Single Molecule Visualization of Stable, Stiffness-Tunable, Flow-Conforming Worm Micelles

Dalhaimer, Paul; Bates, Frank S.; Discher, Dennis E.

doi:10.1021/ma034120d

Cited by 110 publications

(148 citation statements)

References 29 publications

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“…In a systematic study of cross-linking within wormlike micelles formed from a blend of cross-linkable and noncross-linkable copolymers (22), percolation behavior (indicating complete cross-linking) was observed for mol fractions of crosslinkable copolymers Ͼ0.15. Because we only use 8 wt % (Ϸ1.7% mol fraction) pluronic F-127 in the formation of our polymersomes, it seems reasonable that we should observe rigid nanotubes after cross-linking.…”

mentioning

confidence: 99%

Stable and robust polymer nanotubes stretched from polymersomes

Reiner

Wells

Kishore

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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We create long polymer nanotubes by directly pulling on the membrane of polymersomes using either optical tweezers or a micropipette. The polymersomes are composed of amphiphilic diblock copolymers, and the nanotubes formed have an aqueous core connected to the aqueous interior of the polymersome. We stabilize the pulled nanotubes by subsequent chemical crosslinking. The cross-linked nanotubes are extremely robust and can be moved to another medium for use elsewhere. We demonstrate the ability to form networks of polymer nanotubes and polymersomes by optical manipulation. The aqueous core of the polymer nanotubes together with their robust character makes them interesting candidates for nanofluidics and other applications in biotechnology.cross-link ͉ optical tweezers ͉ nanofluidics ͉ vesicles N anotubes are among the most promising structures in nanotechnology. Carbon nanotubes are already finding applications in composite materials requiring high strength-to-weight ratio, and many more applications are expected in the near future (1). Nanotubes also can naturally occur in biology. Transport of genetic material from phage viruses to bacteria can occur via protein nanotubes (2), and phospholipid nanotubes between live cells, purported to be a conduit for intercellular organelle transport, were recently observed (3). The use of nanotubes for transport of biological molecules is particularly exciting, with potentially significant applications in biotechnology. Gold nanotubules in polymer membranes have been used to separate small biological molecules on the basis of molecular size (4) and DNA fragments according to base recognition. Experiments on the movement of DNA in nanofabricated structures (5, 6) showed that new transport mechanisms occur when spatial confinement in one or more dimensions is less than the radius of gyration. Similar effects also have been observed with DNA fragments passing through multiwalled carbon nanotubes (7). All of these nanotubular structures have an interior aqueous environment suitable for biological molecules, but with the exception of ref. 6, the length of an individual channel is only on the order of 1 m.Extremely long, water-filled nanotubes can be formed from self-assembling amphiphilic molecules. For example, phospholipids can spontaneously form nanotubes under appropriate conditions (8). Vesicle membranes composed of self-assembled amphiphilic molecules can exhibit both elastic and viscoelastic properties, which, under the application of a localized force, can result in the formation of a nanotube. Pioneering work by Evans et al. (9) demonstrated the formation of phospholipid nanotubes by using a micropipette to pull on phospholipid vesicle (liposome) membranes. More recently, Orwar and coworkers (10) adopted the technique of Evans to create elaborate networks of liposomes interconnected by phospholipid nanotubes and demonstrated transport through these networks. Similarly, optical tweezers have been used to create phospholipid nanotubes by pulling directly on membranes of ...

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mentioning

confidence: 99%

Stable and robust polymer nanotubes stretched from polymersomes

Reiner

Wells

Kishore

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Filomicelles were prepared from hydration of di-block copolymers with no residual cosolvent 13,23 . Block copolymers of PEG-polyethylethylene (EO m -EE n , designated OE) or PEGpolycaprolactone (EO m -CL n , designated OCL) were synthesized by standard polymerizations 8; Table 1 provides details of the di-blocks used here.…”

