Quantitative assessment of surface functionality effects on microglial uptake and retention of PAMAM dendrimers

Kevin Liaw, Ozgul Gök, Louis B. DeRidder, Sujatha Kannan, Kannan Rangaramanujam

Research output: Contribution to journalArticle

Abstract

Dendrimers are a promising class of polymeric nanoparticles for delivery of therapeutics and diagnostics. Polyamidoamine (PAMAM) dendrimers have shown significant efficacy in many animal models, with performance dependent on surface functionalities. Understanding the effects of end groups on biological interactions is critical for rational design of dendrimer-mediated therapies. In this study, we quantify the cellular trafficking kinetics (endocytosis and exocytosis) of generation 4 neutral (D4-OH), cationic (D4-NH2), anionic (D3.5-COOH), and generation 6 neutral (D6-OH) PAMAM dendrimers to investigate the nanoscale effects of surface functionality and size on cellular interactions. Resting and LPS-activated microglia were studied due to their central roles in dendrimer therapies for central nervous system disorders. D4-OH exhibits greater cellular uptake and lower retention than the larger D6-OH. D4-OH and D3.5-COOH exhibit similar trafficking kinetics, while D4-NH2 exhibits significant membrane interactions, resulting in faster cell association but lower internalization. Cationic charge may also enhance vesicular escape for greater cellular retention and preferential partitioning to nuclei. LPS activation further improves uptake of dendrimers, with smaller and cationic dendrimers experiencing the greatest increases in uptake compared to resting microglia. These studies have implications for the dependence of trafficking pathway on dendrimer properties and inform the design of dendrimer constructs tailored to specific therapeutic needs. Cationic dendrimers are ideal for delivering genetic materials to nuclei, but toxicity may be a limiting factor. Smaller, neutral dendrimers are best suited for delivering high levels of therapeutics in acute neuroinflammation, while larger or cationic dendrimers provide robust retention for sustained release of therapeutics in longer-term diseases.

Original languageEnglish (US)
Article number111
JournalJournal of Nanoparticle Research
Volume20
Issue number4
DOIs
StatePublished - Apr 1 2018

Fingerprint

Dendrimers
Surface Effects
dendrimers
Nucleus
Therapy
Poly(amidoamine)
therapy
Kinetics
Interaction
Animal Model
central nervous system
animal models
nuclei
kinetics
Neurology
interactions
Toxicity
toxicity
Acute
escape

Keywords

  • Cellular trafficking
  • Dendrimer
  • Microglia
  • Nanobiomedicine
  • Nanoparticle
  • Neuroinflammation
  • PAMAM

ASJC Scopus subject areas

  • Bioengineering
  • Atomic and Molecular Physics, and Optics
  • Chemistry(all)
  • Modeling and Simulation
  • Materials Science(all)
  • Condensed Matter Physics

Cite this

Quantitative assessment of surface functionality effects on microglial uptake and retention of PAMAM dendrimers. / Liaw, Kevin; Gök, Ozgul; DeRidder, Louis B.; Kannan, Sujatha; Rangaramanujam, Kannan.

In: Journal of Nanoparticle Research, Vol. 20, No. 4, 111, 01.04.2018.

Research output: Contribution to journalArticle

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