Micelles with ultralow critical micelle concentration

Exploration of an unusual assembling behavior of a zwitterionic polymer-lipid surfactant molecule led to a better formulation for drug delivery

Go to the profile of Zhiqiang Cao
May 09, 2018
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The paper in Nature Biomedical Engineering is here:

The origin of this work dates back to 2009 when I was a Chemical Engineering student at the University of Washington in Seattle. At that time, my PhD advisor Prof. Shaoyi Jiang and I were curious about what would happen if we were to conjugate a zwitterionic betaine polymer (PCB) to a lipid (structure in Figure 1). Polyethylene glycol (PEG)–lipid conjugates have shown promise as drug delivery agents, mostly because of the water-soluble property of PEG that stabilize colloids. We expected that PCB–lipid, by replacing PEG with PCB, would be at least similarly useful—and potentially even better— since PCB is superhydrophilic. 

Figure 1. Ultra-low- critical micelle concentration (CMC) micelles (with sharp polarity contrast) can stabilize cargoes in extremely diluted conditions under micelle concentrations far below the CMCs of common micelles. Conventional micelles dissociate at a concentration below that of CMC, and thus are unable to stabilize a hydrophobic cargo (adapted from Figure 1 from our paper).

The polarity contrast between PCB and lipid in a PCB–lipid construct is sharp, and its synthesis was challenging. The superhydrophilic PCB dissolved in water only and can hardly be dissolved in the common organic solvents used for suspension of the second lipid block. By contrast, PEG is much easier to work with since it can easily dissolve in both water and several organic solvents. We ended up using a precursor polymer for PCB with improved solubility in organic solvents to conjugate with the lipid, followed by regenerating the PCB to finally obtain the PCB–lipid.  

It turned out that this hard-to-synthesize PCB–lipid resulted in unusual stabilizing properties (as shown in our previous study published in 2012; ref.1). In a side-by-side comparison between the PCB–lipid-modified liposome and the PEG–lipid-modified liposome, we found the former could uniquely stabilize the lipid membrane structure whereas the latter tended to destabilize it (as reflected by a decrease and an increase of the melting temperature of the major lipid composition for PCB–lipid and PEG–lipid-modified liposomes, respectively). This stabilization difference resulted in enhanced drug retention by the PCB–lipid-modified liposome without the need for large amounts of cholesterol in the liposome formulation, something that was required by the PEG–lipid-modified liposomes to prevent drug leakage.

Another unusual property of PCB–lipid, we speculated, might be its assembling behavior into micelles. At the time we used a commonly adopted pyrene-based method to determine the CMC of PCB–lipid, which was found to be ~10-3 mM. This CMC value was similar to the CMC of PEG–lipid, so nothing interesting was observed then. But after I joined Wayne State faculty in 2013, a review article caught my attention2. It indicated that the pyrene and majority of methods can only “produce an upper estimation rather than an actual value” of CMC for compounds potentially having very low CMC. Feeling curious about the potential unusual assembling behavior, I resumed the research on the PCB–lipid formulation, and my students and I started to look for ways to determine an ultralow CMC value since then. Our paper in Nature Biomedical Engineering now describes and verifies this new method, and reports that PCB–lipid with 5K molecular weight for PCB showed an undetectable ultralow CMC below 10-6 mM.

We further showed in the paper that the ultralow CMC PCB–lipid micelle formulation has significant implications as drug carriers (Figure 1). These micelles can protect cargoes at extremely diluted conditions, including serum dilution, when conventional micelle entities disassemble into free surfactants and prematurely dump the payloads owing to their relatively high CMCs. The improved drug delivery efficiency of PCB–lipid was showcased in a mouse model of melanoma, in which PCB–lipid micelles encapsulating docetaxel were able to eradicate the tumors when regular docetaxel micellar formulations did not. We expect the PCB–lipid micelle can be utilized to enhance the delivery and therapeutic effects of other hydrophobic drugs.


Our paper: Lu, Y. et al. Micelles with ultralow critical micelle concentration as carriers for drug delivery. Nat. Biomed. Eng. doi: 10.1038/s41551-018-0234-x (2018).

References: 1. Cao, Z.Q., Zhang, L. & Jiang, S.Y. Superhydrophilic zwitterionic polymers stabilize liposomes. Langmuir 28, 11625 (2012). 2. Lukyanov, A.N. & Torchilin, V.P. Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs. Adv. Drug Deliv. Rev. 56, 1273 (2014).

Go to the profile of Zhiqiang Cao

Zhiqiang Cao

Associate Professor, Wayne State University

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