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A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue.

ABSTRACT: Prevailing opinion suggests that only substances up to 64 nm in diameter can move at appreciable rates through the brain extracellular space (ECS). This size range is large enough to allow diffusion of signaling molecules, nutrients, and metabolic waste products, but too small to allow efficient penetration of most particulate drug delivery systems and viruses carrying therapeutic genes, thereby limiting effectiveness of many potential therapies. We analyzed the movements of nanoparticles of various diameters and surface coatings within fresh human and rat brain tissue ex vivo and mouse brain in vivo. Nanoparticles as large as 114 nm in diameter diffused within the human and rat brain, but only if they were densely coated with poly(ethylene glycol) (PEG). Using these minimally adhesive PEG-coated particles, we estimated that human brain tissue ECS has some pores larger than 200 nm and that more than one-quarter of all pores are ? 100 nm. These findings were confirmed in vivo in mice, where 40- and 100-nm, but not 200-nm, nanoparticles spread rapidly within brain tissue, only if densely coated with PEG. Similar results were observed in rat brain tissue with paclitaxel-loaded biodegradable nanoparticles of similar size (85 nm) and surface properties. The ability to achieve brain penetration with larger nanoparticles is expected to allow more uniform, longer-lasting, and effective delivery of drugs within the brain, and may find use in the treatment of brain tumors, stroke, neuroinflammation, and other brain diseases where the blood-brain barrier is compromised or where local delivery strategies are feasible.

SUBMITTER: Nance EA

PROVIDER: S-EPMC3718558 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue.

Nance Elizabeth A EA Woodworth Graeme F GF Sailor Kurt A KA Shih Ting-Yu TY Xu Qingguo Q Swaminathan Ganesh G Xiang Dennis D Eberhart Charles C Hanes Justin J

Science translational medicine 20120801 149

Prevailing opinion suggests that only substances up to 64 nm in diameter can move at appreciable rates through the brain extracellular space (ECS). This size range is large enough to allow diffusion of signaling molecules, nutrients, and metabolic waste products, but too small to allow efficient penetration of most particulate drug delivery systems and viruses carrying therapeutic genes, thereby limiting effectiveness of many potential therapies. We analyzed the movements of nanoparticles of var ...[more]

PMID: 22932224

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Project description:Lymphatic vessels have recently been shown to effectively deliver immune modulatory therapies to the lymph nodes, which enhances their therapeutic efficacy. Prior work has shown that lymphatics transport 10-250 nm nanoparticles from peripheral tissues to the lymph node. However, the surface chemistry required to maximize this transport is poorly understood. Here, we determined the effect of surface poly(ethylene glycol) (PEG) density and size on nanoparticle transport across lymphatic endothelial cells (LECs) by differentially PEGylated model polystyrene nanoparticles. Using an established in-vitro lymphatic transport model, we found PEGylation improved the transport of 100 and 40 nm nanoparticles across LECs 50-fold compared to the unmodified nanoparticles and that transport is maximized when the PEG is in a dense brush conformation or high grafting density (Rf/D = 4.9). We also determined that these trends are not size-dependent. PEGylating 40 nm nanoparticles improved transport efficiency across LECs 68-fold compared to unmodified nanoparticles. We also found that PEGylated 100 nm and 40 nm nanoparticles accumulate in lymph nodes within 4 h after intradermal injection, while unmodified nanoparticles accumulated minimally. Densely PEGylated nanoparticles traveled the furthest distance from the injection site and densely PEGylated 40 nm nanoparticles had maximum accumulation in the lymph nodes compared to low density PEGylated and unmodified nanoparticles. Finally, we determined that nanoparticles are transported via both paracellular and transcellular mechanisms, and that PEG conformation modulates the cellular transport mechanisms. Our results suggest that PEG conformation is crucial to maximize nanoparticle transport across LECs and into lymphatic vessels, making PEG density a crucial design. Optimizing PEG density on nanoparticle formulations has the potential to enhance immunotherapeutic and vaccine outcomes. STATEMENT OF SIGNIFICANCE: Lymphatic vessels are an emerging target for drug delivery both in the context of modulating immune responses and enhancing bioavailability by avoiding first pass hepatic metabolism after oral delivery. Lymphatic vessels are the natural conduits from peripheral tissues to the lymph nodes, where the adaptive immune response is shaped, and eventually to systemic circulation via the thoracic duct. Lymphatics can be targeted via nanoparticles, but the surface chemistry required to maximize nanoparticle transport by lymphatics vessels remains poorly understood. Here, we demonstrate that coating nanoparticles with hydrophilic polyethylene glycol (PEG) effectively enhances their transport across lymphatic endothelial cells in vitro and in vivo and that both paracellular and micropinocytosis mechanisms underly this transport. We found that dense PEG coatings maximize lymphatic transport of nanoparticles, thus providing new material design criteria for lymphatic targeted drug delivery.

Project description:Glioblastoma (GBM) is the most devastating brain cancer, and cures remain elusive with currently available neurosurgical, pharmacological, and radiation approaches. While retrovirus- and adenovirus-mediated suicide gene therapy using DNA encoding herpes simplex virus-thymidine kinase (HSV-tk) and prodrug ganciclovir has been suggested as a promising strategy, a nonviral approach for treatment in an orthotopic human primary brain tumor model has not previously been demonstrated. Delivery challenges include nanoparticle penetration through brain tumors, efficient cancer cell uptake, endosomal escape to the cytosol, and biodegradability. To meet these challenges, we synthesized poly(ethylene glycol)-modified poly(beta-amino ester) (PEG-PBAE) polymers to improve extracellular delivery and coencapsulated plasmid DNA with end-modified poly(beta-amino ester) (ePBAE) polymers to improve intracellular delivery as well. We created and evaluated a library of PEG-PBAE/ePBAE nanoparticles (NPs) for effective gene therapy against two independent primary human stem-like brain tumor initiating cells, a putative target to prevent GBM recurrence. The optimally engineered PEG-PBAE/ePBAE NP formulation demonstrated 54 and 82% transfection efficacies in GBM1A and BTIC375 cells respectively, in comparison to 37 and 66% for optimized PBAE NPs without PEG. The leading PEG-PBAE NP formulation also maintained sub-250 nm particle size up to 5 h, while PBAE NPs without PEG showed aggregation over time to micrometer-sized complexes. The comparative advantage demonstrated in vitro successfully translated into improved in vivo diffusion, with a higher amount of PEG-PBAE NPs penetrating to a distance of 2 mm from the injection site. A significant increase in median survival from 53.5 to 67 days by PEG-PBAE/pHSV-tk NP and systemic ganciclovir treatment compared to a control group in orthotopic murine model of human glioblastoma demonstrates the potential of PEG-PBAE-based NPs as an effective gene therapy platform for the treatment of human brain tumors.

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A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue.

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A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue.

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