Sugar-modified poly(propylene imine) dendrimers as drug delivery agents for cytarabine to overcome drug resistance.
Maltose-modified poly(propylene imine) glycodendrimers (PPI-m OS) of the 4th generation provide a promising strategy for leukemia treatment. Anticancer therapy with nucleoside analog drugs such as cytarabine (Ara-C) frequently has limited efficacy due to drug resistance, inefficient uptake and accumulation of the drug inside cancer cells where it has to be transformed into the active triphosphate congener. The cationic nature of PPI dendrimers makes it possible to form complexes with nucleotide Ara-C triphosphate forms (Ara-CTP). The aim of this work was to test the concept of applying PPI glycodendrimers as drug delivery devices in order to facilitate the delivery of activated cytarabine to cancer cells to overcome metabolic limitations of the drug. The study has been carried out using 1301 and HL-60 leukemic cell lines as well as peripheral blood mononuclear cells. The results of cytotoxicity and apoptosis assays showed enhanced activity of Ara-C triphosphate form (Ara-CTP) complexed with PPI-m dendrimers in relation to free Ara-C and Ara-CTP against 1301 leukemic cells. Secondly, enhanced uptake and cytotoxicity of Ara-CTP-dendrimers complexes toward 1301 cells with blocked human equilibrative nucleoside transporter - hENT1 suggested that this combination might be a versatile candidate for chemotherapy against resistant acute lymphoblastic leukemia cells with lower expression of hENT1.
Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska St., 90-236 Lodz, Poland. Electronic address: aszulcab@gmail.com.
Aleksandra
A
Szulc
Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska St., 90-236 Lodz, Poland. Electronic address: lpulaski@uni.lodz.pl.
Lukasz
L
Pulaski
Leibniz Institute of Polymer Research Dresden, Hohe Str. 6, 01069 Dresden, Germany. Electronic address: applhans@ipfdd.de.
Dietmar
D
Appelhans
Leibniz Institute of Polymer Research Dresden, Hohe Str. 6, 01069 Dresden, Germany. Electronic address: voit@ipfdd.de.
Brigitte
B
Voit
Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska St., 90-236 Lodz, Poland; Leibniz Institute of Polymer Research Dresden, Hohe Str. 6, 01069 Dresden, Germany. Electronic address: aklajn@biol.uni.lodz.pl.
Barbara
B
Klajnert-Maculewicz
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000008:administration & dosage* / Q000494:pharmacology; D050091:Dendrimers / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D007963:Leukocytes, Mononuclear; D008320:Maltose / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D011126:Polypropylenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D050091:Dendrimers; D033721:Equilibrative Nucleoside Transporter 1; D011126:Polypropylenes; C438649:SLC29A1 protein, human; C443641:poly(propyleneimine); D003561:Cytarabine; D008320:Maltose
Cytarabine; Drug carriers; Drug resistance; Leukemia; PPI dendrimers