "7C1," was identified from a library of more than 500 candidate delivery materials as the most effective in silencing target genes in vasculature, with a higher performance per dose ratio than previously reported siRNA nano delivery vehicles (15,23). The capacity to multitarget and the ease of synthesis make 7C1 an attractive therapeutic vehicle for antitumor RNAi.…”

Translational Advances in the Field of Pulmonary Hypertension.Translating MicroRNA Biology in Pulmonary Hypertension. It Will Take More Than “miR” Words

“…Preferential targeting of the pulmonary endothelium rather than the systemic endothelium has been demonstrated and promoted using different nanoparticle-based oligonucleotide delivery partners (86). Multiple strategies for proprietary modifications of the nucleotide backbone provide resistance to degradation in vivo, and provide the means to improve stability and efficacy.…”

Chemical materials and their regulation of the movement of molecules

“…Approaches like those discussed above are not only be useful for DNA delivery, but for new methods of gene therapy such as RNAi (RNA interference) as well. In particular with Dan Anderson, we have created libraries of thousands of lipids and they are being used as delivery systems for RNAi (Akinc et al 2008;Dahlman et al 2014).…”