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The impact of PEGylation patterns on the in vivo biodistribution of mixed shell micelles.

ABSTRACT: Polyethylene glycol (PEG)-ylation is a widely used strategy to fabricate nanocarriers with a long blood circulation time. Further elaboration of the contribution of the surface PEGylation pattern to biodistribution is highly desirable. We fabricated a series of polyion complex (PIC) micelles PEGylated with different ratios (PEG2k and PEG550). The plasma protein adsorption, murine macrophage uptake, and in vivo biodistribution with iodine-125 as the tracer were systematically studied to elucidate the impact of PEGylation patterns on the biodistribution of micelles. We demonstrated that the PEGylated micelles with short hydrophilic PEG chains mixed on the surface were cleared quickly by the reticuloendothelial system (RES), and the single PEG2k PEGylated micelles could efficiently prolong the blood circulation time and increase their deposition in tumor sites. The present study extends the understanding of the PEGylation strategy to further advance the development of ideal nanocarriers for drug delivery and imaging applications.

SUBMITTER: Gao H

PROVIDER: S-EPMC3825670 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The impact of PEGylation patterns on the in vivo biodistribution of mixed shell micelles.

Gao Hongjun H Liu Jinjian J Yang Cuihong C Cheng Tangjian T Chu Liping L Xu Hongyan H Meng Aimin A Fan Saijun S Shi Linqi L Liu Jianfeng J

International journal of nanomedicine 20131105

Polyethylene glycol (PEG)-ylation is a widely used strategy to fabricate nanocarriers with a long blood circulation time. Further elaboration of the contribution of the surface PEGylation pattern to biodistribution is highly desirable. We fabricated a series of polyion complex (PIC) micelles PEGylated with different ratios (PEG2k and PEG550). The plasma protein adsorption, murine macrophage uptake, and in vivo biodistribution with iodine-125 as the tracer were systematically studied to elucidate ...[more]

PMID: 24235825

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Project description:A series of endosomolytic mixed micelles was synthesized from two diblock polymers, poly[ethylene glycol-b-(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate)] (PEG-b-pDPB) and poly[dimethylaminoethyl methacrylate-b-(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate)] (pD-b-pDPB), and used to determine the impact of both surface PEG density and PEG molecular weight on overcoming both intracellular and systemic siRNA delivery barriers. As expected, the percent PEG composition and PEG molecular weight in the corona had an inverse relationship with mixed micelle zeta potential and rate of cellular internalization. Although mixed micelles were internalized more slowly, they generally produced similar gene silencing bioactivity (? 80% or greater) in MDA-MB-231 breast cancer cells as the micelles containing no PEG (100 D/no PEG). The mechanistic explanation for the potent bioactivity of the promising 50 mol% PEG-b-DPB/50 mol% pD-b-pDPB (50 D) mixed micelle formulation, despite its relatively low rate of cellular internalization, was further investigated as a function of PEG molecular weight (5 k, 10 k, or 20 k PEG). Results indicated that, although larger molecular weight PEG decreased cellular internalization, it improved cytoplasmic bioavailability due to increased intracellular unpackaging (quantitatively measured via FRET) and endosomal release. When delivered intravenously in vivo, 50 D mixed micelles with a larger molecular weight PEG in the corona also demonstrated significantly improved blood circulation half-life (17.8 min for 20 k PEG micelles vs. 4.6 min for 5 kDa PEG micelles) and a 4-fold decrease in lung accumulation. These studies provide new mechanistic insights into the functional effects of mixed micelle-based approaches to nanocarrier surface PEGylation. Furthermore, the ideal mixed micelle formulation identified (50 D/20 k PEG) demonstrated desirable intracellular and systemic pharmacokinetics and thus has strong potential for in vivo therapeutic use.

Project description:There are many opportunities in the development of oral inhalation (oi) formulations for the delivery of small molecule therapeutics and biologics to and through the lungs. Nanocarriers have the potential to play a key role in advancing oi technologies and pushing the boundary of the pulmonary delivery market. In this work we investigate the effect of the route of administration and PEGylation on the systemic and lung cellular biodistribution of generation 3, amino-terminated poly(amidoamine) (PAMAM) dendrimers (G3NH2). Pharmacokinetic profiles show that the dendrimers reach their peak concentration in systemic circulation within a few hours after pulmonary delivery, independent of their chemistry (PEGylated or not), charge (+24 mV for G3NH2 vs -3.7 mV for G3NH2-24PEG1000), or size (5.1 nm for G3NH2 and 9.9 nm for G3NH2-24PEG1000). However, high density of surface modification with PEG enhances pulmonary absorption and the peak plasma concentration upon pulmonary delivery. The route of administration and PEGylation also significantly impact the whole body and local (lung cellular) distribution of the dendrimers. While ca. 83% of G3NH2 is found in the lungs upon pulmonary delivery at 6.5 h post administration, only 2% reached the lungs upon intravenous (iv) delivery. Moreover, no measurable concentration of either G3NH2 or G3NH2-24PEG1000 is found in the lymph nodes upon iv administration, while these are the tissues with the second highest mass distribution of dendrimers post pulmonary delivery. Dendrimer chemistry also significantly impacts the (cellular) distribution of the nanocarriers in the lung tissue. Upon pulmonary delivery, approximately 20% of the lung endothelial cells are seen to internalize G3NH2-24PEG1000, compared to only 6% for G3NH2. Conversely, G3NH2 is more readily taken up by lung epithelial cells (35%) when compared to its PEGylated counterpart (24%). The results shown here suggest that both the pulmonary route of administration and dendrimer chemistry combined can be used to passively target tissues and cell populations of great interest, and can thus be used as guiding principles in the development of dendrimer-based drug delivery strategies in the treatment of medically relevant diseases including lung ailments as well as systemic disorders.

Dataset Information

The impact of PEGylation patterns on the in vivo biodistribution of mixed shell micelles.

Publications

The impact of PEGylation patterns on the in vivo biodistribution of mixed shell micelles.

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