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L-Serine–modified polyamidoamine dendrimer as a highly potent renal targeting drug carrier
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L-Serine–modified polyamidoamine dendrimer as a highly potent renal targeting drug carrier
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Journal Article
L-Serine–modified polyamidoamine dendrimer as a highly potent renal targeting drug carrier
2018
Overview
Effective delivery of drug carriers selectively to the kidney is challenging because of their uptake by the reticuloendothelial system in the liver and spleen, which limits effective treatment of kidney diseases and results in side effects. To address this issue, we synthesized L-serine (Ser)–modified polyamidoamine dendrimer (PAMAM) as a potent renal targeting drug carrier. Approximately 82% of the dose was accumulated in the kidney at 3 h after i.v. injection of 111In-labeled Ser-PAMAM in mice, while i.v. injection of 111In-labeled unmodified PAMAM, L-threonine modified PAMAM, and L-tyrosine modified PAMAM resulted in kidney accumulations of 28%, 35%, and 31%, respectively. Single-photon emission computed tomography/computed tomography (SPECT/CT) images also indicated that 111In-labeled Ser-PAMAM specifically accumulated in the kidneys. An intrakidney distribution study showed that fluorescein isothiocyanate-labeled Ser-PAMAM accumulated predominantly in renal proximal tubules. Results of a cellular uptake study of Ser-PAMAM in LLC-PK1 cells in the presence of inhibitors [genistein, 5-(N-ethyl-N-isopropyl)amiloride, and lysozyme] revealed that caveolae-mediated endocytosis, micropinocytosis, and megalin were associated with the renal accumulation of Ser-PAMAM. The efficient renal distribution and angiotensin-converting enzyme (ACE) inhibition effect of captopril (CAP), an ACE inhibitor, was observed after i.v. injection of the Ser-PAMAM-CAP conjugate. These findings indicate that Ser-PAMAM is a promising renal targeting drug carrier for the treatment of kidney diseases. Thus, the results of this study demonstrate efficient renal targeting of a drug carrier via Ser modification.
Publisher
National Academy of Sciences
Subject
/ Angiotensin-Converting Enzyme Inhibitors - administration & dosage
/ Angiotensin-Converting Enzyme Inhibitors - chemistry
/ Angiotensin-Converting Enzyme Inhibitors - pharmacology
/ Animals
/ Captopril - administration & dosage
/ Caveolae
/ Dendrimers - administration & dosage
/ Drug Carriers - administration & dosage
/ Kidney Diseases - drug therapy
/ Kidneys
/ L-Serine
/ Liver
/ Lysozyme
/ Mice
/ Single photon emission computed tomography
/ Spleen
/ Tyrosine
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