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Impact of Surface Polyethylene Glycol (PEG) Density on Biodegradable Nanoparticle Transport in Mucus ex Vivo and Distribution in Vivo.

ABSTRACT: Achieving sustained drug delivery to mucosal surfaces is a major challenge due to the presence of the protective mucus layer that serves to trap and rapidly remove foreign particulates. Nanoparticles engineered to rapidly penetrate mucosal barriers (mucus-penetrating particles, "MPP") have shown promise for improving drug distribution, retention and efficacy at mucosal surfaces. MPP are densely coated with polyethylene glycol (PEG), which shields the nanoparticle core from adhesive interactions with mucus. However, the PEG density required to impart the "stealth" properties to nanoparticles in mucus, and thus, uniform distribution in vivo, is still unknown. We prepared biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles with a range of PEG surface densities by blending various ratios of a diblock copolymer of PLGA and 5 kDa poly(ethylene glycol) (PLGA-PEG5k) with PLGA. We then evaluated the impact of PEG surface density, measured using an (1)H NMR method, on mucin binding in vitro, nanoparticle transport in freshly obtained human cervicovaginal mucus (CVM) ex vivo, and nanoparticle distribution in the mouse cervicovaginal tract in vivo. We found that at least 5% PEG was required to effectively shield the nanoparticle core from interacting with mucus components in vitro and ex vivo, thus leading to enhanced nanoparticle distribution throughout the mouse vagina in vivo. We then demonstrated that biodegradable MPP could be formulated from blends of PLGA and PLGA-PEG polymers of various molecular weights, and that these MPP provide tunable drug loading and drug release rates and durations. Overall, we describe a methodology for rationally designing biodegradable, drug-loaded MPP for more uniform delivery to the vagina.

SUBMITTER: Xu Q

PROVIDER: S-EPMC4890729 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Impact of Surface Polyethylene Glycol (PEG) Density on Biodegradable Nanoparticle Transport in Mucus ex Vivo and Distribution in Vivo.

Xu Qingguo Q Ensign Laura M LM Boylan Nicholas J NJ Schön Arne A Gong Xiaoqun X Yang Jeh-Chang JC Lamb Nicholas W NW Cai Shutian S Yu Tao T Freire Ernesto E Hanes Justin J

ACS nano 20150831 9

Achieving sustained drug delivery to mucosal surfaces is a major challenge due to the presence of the protective mucus layer that serves to trap and rapidly remove foreign particulates. Nanoparticles engineered to rapidly penetrate mucosal barriers (mucus-penetrating particles, "MPP") have shown promise for improving drug distribution, retention and efficacy at mucosal surfaces. MPP are densely coated with polyethylene glycol (PEG), which shields the nanoparticle core from adhesive interactions ...[more]

PMID: 26301576

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Project description:Polyethylene glycol (PEG) is the most prominent clinically administered synthetic polymer. For example, over 300 million people have been administered PEGylated liposome vaccines for SARS-CoV-2. PEG is used in mammals because it has low affinity for most proteins and vice versa. However, this makes it difficult to study the few interactions with proteins that PEG has. On the atomistic level, there are two PEG-protein structures: (1) PEG-LIMP-2 and (2) PEG-αPEG. In the first structure, two monomers of a 1.5 kDa PEG polymer (PEG2) had electron density deep in the postulated cholesterol transport tunnel of LIMP-2, a lysosomal cholesterol transport protein and member of the CD36 super family of proteins. It is unclear how PEG entered this tunnel. In the second structure, PEG wrapped around a surface-exposed tryptophan on its antibody. Since tryptophan is a rare residue, it is unclear if this PEG-Trp interaction is ubiquitous. To gain deeper mechanistic insight into PEG-protein interactions, we surrounded the LIMP-2 apo structure with 13 PEG chains of 10 monomers each (PEG10), water, and KCl and simulated the system using NAMD. One of the 13 chains penetrated LIMP-2 and came within 3 Å of PEG2. This was possible because of the strong hydrogen bonding between multiple oxygens along PEG10 and Arg192 but, most importantly, the clamping of the tertiary structure on PEG10. Clamping stabilized the movements of PEG10, and the leading oxygen of PEG10 was able to penetrate LIMP-2 and head toward to the position occupied by PEG2. Phe383 appears to act as a gate for objects to move through this cavity, which continues to the basal/membrane side of LIMP-2. Of all residues, PEG10 molecules had the most sustained interactions with lysine and arginine because of their strong hydrogen-bonding capabilities. These results show that the oxygens of PEG bind residues with high hydrogen bonding capabilities. However, the PEG-protein interaction is likely to be transient unless groups of resides can clamp down on PEG or a cavity that at least part of the PEG chain can enter is in close proximity to lower PEG's entropy.

Dataset Information

Impact of Surface Polyethylene Glycol (PEG) Density on Biodegradable Nanoparticle Transport in Mucus ex Vivo and Distribution in Vivo.

Publications

Impact of Surface Polyethylene Glycol (PEG) Density on Biodegradable Nanoparticle Transport in Mucus ex Vivo and Distribution in Vivo.

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