PMID- 30472374
OWN - NLM
STAT- MEDLINE
DCOM- 20200319
LR  - 20211204
IS  - 1873-4995 (Electronic)
IS  - 0168-3659 (Linking)
VI  - 293
DP  - 2019 Jan 10
TI  - Folate-dactolisib conjugates for targeting tubular cells in polycystic kidneys.
PG  - 113-125
LID - S0168-3659(18)30665-5 [pii]
LID - 10.1016/j.jconrel.2018.11.019 [doi]
AB  - The aim of the present study was to develop folic acid (FA) conjugates which can 
      deliver the kinase inhibitor dactolisib to the kidneys via folate 
      receptor-mediated uptake in tubular epithelial cells. Dactolisib is a dual 
      inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of 
      rapamycin (mTOR) and is considered an attractive agent for treatment of 
      polycystic kidney disease. The ethylenediamine platinum(II) linker, herein called 
      Lx, was employed to couple dactolisib via coordination chemistry to 
      thiol-containing FA-spacer adducts to yield FA-Lx-dactolisib conjugates. The dye 
      lissamine was coupled via similar linker chemistry to folate to yield fluorescent 
      FA-Lx-lissamine conjugates. Three different spacers (PEG(5)-Cys, PEG(27)-Cys or 
      an Asp-Arg-Asp-Asp-Cys peptide spacer) were used to compare the influence of 
      hydrophilicity and charged groups in the spacer on interaction with target cells 
      and in vivo organ distribution of the final conjugates. The purity and identity 
      of the final products were confirmed by UPLC and LC-MS analysis, respectively. 
      FA-Lx-dactolisib conjugates were stable in serum and culture medium, while 
      dactolisib was released from the conjugates in the presence of glutathione. All 
      three type of conjugates were internalized efficiently by HK-2 cells and uptake 
      could be blocked by an excess of folic acid in the medium, demonstrating FR 
      mediated uptake. FA-Lx-dactolisib conjugates showed nanomolar inhibition of the 
      PI3K pathway (Akt phosphorylation) and mTOR pathway (S6 phosphorylation) in 
      cultured kidney epithelial cells (HK-2 cells). After intraperitoneal 
      administration, all three types conjugates accumulated extensively in kidneys of 
      iKsp-Pkd1(del) mice with polycystic kidney disease. In conclusion, folate 
      conjugates were successfully prepared by platinum(II) coordination chemistry and 
      accumulated in a target-specific manner in kidney cells and polycystic kidneys. 
      The folate conjugate of dactolisib thus may have potential for targeted therapy 
      of polycystic kidney disease.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Shi, Haili
AU  - Shi H
AD  - Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, 
      Utrecht University, Utrecht, The Netherlands.
FAU - Leonhard, Wouter N
AU  - Leonhard WN
AD  - Department of Human Genetics, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Sijbrandi, Niels J
AU  - Sijbrandi NJ
AD  - LinXis B.V., Amsterdam, The Netherlands.
FAU - van Steenbergen, Mies J
AU  - van Steenbergen MJ
AD  - Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, 
      Utrecht University, Utrecht, The Netherlands.
FAU - Fens, Marcel H A M
AU  - Fens MHAM
AD  - Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, 
      Utrecht University, Utrecht, The Netherlands.
FAU - van de Dikkenberg, Joep B
AU  - van de Dikkenberg JB
AD  - Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, 
      Utrecht University, Utrecht, The Netherlands.
FAU - Torano, Javier Sastre
AU  - Torano JS
AD  - Department of Chemical Biology and Drug Discovery, Utrecht Institute for 
      Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
FAU - Peters, Dorien J M
AU  - Peters DJM
AD  - Department of Human Genetics, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Hennink, Wim E
AU  - Hennink WE
AD  - Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, 
      Utrecht University, Utrecht, The Netherlands.
FAU - Kok, Robbert Jan
AU  - Kok RJ
AD  - Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, 
      Utrecht University, Utrecht, The Netherlands. Electronic address: r.j.kok@uu.nl.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181123
PL  - Netherlands
TA  - J Control Release
JT  - Journal of controlled release : official journal of the Controlled Release 
      Society
JID - 8607908
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Imidazoles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
MH  - Antineoplastic Agents/*administration & dosage
MH  - Cell Line
MH  - Drug Liberation
MH  - Folic Acid/*administration & dosage/chemistry
MH  - Humans
MH  - Imidazoles/*administration & dosage/chemistry
MH  - Kidney Tubules/cytology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors/*administration & dosage/chemistry
MH  - Polycystic Kidney Diseases/*drug therapy/metabolism
MH  - Quinolines/*administration & dosage/chemistry
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
OTO - NOTNLM
OT  - Coordination chemistry
OT  - Drug targeting
OT  - Receptor-mediated uptake
OT  - Signal transduction
EDAT- 2018/11/26 06:00
MHDA- 2020/03/20 06:00
CRDT- 2018/11/26 06:00
PHST- 2018/06/04 00:00 [received]
PHST- 2018/11/14 00:00 [revised]
PHST- 2018/11/20 00:00 [accepted]
PHST- 2018/11/26 06:00 [pubmed]
PHST- 2020/03/20 06:00 [medline]
PHST- 2018/11/26 06:00 [entrez]
AID - S0168-3659(18)30665-5 [pii]
AID - 10.1016/j.jconrel.2018.11.019 [doi]
PST - ppublish
SO  - J Control Release. 2019 Jan 10;293:113-125. doi: 10.1016/j.jconrel.2018.11.019. 
      Epub 2018 Nov 23.