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19F- and fluorescently labeled micelles as nanoscopic assemblies for chemotherapeutic delivery.

ABSTRACT: Micelles from amphiphilic star-block copolymers, having a hydrophobic hyperbranched core and amphiphilic fluoropolymer arms, were constructed as drug delivery agent assemblies. A series of polymer structures was constructed from consecutive copolymerizations of 4-chloromethylstyrene with dodecyl acrylate and then 1,1,1- trifluoroethyl methacrylate with tert-butyl acrylate, followed by acidolysis to release the hydrophilic acrylic acid residues. These structures were labeled with cascade blue as a fluorescence reporter. The series of materials differed primarily in the ratio of 1,1,1-trifluoroethyl methacrylate to acrylic acid units, to give differences in fluorine loading and hydrophobicity/hydrophilicity balance. Doxorubicin (DOX) was used as a therapeutic to study the loading, release, and cytotoxicity of these micellar constructs on an U87-MG-EGFRvIII-CBR cell line. The micelles, with TEM-measured diameters ranging 5-9 nm and DLS-measured hydrodynamic diameters 20-30 nm, had loading capacities of ca. 4 wt % of DOX. The DOX-loaded micelles exhibited potent cytotoxicity with cell viabilities of 60-25% at 1.0 microg/mL effective DOX concentrations, depending upon the polymer composition, as determined by MTT assays. These cell viability values are comparable to that of free DOX, suggesting an effective release of the cargo and delivery to the cell nuclei, which was further confirmed by fluorescence microscopy of the cells. 19F-NMR spectroscopy indicated a partial degradation of the surface-available trifluoroethyl ester linkages of the micelles, which may have accelerated the release of DOX. 19F-NMR spectroscopy was also employed to confirm and to quantify the cell uptake of the micelles. These dual fluorescent- and 19F-labeled and chemically functional micelles may be used potentially in a variety of applications, such as cell labeling, imaging, and therapeutic delivery.

SUBMITTER: Du W

PROVIDER: S-EPMC2703787 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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19F- and fluorescently labeled micelles as nanoscopic assemblies for chemotherapeutic delivery.

Du Wenjun W Xu Zhiqiang Z Nyström Andreas M AM Zhang Ke K Leonard Jeffrey R JR Wooley Karen L KL

Bioconjugate chemistry 20081201 12

Micelles from amphiphilic star-block copolymers, having a hydrophobic hyperbranched core and amphiphilic fluoropolymer arms, were constructed as drug delivery agent assemblies. A series of polymer structures was constructed from consecutive copolymerizations of 4-chloromethylstyrene with dodecyl acrylate and then 1,1,1- trifluoroethyl methacrylate with tert-butyl acrylate, followed by acidolysis to release the hydrophilic acrylic acid residues. These structures were labeled with cascade blue as ...[more]

PMID: 19049473

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Project description:Oxidation-sensitive drug delivery systems (DDSs) have attracted attention due to the potential to improve efficacy and safety of chemotherapeutics. These systems are designed to release the payload in response to oxidative stress conditions, which are associated with many types of cancer. Despite extensive research on the development of oxidation-sensitive DDS, the lack of selectivity toward cancer cells over healthy cells remains a challenge. Here, we report the design and characterization of polymeric micelles containing thioether groups with varying oxidation sensitivities within the micellar core, which become hydrophilic upon thioether oxidation, leading to destabilization of the micellar structure. We first used the thioether model compounds, 3-methylthiopropylamide (TPAM), thiomorpholine amide (TMAM), and 4-(methylthio)benzylamide (TPhAM) to investigate the effect of the chemical structures of the thioethers on the oxidation by hydrogen peroxide (H2O2). TPAM shows the fastest oxidation, followed by TMAM and TPhAM, showing that the oxidation reaction of thioethers can be modulated by changing the substituent groups bound to the sulfur atom. We next prepared micelles containing these different thioether groups within the core (TP, TM, and TPh micelles). The micelles containing the thioether groups with a higher oxidation sensitivity were destabilized by H2O2 at a lower concentration. Micelle destabilization was also tested in human liver cancer (HepG2) cells and human umbilical vein endothelial cells (HUVECs). The TP micelles having the highest oxidation sensitivity were destabilized in both HepG2 cells and HUVECs, while the TPh micelles, which showed the lowest reactivity toward H2O2, were stable in these cell lines. The TM micelles possessing a moderate oxidation sensitivity were destabilized in HepG2 cells but were stable in HUVECs. Furthermore, the micelles were loaded with doxorubicin (Dox) to evaluate their potential in drug delivery applications. Among the micelles, the TM micelles loaded with Dox showed the enhanced relative toxicity in HepG2 cells over HUVECs. Therefore, our approach to fine-tune the oxidation sensitivity of the micelles has potential for improving therapeutic efficacy and safety of drugs in cancer treatment.

Dataset Information

19F- and fluorescently labeled micelles as nanoscopic assemblies for chemotherapeutic delivery.

Publications

19F- and fluorescently labeled micelles as nanoscopic assemblies for chemotherapeutic delivery.

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