l -Serine–modified polyamidoamine dendrimer as a highly potent renal targeting drug carrier

Abstract

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 111 In-labeled Ser-PAMAM in mice, while i.v. injection of 111 In-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 111 In-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 angiotensinconverting 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.drug delivery | renal targeting | L-serine | dendrimer

l-Cysteine and l-Serine Modified Dendrimer with Multiple Reduced Thiols as a Kidney-Targeting Reactive Oxygen Species Scavenger to Prevent Renal Ischemia/Reperfusion Injury

“…Ser-PAMAM-Cys was synthesized by reacting Ser and Cys with third-generation (G3) PAMAM according to the HBTU-HOBt method [14]. Briefly, PAMAM dendrimer (86.5 mg, 0.013 mmol) was coupled with 0.22 eq (equivalent to the dendrimer surface amino group) Boc-Cys(Trt)-OH (40.9 mg, 0.088 mmol) and 0.88 eq Boc-Ser( t Bt)-OH (92.1 mg, 0.35 mmol) in DMF/DMSO (1:1) by mixing it with 1.1 eq HBTU (167 mg, 0.44 mmol), 1.1 eq HOBt (59.6 mg, 0.44 mmol), and 2.2 eq DIPEA(154 µL, 0.88 mmol).…”

“…We recently developed the l -serine (Ser)-modified polyamidoamine (PAMAM) dendrimer. It is a highly potent renal-targeting drug carrier [14]. In mice, ~82% of the intravenously administered Ser-PAMAM dose accumulated in the kidney.…”

ROS-responsive chitosan-SS31 prodrug for AKI therapy via rapid distribution in the kidney and long-term retention in the renal tubule

“…Chemical modification of macromolecules is used to generate materials with fascinating physiochemical and biochemical properties for biomedical applications. l -Serine is a potent renal tubule–targeted modifier ( 20 ), which is also a potential targeting agent for kidney injury molecule–1 (Kim-1). Kim-1 is a transmembrane protein markedly up-regulated in injured kidneys, particularly renal proximal tubules, which induces the internalization and, therefore, the clearance of dead cells through the recognition of phosphatidylserine and oxidized lipoprotein on the surfaces of the dead cells ( 21 ).…”

Drug discovery and formulation development for acute pancreatitis

“…Matsuura et al. modified PAMAM dendrimers with l-cysteine and l-serine and achieved dominant renal distribution in a renal ischemia/reperfusion injury animal model (Matsuura et al., 2018a , 2018b ). Their studies first confirmed that PAMAM dendrimers efficiently scavenge ROS and prevent renal ischemia/reperfusion injury.…”