Effects of PEG surface density and chain length on the pharmacokinetics and biodistribution of methotrexate-loaded chitosan nanoparticles

Bachir, Zaina Ait; Huang, Yukun; He, Muye; Huang, Lei; Hou, Xinyu; Chen, Rongjun; Gao, Feng

doi:10.2147/ijn.s167443

Cited by 32 publications

(19 citation statements)

References 45 publications

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“…for mPEG10K-zein), therefore demonstrating that PEGylation with a shorter PEG chain length could improve the cellular uptake efficacy of the zein micelles. Higher uptake with a shorter PEG chain length was consistent with several types of PEGylated nanocarriers [34,36,37]. Increasing PEG MW was shown to prevent nanoparticle-cell interactions, as higher MW PEG grafting led to a larger surface shielding of the micelles [38,39].…”

Section: Size and Zeta Potential Of Mpeg-zein Micelles In The Presenc...supporting

confidence: 62%

“…The increased entrapment with the higher PEG MW was also observed in PEG-coated fluconazole nanoparticles [32]. However, in some delivery systems, such as PEG-PLGA and chitosan nanoparticles, the encapsulation efficiency was independent of the PEG MW [33,34]. It was even found to decrease with increasing PEG MW, for example, in the case of cholesterol-bearing PEGylated polymeric micelles, due to the overall low cholesterol content in the co-polymer chain for polymers with higher MW PEG, making these micelles less favorable for drug encapsulation [35].…”

Section: Characterization Of Mpeg-zein Micellesmentioning

confidence: 88%

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Limited Impact of the Protein Corona on the Cellular Uptake of PEGylated Zein Micelles by Melanoma Cancer Cells

et al. 2022

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The formation of a protein layer “corona” on the nanoparticle surface upon entry into a biological environment was shown to strongly influence the interactions with cells, especially affecting the uptake of nanomedicines. In this work, we present the impact of the protein corona on the uptake of PEGylated zein micelles by cancer cells, macrophages, and dendritic cells. Zein was successfully conjugated with poly(ethylene glycol) (PEG) of varying chain lengths (5K and 10K) and assembled into micelles. Our results demonstrate that PEGylation conferred stealth effects to the zein micelles. The presence of human plasma did not impact the uptake levels of the micelles by melanoma cancer cells, regardless of the PEG chain length used. In contrast, it decreased the uptake by macrophages and dendritic cells. These results therefore make PEGylated zein micelles promising as potential drug delivery systems for cancer therapy.

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Section: Size and Zeta Potential Of Mpeg-zein Micelles In The Presenc...supporting

confidence: 62%

Section: Characterization Of Mpeg-zein Micellesmentioning

confidence: 88%

Limited Impact of the Protein Corona on the Cellular Uptake of PEGylated Zein Micelles by Melanoma Cancer Cells

et al. 2022

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“…Similarly, Bachir et al compared chitosan (MW 11 kDa) NPs conjugated with PEG at various degrees of substitution loaded with methotrexate having a particle size of about 110-171 nm and zeta potential +7-35 mV found that non-PEGylated chitosan NPs accumulated significantly in the liver and spleen at 24 h following intravenous administration and to a lower extent in lungs, kidneys, and heart. In contrast, PEGylated chitosan NPs distributed primarily to the kidneys [167]. Intraperitoneal injection of FITC-labeled carboxymethyl chitosan revealed similar high uptake in the liver of 300 kDa molecular weight chitosan, whereas unspecified chitosan degradation products of about 45 kDa were found in the urine [168].…”

