Comparison of Polymeric siRNA Nanocarriers in a Murine LPS-Activated Macrophage Cell Line: Gene Silencing, Toxicity and Off-Target Gene Expression

Jensen, Linda; Griger, Joscha; Naeye, Broes; Varkouhi, Amir K.; Raemdonck, Koen; Schiffelers, Raymond M.; Lammers, Twan; Storm, Gert; Smedt, Stefaan C. De; Sproat, Brian S.; Nielsen, Hanne Mørck; Foged, Camilla

doi:10.1007/s11095-011-0589-0

Cited by 38 publications

(27 citation statements)

References 63 publications

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“…Transfection experiments were performed essentially as previously described 14 . In brief, cells were seeded in 6-well culture plates at a density of 1 × 10 6 cells per well in full culture medium and left overnight.…”

Section: Cell Transfectionmentioning

confidence: 99%

Anti-Inflammatory Effect of Anti-TNF-α SiRNA Cationic Phosphorus Dendrimer Nanocomplexes Administered Intranasally in a Murine Acute Lung Injury Model

et al. 2017

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Inflammation is an essential component of many lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), or acute lung injury. Our purpose was to design efficient carriers for lung delivery of small interfering RNA (siRNA) targeting tumor necrosis factor (TNF-α) in an acute lung injury model. To achieve this goal, two different types of phosphorus-based dendrimers with either pyrrolidinium or morpholinium as terminal protonated amino groups were selected for their better biocompatibility compared to other dendrimers. Dendriplexes containing pyrrolidinium surface groups demonstrated a stronger siRNA complexation, a higher cellular uptake, and enhanced in vitro silencing efficiency of TNF-α in the lipopolysaccharide (LPS)-activated mouse macrophage cell line RAW264.7, compared to morpholinium-containing dendriplexes. The better performance of the pyrrolidium dendriplexes was attributed to their higher pK value leading to a stronger siRNA complexation and improved protection against enzymatic degradation resulting in a higher cellular uptake. The superior silencing effect of the pyrrolidinium dendriplexes, compared to noncomplexed siRNA, was confirmed in vivo in an LPS-induced murine model of short-term acute lung injury upon lung delivery via nasal administration. These data suggest that phosphorus dendriplexes have a strong potential in lung delivery of siRNA for treating inflammatory lung diseases.

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Section: Cell Transfectionmentioning

confidence: 99%

Anti-Inflammatory Effect of Anti-TNF-α SiRNA Cationic Phosphorus Dendrimer Nanocomplexes Administered Intranasally in a Murine Acute Lung Injury Model

et al. 2017

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“…Examples include a new acid-degradable poly(ketal amidoamine) (PKKA) carrier, which was successfully tested in an acetaminophen-induced liver failure rat model [93], and polyamidoamine (PAMAM) dendrimers and dextran nanogels, which were assayed in vitro in LPS-activated RAW 264.7 macrophages with promising results [94]. …”

Section: Delivering Molecules To Control Macrophage Polarizationmentioning

confidence: 99%

Delivery strategies to control inflammatory response: Modulating M1–M2 polarization in tissue engineering applications

Álvarez

Liu

Santiago

et al. 2016

Journal of Controlled Release

203

119

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Macrophages are key players in many physiological scenarios including tissue homeostasis. In response to injury, typically the balance between macrophage sub-populations shifts from an M1 phenotype (pro-inflammatory) to an M2 phenotype (anti-inflammatory). In tissue engineering scenarios, after implantation of any device, it is desirable to exercise control on this M1-M2 progression and to ensure a timely and smooth transition from the inflammatory to the healing stage. In this review, we briefly introduce the current state of knowledge regarding macrophage function and nomenclature. Next, we discuss the use of controlled release strategies to tune the balance between the M1 and M2 phenotypes in the context of tissue engineering applications. We discuss recent literature related to the release of anti-inflammatory molecules (including nucleic acids) and the sequential release of cytokines to promote a timely M1-M2 shift. In addition, we describe the use of macrophages as controlled release agents upon stimulation by physical and/or mechanical cues provided by scaffolds. Moreover, we discuss current and future applications of “smart” implantable scaffolds capable of controlling the cascade of biochemical events related to healing and vascularization. Finally, we provide our opinion on the current challenges and the future research directions to improve our understanding of the M1-M2 macrophage balance and properly exploit it in tissue engineering and regenerative medicine applications.

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“…In the latter report, colloidally stable PScoated and siRNA-loaded dextran nanogels were constructed. The high siRNA delivery efficiency of the nanogels had previously been established in various cell lines in vitro [99][100][101][102].…”

Section: The Interplay Between Pulmonary Surfactant and Nanoparticlesmentioning

confidence: 99%

Bio-inspired materials in drug delivery: Exploring the role of pulmonary surfactant in siRNA inhalation therapy

Backer

Cerrada²,

Pérez‐Gil³

et al. 2015

Journal of Controlled Release

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Many pathologies of the respiratory tract are inadequately treated with existing small molecule-based therapies. The emergence of RNA interference (RNAi) enables the post-transcriptional silencing of key molecular disease factors that cannot readily be targeted with conventional small molecule drugs. Pulmonary administration of RNAi effectors, such as small interfering RNA (siRNA), allows direct delivery into the lung tissue, hence reducing systemic exposure. Unfortunately, the clinical translation of RNAi is severely hampered by inefficient delivery of siRNA therapeutics towards the cytoplasm of the target cells. In order to have a better control of the siRNA delivery process, both extra- and intracellular, siRNAs are typically formulated in nanosized delivery vehicles (nanoparticles, NPs). In the lower airways, which are the targeted sites of action for multiple pulmonary disorders, these siRNA-loaded NPs will encounter the pulmonary surfactant (PS) layer, covering the entire alveolar surface. The interaction between the instilled siRNA-loaded NPs and the PS at this nano-bio interface results in the adsorption of PS components onto the surface of the NPs. The formation of this so-called biomolecular corona conceals the original NP surface and will therefore profoundly determine the biological efficacy of the NP. Though this interplay has initially been regarded as a barrier towards efficient siRNA delivery to the respiratory target cell, recent reports have illustrated that the interaction with PS might also be beneficial for local pulmonary siRNA delivery.

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Comparison of Polymeric siRNA Nanocarriers in a Murine LPS-Activated Macrophage Cell Line: Gene Silencing, Toxicity and Off-Target Gene Expression

Abstract: Dextran nanogels and PAMAM dendrimers mediated high gene silencing with minor toxicity and off-target transcriptional changes and are therefore expected to be suitable siRNA delivery systems in vivo.

Cited by 38 publications

References 63 publications

Anti-Inflammatory Effect of Anti-TNF-α SiRNA Cationic Phosphorus Dendrimer Nanocomplexes Administered Intranasally in a Murine Acute Lung Injury Model

Anti-Inflammatory Effect of Anti-TNF-α SiRNA Cationic Phosphorus Dendrimer Nanocomplexes Administered Intranasally in a Murine Acute Lung Injury Model

Delivery strategies to control inflammatory response: Modulating M1–M2 polarization in tissue engineering applications

Bio-inspired materials in drug delivery: Exploring the role of pulmonary surfactant in siRNA inhalation therapy

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