Block copolymer micelles with acid-labile ortho ester side-chains: Synthesis, characterization, and enhanced drug delivery to human glioma cells
作者：tang rp, et al
關鍵字：drug delievery
論文來源：期刊
具體來源：Journal of Controlled Release
發表時間：2011年
A new type of block copolymer micelles for pH-triggered delivery of poorly water-oluble anticancer drugs has been synthesized and characterized. The micelles were formed by the self-assembly of an amphiphilic diblock copolymer consisting of a hydrophilic poly(ethylene glycol) (PEG) block and a hydrophobic polymethacrylate block (PEYM) bearing acid-labile ortho ester side-chains. The diblock copolymer was synthesized by atom transfer radical polymerization (ATRP) from a PEG macro-initiator to obtain welldefined polymer chain-length. The PEG-b-PEYM micelles assumed a stable core–shell structure in aqueous buffer at physiological pH with a low critical micelle concentration as determined by proton NMR and pyrene fluorescence spectroscopy. The hydrolysis of the ortho ester side-chain at physiological pH was minimal yet much accelerated at mildly acidic pHs. Doxorubicin (Dox) was successfully loaded into the micelles at pH 7.4
and was released at a much higher rate in response to slight acidification to pH 5. Interestingly, the release of Dox at pH 5 followed apparently a biphasic profile, consisting of an initial fast phase of several hours followed by a sustained release period of several days. Dox loaded in the micelles was rapidly taken up by human glioma (T98G) cells in vitro, accumulating in the endolysosome and subsequently in the nucleus in a few
hours, in contrast to the very low uptake of free drug at the same dose. The dose-dependent cytotoxicity of the
Dox-loaded micelles was determined by the MTT assay and compared with that of the free Dox. While the
empty micelles themselves were not toxic, the IC50 values of the Dox-loaded micelles were approximately
ten-times (by 24 h) and three-times (by 48 h) lower than the free drug. The much enhanced potency in killing
the multi-drug-resistant human glioma cells by Dox loaded in the micelles could be attributed to high
intracellular drug concentration and the subsequent pH-triggered drug release. These results establish the
PEG-b-PEYM block copolymer with acid-labile ortho ester side-chains as a novel and effective pH-responsive
nano-carrier for enhancing the delivery of drugs to cancer cells.
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