Section: Methodsmentioning

confidence: 99%

Shape Effects of Filaments Versus Spherical Particles in Flow and Drug Delivery

Discher

2008

ASME 2008 Summer Bioengineering Conference, Parts a and B

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Interaction of spherical particles with cells and within animals has been studied extensively, but the effects of shape have received little attention. Here we use highly stable, polymer micelle assemblies known as filomicelles to compare the transport and trafficking of flexible filaments with spheres of similar chemistry. In rodents, filomicelles persisted in the circulation up to one week after intravenous injection. This is about ten times longer than their spherical counterparts and is more persistent than any known synthetic nanoparticle. Under fluid flow conditions, spheres and short filomicelles are taken up by cells more readily than longer filaments because the latter are extended by the flow. Preliminary results further demonstrate that filomicelles can effectively deliver the anticancer drug paclitaxel and shrink human-derived tumours in mice. Although these findings show that longcirculating vehicles need not be nanospheres, they also lend insight into possible shape effects of natural filamentous viruses.It is well known that, after intravenous injection, micrometre-sized rigid spheroids are cleared immediately in the first pass through the microvasculature of various bodily organs. Such particles also do not enter most cells. In contrast nanovehicles that are spherically shaped, such as viruses, liposomes or quantum dots, have been widely applied as gene, drug or dye carriers because they tend to circulate in vivo for a few hours or perhaps a day (in rodents) and because they can enter cells. Non-spherical nanoparticles have not received significant attention, except perhaps water-soluble carbon nanotubes, which are cleared from the body within hours after intravenous injection 1 and will also enter mammalian cells 2,3 . In nature, a number of viruses that infect animals are likewise filamentous, providing additional motivation for the development and study of soft filamentous vehicles ( Fig. 1a; see also Supplementary Information, Fig. S1) [4][5][6] . Here we examine the distinctive in vivo circulation behaviour of such filaments for comparison with spheres of a very similar surface chemistry.Cylindrically shaped micelles can self-assemble in water from block copolymers that are lipidlike in amphiphilicity [7][8][9] . However, the copolymers used here are more symmetric than lipids * Correspondence and requests for material should be addressed to D.E.D. e-mail: discher@seas.upenn.edu. in their hydrophilic/hydrophobic ratio, which leads to the cylindrical shapes. The copolymers are also considerably larger in molecular weight than lipids, which imparts physical stability and aggregate lifetimes of weeks or longer 9 . Our copolymers possess one hydrophilic chain of polyethyleneglycol (PEG), which is widely used to prolong circulation in vivo [10][11][12] , and one of two hydrophobic chain chemistries (Table 1): inert polyethylethylene 12 or biodegradable polycaprolactone, which hydrolyses over hours to days in these micelles 13 . The simulation snapshot in Fig. 1a presents a cylinder micel...

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“…Although numerous attempts to mimic some or all of the above properties of RBCs have met with various degrees of success, efforts to replicate their long circulation times have only recently showed promise. One of the most promising carriers in this regard is the self-assembled worm-like filomicelles (16)(17)(18)(19), which are intermediate amphiphilic aggregates between micelles and lamellar vesicles. By choosing appropriate diblock polymer combinations, worm stability, stiffness, and flow characteristics can be finely tuned.…”

Section: Geometries For Res Evasion and Enhanced Circulation Persistencementioning

confidence: 99%

Novel platforms for vascular carriers with controlled geometry

et al. 2011

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SummaryThe first-generation platforms for vascular drug delivery adopted spherical morphologies. These carriers relied primarily on the size dependence of the enhanced permeability and retention effect to passively target vasculature, resulting in inefficient delivery due to significant variation in endothelial permeability. Enhanced delivery typically requires active targeting via receptor-mediated endocytosis by surface conjugation of targeting ligands. However, vascular carriers (VCs) still face numerous challenges en route to reaching their targets before delivery. The control of carrier shape offers opportunities to overcome in vivo barriers and enhance vascular drug delivery. Geometric features influence the ability of carrier particles to navigate physiological flow patterns, evade biological clearance mechanisms, sustain circulation, adhere to the vascular surface, and finally transport across or internalize into the endothelium. Although previous formulation strategies limited the fabrication of nonspherical carriers, numerous recent advances in both top-down and bottom-up fabrication techniques have enabled shape modulation as a key design element. As part of a series on vascular drug delivery, this review focuses on recent developments in novel vascular platforms with controlled geometry that enhance or modulate delivery functions. Starting with an overview of controlled geometry platforms, we review their shape-dependent functional characteristics for each stage of their vascular journey in vivo. We sequentially explore carrier geometries that evade reticuloendothelial system uptake, display enhanced circulation persistence and margination dynamics in flow, encourage adhesion to the vascular surface or extravasation through endothelium, and impact extravascular transport and cell internalization. The eventual biodistribution of VCs results from the culmination of their successive navigation of all these barriers and is profoundly influenced by their morphology. To enhance delivery efficacy, carrier designs synergistically combining controlled geometry with standard drug delivery strategies such as targeting moieties, surface decorations, and bulk material properties are discussed. Finally, we speculate on possibilities for innovation, harnessing shape as a design parameter for the next generation of vascular drug delivery platforms.

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Single Molecule Visualization of Stable, Stiffness-Tunable, Flow-Conforming Worm Micelles

Cited by 110 publications

References 29 publications

Stable and robust polymer nanotubes stretched from polymersomes

Stable and robust polymer nanotubes stretched from polymersomes

Shape Effects of Filaments Versus Spherical Particles in Flow and Drug Delivery

Novel platforms for vascular carriers with controlled geometry

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