期刊
BIOMATERIALS SCIENCE
卷 1, 期 3, 页码 265-275出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c2bm00096b
关键词
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资金
- ARC (Australian Research Council) [FT0991273, DP110102409]
- Centre for Advanced Macromolecular Design (CAMD)
- UNSW Mark Wainwright Analytical Centre
Uptake of drug-loaded micelles by tumour cell lines can be the crucial step in the creation of an efficient drug delivery system. Crosslinking of micelles has increasingly been proposed as a pathway to create stable nanoparticles. So far, little is known how crosslinking can affect the interaction of these nano-carriers with cells. The aim of this study is therefore to investigate the effect of crosslinking on exo- and endocytosis. RAFT (reversible addition fragmentation chain transfer) polymerization has been used to synthesize the block copolymer poly(methyl methacrylate)-block-poly(polyethylene glycol methyl ether methacrylate) PMMA-b-P(PEGMEMA), which was subsequently self-assembled into micelles of 20 nm. For comparison, the micelles were shell-crosslinked by incorporating methacrylic acid into the shell, which was used as a reactive group for crosslinking with 1,8-diaminooctane. The hydrodynamic diameter of the shell-crosslinked micelle was with 25 nm similar to that of the non-crosslinked one. Endocytosis of both micelles was significantly reduced by the presence of NaN3 or at 4 degrees C suggesting an energy dependent process. The internalization pathways of the block copolymer micelles in OVCAR-3 cells were elucidated using endocytosis inhibitors. Both nanoparticles, micelles and shell-crosslinked micelles, were internalized by caveolae mediated endocytosis while clathrin mediated endocytosis did not play a noticeable role. Shell-crosslinking therefore did not have an effect on endocytosis. However, a considerable difference was found in the exocytosis of both particles. While the micelle was lodged inside the cell for an extended period of time with less than 3% released in two hours, the shell-crosslinked micelle quickly exited the OVCAR-3 cells (25% in two hours). For comparison, a small molecule (Lucifer yellow) was found to be only marginally faster than the crosslinked micelles (40% in 2 h). These results could have implications on the use polymer-drug conjugates or drug carriers where the drug needs to be released before the polymer undergoes exocytosis.
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