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Issue 10, 2012
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Efficient inhibition of colorectal peritoneal carcinomatosis by drug loaded micelles in thermosensitive hydrogel composites

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Abstract

In this work, we aim to develop a dual drug delivery system (DDDS) of self-assembled micelles in thermosensitive hydrogel composite to deliver hydrophilic and hydrophobic drugs simultaneously for colorectal peritoneal carcinomatosis (CRPC) therapy. In our previous studies, we found that poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-caprolactone) (PCEC) copolymers with different molecular weight and PEG/PCL ratio could be administered to form micelles or thermosensitive hydrogels, respectively. Therefore, the DDDS was constructed from paclitaxel (PTX) encapsulated PCEC micelles (PTX-micelles) and a fluorouracil (Fu) loaded thermosensitive PCEC hydrogel (Fu-hydrogel). PTX-micelles were prepared by self-assembly of biodegradable PCEC copolymer (Mn = 3700) and PTX without using any surfactants or excipients. Meanwhile, biodegradable and injectable thermosensitive Fu-hydrogel (Mn = 3000) with a lower sol–gel transition temperature at around physiological temperature was also prepared. The obtained PTX-micelles in thermosensitive Fu-hydrogel (PTX-micelles–Fu-hydrogel) composite is a free-flowing sol at ambient temperature and rapidly turned into a non-flowing gel at physiological temperature. In addition, the results of cytotoxicity, hemolytic study, and acute toxicity evaluation suggested that the PTX-micelles–Fu-hydrogel was non-toxic and biocompatible. In vitro release behaviors of PTX-micelles–Fu-hydrogel indicated that both PTX and Fu have a sustained release behavior. Furthermore, intraperitoneal application of PTX-micelles–Fu-hydrogel effectively inhibited growth and metastasis of CT26 peritoneal carcinomatosis in vivo (p < 0.001), and induced a stronger antitumor effect than that of Taxol® plus Fu (p < 0.001). The pharmacokinetic study indicated that PTX-micelles–Fu-hydrogel significantly increased PTX and Fu concentration and residence time in peritoneal fluids compared with Taxol® plus Fu group. Thus, the results suggested the micelles–hydrogel DDDS may have great potential clinical applications.

Graphical abstract: Efficient inhibition of colorectal peritoneal carcinomatosis by drug loaded micelles in thermosensitive hydrogel composites

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Publication details

The article was received on 05 Feb 2012, accepted on 27 Mar 2012 and first published on 02 Apr 2012


Article type: Paper
DOI: 10.1039/C2NR30278K
Citation: Nanoscale, 2012,4, 3095-3104
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    Efficient inhibition of colorectal peritoneal carcinomatosis by drug loaded micelles in thermosensitive hydrogel composites

    C. Gong, C. Wang, Y. Wang, Q. Wu, D. Zhang, F. Luo and Z. Qian, Nanoscale, 2012, 4, 3095
    DOI: 10.1039/C2NR30278K

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