Effect of mannose targeting of hydroxyl PAMAM dendrimers on cellular and organ biodistribution in a neonatal brain injury model

Anjali Sharma; Joshua E Porterfield; Elizabeth Smith; Rishi Sharma; Sujatha Kannan; Rangaramanujam M Kannan

doi:10.1016/j.jconrel.2018.06.003

Effect of mannose targeting of hydroxyl PAMAM dendrimers on cellular and organ biodistribution in a neonatal brain injury model

J Control Release. 2018 Aug 10:283:175-189. doi: 10.1016/j.jconrel.2018.06.003. Epub 2018 Jun 5.

Authors

Anjali Sharma¹, Joshua E Porterfield², Elizabeth Smith³, Rishi Sharma¹, Sujatha Kannan⁴, Rangaramanujam M Kannan⁵

Affiliations

¹ Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
² Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
³ Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁴ Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Hugo W. Moser Research Institute at Kennedy Krieger, Inc., Baltimore, MD 21205, USA; Kennedy Krieger Institute - Johns Hopkins University for Cerebral Palsy Research Excellence, Baltimore, MD 21218, USA.
⁵ Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Hugo W. Moser Research Institute at Kennedy Krieger, Inc., Baltimore, MD 21205, USA; Kennedy Krieger Institute - Johns Hopkins University for Cerebral Palsy Research Excellence, Baltimore, MD 21218, USA. Electronic address: krangar1@jhmi.edu.

Abstract

Neurotherapeutics for the treatment of central nervous system (CNS) disorders must overcome challenges relating to the blood-brain barrier (BBB), brain tissue penetration, and the targeting of specific cells. Neuroinflammation mediated by activated microglia is a major hallmark of several neurological disorders, making these cells a desirable therapeutic target. Building on the promise of hydroxyl-terminated generation four polyamidoamine (PAMAM) dendrimers (D4-OH) for penetrating the injured BBB and targeting activated glia, we explored if conjugation of targeting ligands would enhance and modify brain and organ uptake. Since mannose receptors [cluster of differentiation (CD) 206] are typically over-expressed on injured microglia, we conjugated mannose to the surface of multifunctional D4-OH using highly efficient, atom-economical, and orthogonal Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click chemistry and evaluated the effect of mannose conjugation on the specific cell uptake of targeted and non-targeted dendrimers both in vitro and in vivo. In vitro results indicate that the conjugation of mannose as a targeting ligand significantly changes the mechanism of dendrimer internalization, giving mannosylated dendrimer a preference for mannose receptor-mediated endocytosis as opposed to non-specific fluid phase endocytosis. We further investigated the brain uptake and biodistribution of targeted and non-targeted fluorescently labeled dendrimers in a maternal intrauterine inflammation-induced cerebral palsy (CP) rabbit model using quantification methods based on fluorescence spectroscopy and confocal microscopy. We found that the conjugation of mannose modified the distribution of D4-OH throughout the body in this neonatal rabbit CP model without lowering the amount of dendrimer delivered to injured glia in the brain, even though significantly higher glial uptake was not observed in this model. Mannose conjugation to the dendrimer modifies the dendrimer's interaction with cells, but does not minimize its inherent inflammation-targeting abilities.

Keywords: Activated glia; CD206; Cerebral palsy; Dendrimer; Mannose receptors; Nanoparticle; Neuroinflammation; Targeting.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Animals, Newborn
Brain Injuries / metabolism
Cerebral Palsy / metabolism*
Dendrimers / administration & dosage*
Dendrimers / pharmacokinetics
Disease Models, Animal
Female
Mannose / administration & dosage*
Mannose / pharmacokinetics
Mice
RAW 264.7 Cells
Rabbits
Tissue Distribution

Substances

Dendrimers
PAMAM Starburst
Mannose

Abstract

Publication types

MeSH terms

Substances

Grants and funding