Section: Effect Of Physical Properties On Biodistributionmentioning

confidence: 92%

Chitosan Nanoparticles at the Biological Interface: Implications for Drug Delivery

et al. 2021

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The unique properties of chitosan make it a useful choice for various nanoparticulate drug delivery applications. Although chitosan is biocompatible and enables cellular uptake, its interactions at cellular and systemic levels need to be studied in more depth. This review focuses on the various physical and chemical properties of chitosan that affect its performance in biological systems. We aim to analyze recent research studying interactions of chitosan nanoparticles (NPs) upon their cellular uptake and their journey through the various compartments of the cell. The positive charge of chitosan enables it to efficiently attach to cells, increasing the probability of cellular uptake. Chitosan NPs are taken up by cells via different pathways and escape endosomal degradation due to the proton sponge effect. Furthermore, we have reviewed the interaction of chitosan NPs upon in vivo administration. Chitosan NPs are immediately surrounded by a serum protein corona in systemic circulation upon intravenous administration, and their biodistribution is mainly to the liver and spleen indicating RES uptake. However, the evasion of RES system as well as the targeting ability and bioavailability of chitosan NPs can be improved by utilizing specific routes of administration and covalent modifications of surface properties. Ongoing clinical trials of chitosan formulations for therapeutic applications are paving the way for the introduction of chitosan into the pharmaceutical market and for their toxicological evaluation. Chitosan provides specific biophysical properties for effective and tunable cellular uptake and systemic delivery for a wide range of applications.

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“…Surface PEG conformation on nanoparticles has been shown to affect nanoparticle uptake by cells [36]. Several studies have shown that as PEG density increases on nanoparticles, uptake by macrophages and dendritic cells [37-42], as well as cancer cells [37, 43], is reduced. PEGylation appears to have differing results depending on the cell type – PEGylation reduces nanoparticle uptake by macrophages and dendritic cells, as indicated by studies demonstrating that PEG needed to be in a brush conformation to evade uptake and clearance by macrophages [41].…”

Section: Discussionmentioning

confidence: 99%

Dense poly(ethylene glycol) coatings maximize nanoparticle transport across lymphatic endothelial cells and accumulate in the skindraining lymph nodes

McCright

Skeen

Yarmovsky

et al. 2020

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Lymphatic vessels have received considerable attention in recent years as delivery route for immune modulatory therapies to the lymph nodes. Lymph node targeting of immunotherapies and vaccines has been shown to significantly enhance their therapeutic efficacy. Lymphatics transport functions materials from peripheral tissues to the lymph nodes, including small 10 – 250 nm therapeutic nanoparticles. While size required to enter lymphatic vessels, surface chemistry is more poorly studied. Here, we probed the effects of surface poly(ethylene glycol) (PEG) density on nanoparticle transport across lymphatic endothelial cells (LECs). We differentially PEGylated model carboxylate-modified polystyrene nanoparticles to form either a brush or dense brush PEG conformation on the nanoparticle surfaces. Using an established in-vitro lymphatic transport model, we found that the addition of any PEG improved the transport of nanoparticles through lymphatic endothelial cells (2.5 - 2.6 ± 0.9% transport efficiency at 24 hours) compared to the unmodified PS-COOH nanoparticles (0.05 ± 0.05% transport efficiency at 24 hours). Additionally, we found that transcellular transport is maximized (4.2 ± 0.7% transport efficiency at 24 hours) when the PEG is in a dense brush conformation on nanoparticle surfaces, corresponding with a high grafting density (Rf/D = 4.9). These results suggest that PEG conformation has a crucial role in determining translocation of nanoparticles across LECs and into lymphatic vessels. Thus, we identified PEG density as a major design criteria for maximizing lymphatic targeting of therapeutic nanoparticle formulations that can be widely applied to enhance immunotherapeutic and vaccine outcomes in future studies.

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Effects of PEG surface density and chain length on the pharmacokinetics and biodistribution of methotrexate-loaded chitosan nanoparticles

Cited by 32 publications

References 45 publications

Limited Impact of the Protein Corona on the Cellular Uptake of PEGylated Zein Micelles by Melanoma Cancer Cells

Limited Impact of the Protein Corona on the Cellular Uptake of PEGylated Zein Micelles by Melanoma Cancer Cells

Chitosan Nanoparticles at the Biological Interface: Implications for Drug Delivery

Dense poly(ethylene glycol) coatings maximize nanoparticle transport across lymphatic endothelial cells and accumulate in the skindraining lymph nodes

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