title: Click synthesis of a polyamidoamine dendrimer-based camptothecin prodrug.
abstract: In the present work we report on the click synthesis of a new camptothecin (CPT) prodrug based on anionic polyamidoamine (PAMAM) dendrimer intended for cancer therapy. We applied 'click' chemistry to improve polymer-drug coupling reaction efficiency. Specifically, CPT was functionalized with a spacer, 1-azido-3,6,9,12,15-pentaoxaoctadecan-18-oic acid (APO), via EDC/DMAP coupling reaction. In parallel, propargylamine (PPA) and methoxypoly(ethylene glycol) amine were conjugated to PAMAM dendrimer G4.5 in sequence using an effective coupling agent 4-(4,6-dimethoxy-(1,3,5)triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM). CPT-APO was then coupled to PEGylated PAMAM dendrimer G4.5-PPA via a click reaction using copper bromide/2,2'-bipyridine/ dimethyl sulfoxide (catalyst/ligand/solvent). Human glioma cells were exposed to the CPT-conjugate to determine toxicity and cell cycle effects using WST-1 assay and flow cytometry. The CPT-conjugate displayed a dose-dependent toxicity with an IC50of 5 μM, a 185-fold increase relative to free CPT, presumably as a result of slow release. As expected, conjugated CPT resulted in G2/M arrest and cell death while the dendrimer itself had little to no toxicity. Altogether, highly efficient click chemistry allows for the synthesis of multifunctional dendrimers for sustained drug delivery.
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284.
authors.forename: Olga Yu
authors.initials: OY
authors.lastname: Zolotarskaya
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284.
authors.forename: Leyuan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA 23298 ; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Valerie
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284 ; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Hu
authors.initials: H
authors.lastname: Yang