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

Abstract

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...

Precise and Controllable Assembly of Block Copolymers†

“…Cylindrical micelles with a certain aspect ratio would circulate about ten times longer in vivo than spherical micelles. [133] At the same time, studies had also demonstrated that polypeptide fiber structures with larger aspect ratios had lower cytotoxicity. [134] Therefore, in recent years, researchers have begun to explore the application of BCP micelles with uniform sizes and morphologies in the biological field.…”