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Title: Altered Biodistribution and Tissue Retention of Nanoparticles Targeted with Pglycoprotein Substrates
Low molecular weight substrates of the efflux transporter, P-glycoprotein, alter the biodistribution and tissue retention of nanoparticles following intravenous administration. Of particular interest is the retention of the targeted nanoparticles in the brain. Drug delivery to the brain is hindered by the restricted transport of drugs through the blood-brain barrier (BBB). Drugs that passively diffuse across the BBB also have large volumes of distribution; therefore, alteration of their biodistribution to increase their concentration in the brain may help to enhance efficacy and reduce off-target side effects. In this work, targeted nanoparticles were used to explore a new approach to target drugs to the brain--the exploitation of the P-glycoprotein efflux pump. The retention of nanoparticles containing a strong P-glycoprotein substrate, rhodamine 6G, tethered to a PLA nanoparticle through a PEG spacer was greater than two-fold relative to untargeted nanoparticles and to nanoparticles tethered to a weaker Pglycoprotein substrate, rhodamine 123. In a P-glycoprotein knockout mouse model (mdr1a (-/-)), there were no significant differences in brain accumulation between rhodamine 6G targeted particles and controls, strongly supporting the role of Pglycoprotein. This proof of concept report shows the potential applicability of low molecular weight P-gp substrates to alter nanoparticle biodistribution.  more » « less
Award ID(s):
1719875
PAR ID:
10146860
Author(s) / Creator(s):
; ; ;
Date Published:
Journal Name:
Cornell University Library
ISSN:
1947-1955
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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