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Superamphiphile Based Cross-Linked Small-Molecule Micelles for pH-Triggered Release of Anticancer Drugs Yun Chen, Jingsheng Huang, Shiyong Zhang, and Zhongwei Gu Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.7b00097 • Publication Date (Web): 01 Mar 2017 Downloaded from http://pubs.acs.org on March 1, 2017
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Chemistry of Materials
Superamphiphile Based Cross-Linked Small-Molecule Micelles for pH-Triggered Release of Anticancer Drugs Yun Chen,† Jingsheng Huang,‡ Shiyong Zhang,*,†,‡ and Zhongwei Gu† †
National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064,
China; ‡ College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China. *
To whom correspondence should be addressed. S. Zhang, E-mail:
[email protected]; Phone: +86-28-85411109. Fax:
+86-28-85411109.
ABSTRACT. A new superamphiphile based cross-linked small-molecule micelle (SA-CSM) is developed for pH-triggered release of anticancer drugs. This strategy resolves around the use of a noncovalent superamphiphile formed by the elaborate zwitterion 1 and anticancer drug doxorubicin (DOX) via their “spontaneous attraction” of carboxylic acid and amino group. The superamphiphiles selfassemble into micelles in water, which were further stabilized by cross-linking the surface via the thiolacrylate Michael addition to achieve the establishment of the pH-sensitive SA-CSMs. The biological
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evaluation shows that the new drug delivery system exhibits highly efficient anticancer efficacy both in vitro, on HeLa cancer cell line, and in vivo, on HeLa xenograft model, while suppressing the inherent toxicity of the employed chemotherapeutics. Compared with the reported covalent amphiphile based CSMs, the non-covalent superamphiphile based CSMs not only owns the comparable drug loading content (up to 45.0%), robust stability and superior predictable biosafety, but also features the nonchemical synthesis, low production cost, specific stimulus response, and anticancer activity of original drugs, and thus represents a closer example for the clinical application.
INTRODUCTION As probably the most widely used drug delivery platform, the polymeric micelles can tremendously enhance the water solubility of drugs, prolong the circulation in blood compartments, and increase their enrichment in tumors via an enhanced permeability and retention (EPR) effect, thereby enhancing the efficacy of the drug and suppressing the associated side-effects.1-3 Since they were first reported as drug carriers in the late 1980s,4 the polymeric micelle based drug delivery systems (PM-DDSs) have achieved many breakthroughs in the benchtop investigations. However, for further clinical applications, the polymeric micelles have to overcome some inherent flaws, that is, low drug loading contents, metastability and uncertain monomer purity.5-9 Although many attempts, so far there has not been a universal method for solving all of the problems. In this case, development of alternative carriers with polymeric micelle-like features while overcoming above limitations would be highly desirable. The cross-linked small-molecule micelles consist of monodisperse monomers (molecular weight of
