A facile approach for dual-responsive prodrug nanogels based on dendritic polyglycerols with minimal leaching.
A novel pH and redox dual-responsive prodrug nanogel was prepared by an inverse nanoprecipitation method, which is mild and surfactant free, and based on a thiol-disulfide exchange reaction and thiol-Michael addition reaction. Highly biocompatible hyperbranched polyglycerol (hPG) was cross-linked with disulfide bonds, to obtain biodegradable nanogels, which could be degraded under intracellular reductive conditions. Doxorubicin (DOX) was conjugated to the biodegradable nanogel matrix via an acid-labile hydrazone linker. This is the first dual-responsive prodrug nanogel system that shows very low unspecific drug leaching, but efficient intracellular release of the payload triggered by the intracellular conditions. Two different prodrug nanogels were prepared with a size of approximately 150nm, which is big enough to take the advantage of the enhanced permeation and retention (EPR) effect in tumor tissue. Cell culture analysis by microscopy and flow cytometry revealed that the prodrug nanogels were efficiently internalized by tumor cells. Distinct release profiles of DOX were achieved by adjusting the nanogel architecture, and online detection of cytotoxicity showed that, unlike free DOX, the dual-responsive prodrug nanogels exhibited a delay in the onset of toxicity, indicating the different uptake mechanism and the need for prodrug activation to induce cell death.
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustraße 3, 14195 Berlin, Germany.
Xuejiao
X
Zhang
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustraße 3, 14195 Berlin, Germany; Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany.
Katharina
K
Achazi
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustraße 3, 14195 Berlin, Germany.
Dirk
D
Steinhilber
Tumor Biology Center and Proqinase GmbH, Breisacher Strasse 117, D-79106 Freiburg, Germany.
Felix
F
Kratz
Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany.
Jens
J
Dernedde
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustraße 3, 14195 Berlin, Germany. Electronic address: haag@chemie.fu-berlin.de.
Rainer
R
Haag
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry; D004339:Drug Compounding / Q000379:methods*; D005782:Gels / Q000008:administration & dosage / Q000737:chemistry*; D005990:Glycerol / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry*
D000903:Antibiotics, Antineoplastic; D005782:Gels; D011108:Polymers; D011355:Prodrugs; C043941:polyglycerol; D004317:Doxorubicin; D005990:Glycerol
Cellular uptake; Controlled drug release; Nanogel degradation; Polyglycerol nanogel; Prodrug