title: Dendritic polyglycerol sulfate as a novel platform for paclitaxel delivery: pitfalls of ester linkage.
abstract: In this study, dendritic polyglycerol sulfate (dPGS) is evaluated as a delivery platform for the anticancer, tubulin-binding drug paclitaxel (PTX). The conjugation of PTX to dPGS is conducted via a labile ester linkage. A non-sulfated dendritic polyglycerol (dPG) is used as a control, and the labeling with an indocarbocyanine dye (ICC) renders multifunctional conjugates that can be monitored by fluorescence microscopy. The conjugates are characterized by (1)H NMR, UV-vis measurements, and RP-HPLC. In vitro cytotoxicity of PTX and dendritic conjugates is evaluated using A549 and A431 cell lines, showing a reduced cytotoxic efficacy of the conjugates compared to PTX. The study of uptake kinetics reveals a linear, non saturable uptake in tumor cells for dPGS-PTX-ICC, while dPG-PTX-ICC is hardly taken up. Despite the marginal uptake of dPG-PTX-ICC, it prompts tubulin polymerization to a comparable extent as PTX. These observations suggest a fast ester hydrolysis and premature drug release, as confirmed by HPLC measurements in the presence of plasma enzymes.
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany. marcelo.calderon@fu-berlin.de.
authors.forename: Ana
authors.initials: A
authors.lastname: Sousa-Herves
authors.forename: Patrick
authors.initials: P
authors.lastname: Würfel
authors.forename: Nicole
authors.initials: N
authors.lastname: Wegner
authors.forename: Jayant
authors.initials: J
authors.lastname: Khandare
authors.forename: Kai
authors.initials: K
authors.lastname: Licha
authors.forename: Rainer
authors.initials: R
authors.lastname: Haag
authors.forename: Pia
authors.initials: P
authors.lastname: Welker
authors.forename: Marcelo
authors.initials: M
authors.lastname: Calderón
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D004952:Esters; D005990:Glycerol / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008856:Microscopy, Fluorescence; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry*; D013431:Sulfates / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D050091:Dendrimers; D004337:Drug Carriers; D004952:Esters; D011108:Polymers; D013431:Sulfates; C043941:polyglycerol; D017239:Paclitaxel; D005990:Glycerol