Watching the gorilla and questioning delivery dogma

Anchordoquy, Thomas J.; Simberg, Dmitri

doi:10.1016/j.jconrel.2017.07.021

Cited by 24 publications

(17 citation statements)

References 70 publications

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“…While the role of complement in infusion reactions to nanomedicine is being debated, 11 there is a concern that uncontrolled complement activation may affect the disease outcome and nanomedicine performance in general. 12, 13, 14…”

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confidence: 99%

Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles

et al. 2019

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Deposition of complement factors (opsonisation) on nanoparticles may promote clearance from the blood by macrophages and trigger proinflammatory responses, but the mechanisms regulating the efficiency of complement activation are poorly understood. We previously demonstrated that opsonisation of superparamagnetic iron oxide nanoworms (SPIO NWs) with the third complement protein (C3) was dependent on the biomolecule corona. Here we show that natural antibodies play a critical role in C3 opsonisation of SPIO NWs and a range of clinically approved nanopharmaceuticals. The dependency of C3 opsonisation on immunoglobulin binding is predominantly universal and is observed regardless of the complement activation pathway. Few surface-bound immunoglobulin molecules trigger complement activation and opsonisation. While the total amount of nanoparticle-absorbed protein does not determine C3 deposition efficiency, the biomolecule corona per se enhances immunoglobulin binding to all nanoparticle types. We therefore show that natural antibodies represent a link between biomolecule corona and C3 opsonisation, and may determine individual complement responses to nanomedicines.

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Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles

et al. 2019

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“…1–4, contemporary nanoparticles typically employ some type of polymeric coating (e.g., PEG, poloxamer, polyethylenoxide, dextran) to extend circulation times and improve biodistribution [32, 33, 35, 36]. Of these coating strategies, PEGylation is by far the most common despite the expanding number of studies documenting problems associated with its immunogenicity [47, 59–63]. Consistent with the ability of PEG to prevent uptake by macrophages, leukocyte uptake was dramatically reduced (29% vs. 87% particle positive), and the vast majority of circulating lipoplexes were present in the plasma (Figs.…”

Section: Discussionmentioning

confidence: 99%

Nanoparticle uptake by circulating leukocytes: A major barrier to tumor delivery

Betker

Jones

Childs

et al. 2018

Journal of Controlled Release

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Decades of research into improving drug delivery to tumors has documented uptake of particulate delivery systems by resident macrophages in the lung, liver, and spleen, and correlated short circulation times with reduced tumor accumulation. An implicit assumption in these studies is that nanoparticles present in the blood are available for distribution to the tumor. This study documents significant levels of lipoplex uptake by circulating leukocytes, and its effect on distribution to the tumor and other organs. In agreement with previous studies, PEGylation dramatically extends circulation times and enhances tumor delivery. However, our studies suggest that this relationship is not straightforward, and that particle sequestration by leukocytes can significantly alter biodistribution, especially with non-PEGylated nanoparticle formulations. We conclude that leukocyte uptake should be considered in biodistribution studies, and that delivery to these circulating cells may present opportunities for treating viral infections and leukemia.

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“…The technology continues to be upgraded and a process using supercritical fluids has recently been proposed for physical adsorption of PEG on liposome surface [ 9 ]. Pegylation, however, does not prevent non-specific binding of proteins, which often results in complement activation-related infusion reactions of varying severity [ 10 , 11 ] and other anti-PEG immunity-associated issues [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Phosphatidylinositol Stabilizes Fluid-Phase Liposomes Loaded with a Melphalan Lipophilic Prodrug

et al. 2021

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Previously, a liposomal formulation of a chemotherapeutic agent melphalan (Mlph) incorporated in a fluid lipid bilayer of natural phospholipids in the form of dioleoylglyceride ester (MlphDG) was developed and the antitumor effect was confirmed in mouse models. The formulation composed of egg phosphatidylcholine (ePC), soybean phosphatidylinositol (PI), and MlphDG (8:1:1, by mol) showed stability in human serum for at least 4–5 h. On the contrary, replacing PI with pegylation of the liposomes, promoted fast dissociation of the components from the bilayer. In this work, interactions of MlphDG-liposomes with the most abundant plasma protein—albumin—in function of the presence of PI in the formulation were explored using Fourier transform infrared spectroscopy. The release of MlphDG from the liposomes was studied by asymmetrical flow field-flow fractionation (AF4) using micelles formed by a polyethylene glycol conjugate with phosphatidylethanolamine to mimic the physiological lipid sink like lipoproteins. Our results show that PI actually protects the membrane of MlphDG-liposomes from the protein penetration, presumably due to pairing between the positively charged MlphDG and negatively charged PI, which compensates for the heterogeneity of the lipid bilayer. The AF4 technique also evidences high stability of the formulation as a drug carrier.

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Watching the gorilla and questioning delivery dogma

Cited by 24 publications

References 70 publications

Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles

Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles

Nanoparticle uptake by circulating leukocytes: A major barrier to tumor delivery

Phosphatidylinositol Stabilizes Fluid-Phase Liposomes Loaded with a Melphalan Lipophilic Prodrug

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