Mechanistic profiling of the release kinetics of siRNA from lipidoid-polymer hybrid nanoparticles in vitro and in vivo after pulmonary administration

Thanki, Kaushik; Eetvelde, Delphine van; Geyer, Antonia; Fraire, Juan C.; Hendrix, Remi; Eygen, Hannelore Van; Putteman, Emma; Sami, Haider; Carvalho-Wodarz, Cristiane de Souza; Franzyk, Henrik; Nielsen, Hanne Mørck; Braeckmans, Kevin; Lehr, Claus‐Michael; Ogris, Manfred; Foged, Camilla

doi:10.1016/j.jconrel.2019.08.004

Cited by 39 publications

(25 citation statements)

References 54 publications

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“…The data show that a quick response occurs not lasting long which might be related to a very quick dissociation in the lungs. Thanki et al [7] demonstrated that although part of complexed siRNA was staying in the lungs, around 50% was permeating across the air-blood barrier within 6 h and subsequently excreted via the kidneys [7] . The low stability as well might explain why the efficacy does not stand for longer times.…”

Section: Resultsmentioning

confidence: 99%

“…Local pulmonary delivery displays several therapeutic advantages, compared with systemic delivery, including (i) a quick onset of action, (ii) a reduced therapeutic dose required, and (iii) reduced side effects [6] . Besides, inhalation and nasal administration represent non-invasive routes of administration, which increases patient compliance, and the fast renal clearance of siRNA, observed after systemic administration, is reduced after local delivery [7] .…”

Section: Introductionmentioning

confidence: 99%

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Treatment of acute lung inflammation by pulmonary delivery of anti-TNF-α siRNA with PAMAM dendrimers in a murine model

Bohr

Tsapis

Foged

et al. 2020

European Journal of Pharmaceutics and Biopharmaceutics

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Treatment of acute lung inflammation by pulmonary delivery of anti-TNF-α siRNA with PAMAM dendrimers in a murine model

Bohr

Tsapis

Foged

et al. 2020

European Journal of Pharmaceutics and Biopharmaceutics

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“…Therefore, we have designed LPNs for delivering siRNA by combining lipidoids with PLGA (Thanki et al, 2017) to exploit the advantages of both lipids and polymers. Hence, siRNA-loaded lipidoid-modified PLGA nanoparticle are biocompatible, have high loading and transfection efficiency, high colloidal stability, and allow for sustained siRNA release (Thanki et al, 2019a). In these LPNs, the anionic siRNA is complexed with the outer lipidoid shell, and also with the PLGA core by incorporating some of the net-neutral lipophilic complexes of siRNA and lipidoid (Colombo et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Optimizing the Intracellular Delivery of Therapeutic Anti-inflammatory TNF-α siRNA to Activated Macrophages Using Lipidoid-Polymer Hybrid Nanoparticles

Lokras

Thakur

Wadhwa

et al. 2021

Front. Bioeng. Biotechnol.

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RNA interference (RNAi) has an unprecedented potential as a therapeutic strategy for reversibly silencing the expression of any gene. Therapeutic delivery of the RNAi mediator, i.e., small interfering RNA (siRNA), can be used to address diseases characterized by gene overexpression, for example inflammatory conditions like chronic obstructive pulmonary disease (COPD). Macrophages play a key role in COPD pathogenesis and are recruited to the airways and lung parenchyma, where they release proinflammatory cytokines, e.g., tumor necrosis factor-alpha (TNF-α). Hence, targeting TNF-α with siRNA is a promising therapeutic approach for COPD management. However, a safe and effective delivery system is required for delivery of TNF-α siRNA into the cytosol of hard-to-transfect macrophages. The purpose of this study was to optimize the intracellular delivery of TNF-α siRNA to the lipopolysaccharide-activated murine macrophage cell line RAW 264.7 using lipidoid-polymer hybrid nanoparticles (LPNs) composed of the lipid-like transfection agent lipidoid 5 (L5) and the biodegradable polymer poly (D,L-lactide-co-glycolide). Applying a quality-by-design approach, the influence of critical formulation variables, i.e., the L5 content and the L5:siRNA ratio (w/w), on critical quality attributes (CQAs) was investigated systematically using risk assessment and design of experiments, followed by delineation of an optimal operating space (OOS). The CQAs were identified based on the quality target product profile and included size, polydispersity index, zeta potential, encapsulation efficiency and loading for achieving efficient and safe TNF-α gene silencing in activated RAW 264.7 cells. Formulations inducing efficient gene silencing and low cytotoxicity were identified, and the optimal formulations displayed L5 contents of 15 and 20% (w/w), respectively, and an L5:siRNA weight ratio of 15:1. All tested formulations within the OOS mediated efficient and sequence-specific TNF-α gene silencing in RAW 264.7 cells at TNF-α-siRNA concentrations, which were significantly lower than the concentrations required of non-encapsulated TNF-α-siRNA, highlighting the benefit of the delivery system. The results also demonstrate that increasing the loading of siRNA into the delivery system does not necessarily imply enhanced gene silencing. This opens new avenues for further exploitation of LPNs as a robust platform technology for delivering TNF-α siRNA to macrophages, e.g., in the management of COPD.

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“…The combination of lipids with polymers intends to address the problems of poor structural stability associated with lipids and the low biocompatibility of polymers. Thanki et al developed lipid–polymer nanoparticles (LPNs) comprising a poly(lactic-co-glycolic acid) (PLGA) matrix core coated with lipidoid, with siRNA localized in both the core and the shell [ 60 ]. This design compensated the low siRNA-loading capacity of PLGA by introducing cationic lipidoids while controlling the rate of siRNA release through degradation of the polymer.…”

Section: Rna Delivery Vectors For Pulmonary Deliverymentioning

confidence: 99%

Inhaled RNA Therapy: From Promise to Reality

Chow

Qiu

Lam

2020

Trends in Pharmacological Sciences

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RNA-based medicine is receiving growing attention for its diverse roles and potential therapeutic capacity. The largest obstacle in its clinical translation remains identifying a safe and effective delivery system. Studies investigating RNA therapeutics in pulmonary diseases have rapidly expanded and drug administration by inhalation allows the direct delivery of RNA therapeutics to the target site of action while minimizing systemic exposure. In this review, we highlight recent developments in pulmonary RNA delivery systems with the use of nonviral vectors. We also discuss the major knowledge gaps that require thorough investigation and provide insights that will help advance this exciting field towards the bedside.

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Mechanistic profiling of the release kinetics of siRNA from lipidoid-polymer hybrid nanoparticles in vitro and in vivo after pulmonary administration

Cited by 39 publications

References 54 publications

Treatment of acute lung inflammation by pulmonary delivery of anti-TNF-α siRNA with PAMAM dendrimers in a murine model

Treatment of acute lung inflammation by pulmonary delivery of anti-TNF-α siRNA with PAMAM dendrimers in a murine model

Optimizing the Intracellular Delivery of Therapeutic Anti-inflammatory TNF-α siRNA to Activated Macrophages Using Lipidoid-Polymer Hybrid Nanoparticles

Inhaled RNA Therapy: From Promise to Reality

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