TY - JOUR
T1 - Quantitative assessment of surface functionality effects on microglial uptake and retention of PAMAM dendrimers
AU - Liaw, Kevin
AU - Gök, Ozgul
AU - DeRidder, Louis B.
AU - Kannan, Sujatha
AU - Kannan, Rangaramanujam M.
N1 - Funding Information:
This work was funded by the National Institute of Biomedical Imaging and Bioengineering grant no. 5R01EB018306-02. We thank the Wilmer Core Grant for Vision Research, Microscopy and Imaging Core Module grant no. EY001865 for access to the Zen LSM710 confocal microscope and Accuri C6 flow cytometer. We kindly thank Drs. Fan Zhang, Yi-An Lin, and Siva Kambhampati for providing the dendrimers for this study.
Publisher Copyright:
© 2018, Springer Science+Business Media B.V., part of Springer Nature.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
KW - Cellular trafficking
KW - Dendrimer
KW - Microglia
KW - Nanobiomedicine
KW - Nanoparticle
KW - Neuroinflammation
KW - PAMAM
UR - http://www.scopus.com/inward/record.url?scp=85046094935&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046094935&partnerID=8YFLogxK
U2 - 10.1007/s11051-018-4219-1
DO - 10.1007/s11051-018-4219-1
M3 - Article
AN - SCOPUS:85046094935
SN - 1388-0764
VL - 20
JO - Journal of Nanoparticle Research
JF - Journal of Nanoparticle Research
IS - 4
M1 - 111
ER -