PEGylated PRINT Nanoparticles: The Impact of PEG Density on Protein Binding, Macrophage Association, Biodistribution, and Pharmacokinetics

Perry, Jillian L.; Reuter, Kevin; Kai, Marc P.; Herlihy, Kevin P.; Jones, Stephen; Luft, J. Christopher; Napier, Mary E.; Bear, James E.; DeSimone, Joseph M.

doi:10.1021/nl302638g

Cited by 531 publications

(577 citation statements)

References 58 publications

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“…The duration of blood circulation and the plasma concentration are two critical factors for nanomedicine to obtain the target tissue accumulation after intravenous injection 22. Thus, we investigated the pharmacokinetics of these vectors in rats.…”

Section: Resultsmentioning

confidence: 99%

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

et al. 2017

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Efficient microRNAs (miRNA) delivery into cells is a promising strategy for disease therapy, but is a major challenge because the available conventional nonviral vectors have significant drawbacks. In particular, after these vectors are entrapped in lysosomes, the escape efficiency of genes from lysosomes into the cytosol is less than 2%. Here, a novel approach for lethal‐7a (let‐7a) replacement therapy using rod‐shaped active pure drug nanoparticles (≈130 nm in length, PNPs) with a dramatically high drug‐loading of ≈300% as vectors is reported. Importantly, unlike other vectors, the developed PNPs/let‐7a complexes (≈178 nm, CNPs) can enter cells and bypass the lysosomal route to localize to the cytosol, achieving efficient intracellular delivery of let‐7a and a 50% reduction in expression of the target protein (KRAS). Also, CNPs prolong the t 1/2 of blood circulation by ≈threefold and increase tumor accumulation by ≈1.5–2‐fold, resulting in significantly improved antitumor efficacies. Additionally, no damage to normal organs is observed following systemic injection of CNPs. In conclusion, rod‐shaped active PNPs enable efficient and safe delivery of miRNA with synergistic treatment for disease. This nanoplatform would also offer a viable strategy for the potent delivery of proteins and peptides in vitro and in vivo.

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Section: Resultsmentioning

confidence: 99%

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

et al. 2017

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“…administration. In the lung, the nanocapsules remained primarily in the lung lining fluid avoiding phagocytosis by alveolar macrophages, a behaviour which was attributed to the pegylated ('stealth') surface chemistry and the small particle size, which reduce macrophage detection and phagocytosis [36][37][38], whilst promoting translocation across the air-blood barrier [29,30,39]. The increase in signal in the liver at t=24 h post-administration (absent in the 111 In-DTPA groups) suggests that at least a fraction of the lung dose was able to cross the air-blood barrier and enter into the systemic circulation as intact nanoparticles, accumulating subsequently in the liver [29,30].…”

Section: Discussionmentioning

confidence: 99%

Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration

Patel

Woods

Riffo‐Vasquez

et al. 2016

Journal of Controlled Release

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Lipid nanocapsules (LNCs) are semi-rigid spherical capsules with a triglyceride core that present a promising formulation option for the pulmonary delivery of drugs with poor aqueous solubility. Whilst the biodistribution of LNCs of different size has been studied following intravenous administration, the fate of LNCs following pulmonary delivery has not been reported. We investigated quantitatively whether lung inflammation affects the clearance of 50 nm lipid nanocapsules, or is exacerbated by their pulmonary administration. Studies were conducted in mice with lipopolysaccharide-induced lung inflammation compared to healthy controls. Particle deposition and nanocapsule clearance kinetics were measured by single photon emission computed tomography/computed tomography (SPECT/CT) imaging over 48 h. A significantly lower lung dose of 111 In-LNC50 was achieved in the lipopolysaccharide (LPS)-treated animals compared with healthy controls (p < 0.001). When normalised to the delivered lung dose, the clearance kinetics of 111 In-LNC50 from the lungs fit a first order model with an elimination half-life of 10.5 ± 0.9 h (R 2 = 0.995) and 10.6 ± 0.3 h (R 2 = 1.000) for healthy and inflamed lungs respectively (n = 3). In contrast, 111 In-diethylene triamine pentaacetic acid (DTPA), a small hydrophilic molecule, was cleared rapidly from the lungs with the majority of the dose absorbed within 20 min of administration. Biodistribution to lungs, stomach-intestine, liver, trachea-throat and blood at the end of the imaging period was unaltered by lung inflammation. This study demonstrated that lung clearance and whole body distribution of lipid nanocapsules were unaffected by the presence of acute lung inflammation.

