title: An amphiphilic graft copolymer-based nanoparticle platform for reduction-responsive anticancer and antimalarial drug delivery.
abstract: Medical applications of anticancer and antimalarial drugs often suffer from low aqueous solubility, high systemic toxicity, and metabolic instability. Smart nanocarrier-based drug delivery systems provide means of solving these problems at once. Herein, we present such a smart nanoparticle platform based on self-assembled, reduction-responsive amphiphilic graft copolymers, which were successfully synthesized through thiol-disulfide exchange reaction between thiolated hydrophilic block and pyridyl disulfide functionalized hydrophobic block. These amphiphilic graft copolymers self-assembled into nanoparticles with mean diameters of about 30-50 nm and readily incorporated hydrophobic guest molecules. Fluorescence correlation spectroscopy (FCS) was used to study nanoparticle stability and triggered release of a model compound in detail. Long-term colloidal stability and model compound retention within the nanoparticles was found when analyzed in cell media at body temperature. In contrast, rapid, complete reduction-triggered disassembly and model compound release was achieved within a physiological reducing environment. The synthesized copolymers revealed no intrinsic cellular toxicity up to 1 mg mL(-1). Drug-loaded reduction-sensitive nanoparticles delivered a hydrophobic model anticancer drug (doxorubicin, DOX) to cancer cells (HeLa cells) and an experimental, metabolically unstable antimalarial drug (the serine hydroxymethyltransferase (SHMT) inhibitor (±)-1) to Plasmodium falciparum-infected red blood cells (iRBCs), with higher efficacy compared to similar, non-sensitive drug-loaded nanoparticles. These responsive copolymer-based nanoparticles represent a promising candidate as smart nanocarrier platform for various drugs to be applied to different diseases, due to the biocompatibility and biodegradability of the hydrophobic block, and the protein-repellent hydrophilic block.
authors.affiliation: Department of Chemistry, University of Basel, Klingelbergstrasse 80, CH-4056 Basel, Switzerland. wolfgang.meier@unibas.ch.
authors.forename: Adrian
authors.initials: A
authors.lastname: Najer
authors.forename: Dalin
authors.initials: D
authors.lastname: Wu
authors.forename: Martin G
authors.initials: MG
authors.lastname: Nussbaumer
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Schwertz
authors.forename: Anatol
authors.initials: A
authors.lastname: Schwab
authors.forename: Matthias C
authors.initials: MC
authors.lastname: Witschel
authors.forename: Anja
authors.initials: A
authors.lastname: Schäfer
authors.forename: François
authors.initials: F
authors.lastname: Diederich
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.forename: Cornelia G
authors.initials: CG
authors.lastname: Palivan
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Beck
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Meier
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage; D004337:Drug Carriers / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008823:Micelles; D053758:Nanoparticles; D011108:Polymers
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D004317:Doxorubicin