Micelles with ultralow critical micelle concentration as carriers for drug delivery

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Conventional micellar carriers disassemble into free surfactants when diluted at concentrations below the critical micelle concentration (CMC). This limits the bioavailability in vivo of injected hydrophobic drugs encapsulated in micellar systems. Here, we show that a micelle comprising a superhydrophilic zwitterionic polymer domain and a superhydrophobic lipid domain has an undetectable CMC below 106 mM—a value that is orders of magnitude lower than the CMCs (>10−3 mM) of typical micellar systems. We also show that zwitterionic moieties or zwitterionic polymers added to a micelle solution stabilize the micelles at concentrations below their inherent CMC. In a mouse model of melanoma, ultralow-CMC micelles encapsulating docetaxel led to the complete eradication of tumours, whereas conventional docetaxel micellar formulations did not reverse tumour growth. Ultralow-CMC micelles might become next-generation carriers for drug delivery.

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Fig. 1: Ultralow-CMC micelles and their unusual ability to stabilize cargoes in extremely diluted conditions with micelle concentrations far below the CMC of conventional micelles.
Fig. 2: TEM and DLS measurements for DSPE-PCB 5K micelles.
Fig. 3: Diluting–concentrating method to probe CMCs for micelles.
Fig. 4: Effect of supplying zwitterionic moieties on the CMC of conventional micelles, and impact of the zwitterionic PCB MW on the CMC of DSPE-PCB.
Fig. 5: Stability of ultralow-CMC micelles and conventional micelles with gold NP probes encapsulated at a 5.5 × 10–2 mM micelle concentration in 100% FBS over 72 h at room temperature.
Fig. 6: Stability of docetaxel/DSPE-PCB 5K formulation and its antitumour performance compared with control formulations.


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This work was supported by the faculty start-up fund at Wayne State University, National Science Foundation (DMR-1410853) and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (DP2DK111910). This work made use of the JEOL 2010 transmission electron microscope supported by National Science Foundation Award 0216084. We thank C.-H. Liu and W. Zhang at Michigan State University for support with static-light-scattering measurements.

Author contributions

Z.C., Y.L. and Z.Y. designed the experiments. Y.L. performed the experiments. J.X. and W.W. helped with the TEM figures. E.Z. and H.Z. helped with the animal experiments. Z.C. and Y.L. outlined and wrote the paper. Z.C. supervised the study.

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Correspondence to Zhiqiang Cao.

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Lu, Y., Yue, Z., Xie, J. et al. Micelles with ultralow critical micelle concentration as carriers for drug delivery. Nat Biomed Eng 2, 318–325 (2018) doi:10.1038/s41551-018-0234-x

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