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“…This technique allows for screening the relative nanoparticle resident times in the blood using as few as 4 animals per condition. In order to reduce variation in nanoparticles for these experiments, we used the PRINT technique to generate monodisperse 300-nm cylindrical PEG hydrogel nanoparticles containing far-red fluorescent dyes for in vivo and in vitro imaging (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI66895DS1); these particles are similar in size and composition to those used in a recent study by our group (31). When i.v.…”

Section: Ivm Allows For Rapid Screening Of Nanoparticle Clearancementioning

confidence: 99%

“…This results in low batch-to-batch variability with very low polydispersity values (29,30). Recent work has demonstrated that the PK of PRINT nanoparticles can be carefully and reproducibly calibrated by adjusting the density of PEG chains present on the surface (31).…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

Jones¹,

Roberts²,

Robbins³

et al. 2013

J. Clin. Invest.

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Extended circulation of nanoparticles in blood is essential for most clinical applications. Nanoparticles are rapidly cleared by cells of the mononuclear phagocyte system (MPS). Approaches such as grafting polyethylene glycol onto particles (PEGylation) extend circulation times; however, these particles are still cleared, and the processes involved in this clearance remain poorly understood. Here, we present an intravital microscopybased assay for the quantification of nanoparticle clearance, allowing us to determine the effect of mouse strain and immune system function on particle clearance. We demonstrate that mouse strains that are prone to Th1 immune responses clear nanoparticles at a slower rate than Th2-prone mice. Using depletion strategies, we show that both granulocytes and macrophages participate in the enhanced clearance observed in Th2-prone mice. Macrophages isolated from Th1 strains took up fewer particles in vitro than macrophages from Th2 strains. Treating macrophages from Th1 strains with cytokines to differentiate them into M2 macrophages increased the amount of particle uptake. Conversely, treating macrophages from Th2 strains with cytokines to differentiate them into M1 macrophages decreased their particle uptake. Moreover, these results were confirmed in human monocyte-derived macrophages, suggesting that global immune regulation has a significant impact on nanoparticle clearance in humans. IntroductionThe potential clinical applications of nanoparticles and nanoformulations have been investigated for more than 30 years. Nanoparticle approaches have the potential to revolutionize drug delivery by allowing for the encapsulation of drugs with poor solubility or stability in a stable carrier particle. In addition, targeting nanoparticles to specific pathological sites may allow an increased effective dose of drug at the needed site, while decreasing systemic drug exposure, and therefore side effects. However, to date, only 2 nanoformulations for cancer treatment have been approved for clinical use (liposomal doxorubicin [Doxil] and protein-bound paclitaxel [Abraxane]) (1-3). One major obstacle for the use of nanoparticles in vivo is rapid clearance by the cells of the reticuloendothelial system (RES)/mononuclear phagocyte system (MPS) (4-7). In addition to rapid clearance, variable activity of the MPS among patients leads to widely variable pharmacokinetics of nanoformulations in the clinic, reducing the efficacy of both approved and future experimental nanoformulations (8).

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PEGylated PRINT Nanoparticles: The Impact of PEG Density on Protein Binding, Macrophage Association, Biodistribution, and Pharmacokinetics

Cited by 531 publications

References 58 publications

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration

Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

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