M AT E R I A L S S C I E N C E

To bind or not to bindFinding a way to control how particles bind to cells could open up opportunities for biomedical research. The discovery of a method for directing the orientation of particle–cell interactions is therefore a cause for excitement.

A N D R E A J . O ’ C O N N O R & F R A N K C A R U S O

The interactions of small particles with cells are crucial in biology, such as when immune-system cells remove dirt and

bacteria to stop an infection. Such inter actions have many potential applications in promis-ing medical therapies, and have fuelled the growing field of nanomedicine. Writing in Advanced Materials, Gilbert et al.1 report a significant contribution to this field: the prepa-ration of tube-shaped particles that attach to cells in different ways depending on the tubes’ surface properties. This could lead to new ways to deliver drugs into target cells and to create constructs from cells.

Small particles (nanometres to micro metres in size) can interact with cells in many differ-ent ways, depending on the type of cell, the local environment and, notably, the physico-chemical properties of the particles. Scien-tists and engineers are therefore working on approaches to tailor both the physical and the chemical properties of particles in order to develop control over their interactions with cells and tissues.

The size, stiffness, shape and chemi-cal make-up of small particles all strongly

influence how such particles interact with cells — they may bind to the outside of a cell, be taken up by the cell and trafficked through dif-ferent pathways within it, and ultimately even change aspects of the cell’s functions. Gilbert et al. have designed and made hollow, tubular, polymeric particles that can have non-uniform chemical properties, to see how this affected the particles’ interactions with cells.

Gilbert et al. made the microtubes by assem-bling layers of oppositely charged polymers

— polyelectrolytes — in the pores of a special type of filtration membrane that has straight pores. They then chemically cross-linked the polyelectrolytes to stabilize them, and dissolved away the membrane. Benefits of this method are that it can be used to make millions of microtubes at a time, and that it could be scaled up using multiple mem-branes. The dimensions of the microtubes could also be easily changed by altering the pore size or the thickness of the templating membrane.

The authors prepared microtubes that were either cell-resistant or cell-adhesive by chang-ing the polymers used to make them. In a smart variation, they also made microtubes that were cell-resistant along their length on the outside but cell-adhesive inside. Because cells cannot fit inside the tubes, they can bind only to the ends of the microtubes where the adhesive molecules are exposed. The research-ers therefore observed that these particles tend

Cell

a b c

Figure 1 | Surface properties control interactions of polymer tubes with cells. Gilbert et al.1 have prepared polymeric, micrometre-scale tubes from cell-resistant (pink) and cell-adhesive (green) polymers. a, When incubated with mouse cells, the microtubes made from only the cell-resistant polymer did not bind to the cells. b, Microtubes that were cell-adhesive along the sides but cell-resistant on the ends bound to cells side-on. c, Microtubes that were cell-resistant along the sides, but cell-adhesive at the ends, bound to the cells end-on.

The reason for the high susceptibility of cancer cells to ASM targeting is not completely understood. However, it might be explained by the fact that ASM activity is already low in cancer cells, and a further decrease could lead to a membrane-destabilizing level of sphingo-myelin in the lysosomes of these cells. Cancer cells have higher levels of membrane dynamics and cellular signalling than normal cells, and high concentrations of sphingomyelin might inhibit these processes. It is likely that other lipids that are ASM substrates also contribute to the fragility of lysosomal membranes in tumour cells. An additional aspect of the high sphingomyelin levels in cancer cells is that the export of cholesterol from lysosomes is inhib-ited10; this leads to the inactivation of saposins (essential cofactors for sphingolipid-degrading enzymes), and thereby a further reduction in sphingolipid degradation.

Thus, it seems that CAD treatment may lead to a generally dysfunctional lysosomal-lipid homeostasis that severely affects the physiol-ogy of this cellular compartment and favours lysosome-related cell-death pathways. It would

be useful to analyse the specificity of CADs for tumour-cell targeting in genetically defined animal models, such as mice lacking or over-expressing ASM. Another aspect yet to be inves-tigated is the rate of uptake of CADs in tumour cells compared with healthy cells. Surprisingly, although the events following LMP are well understood, a long-standing question is how LMP is mediated at a molecular level. Further studies of the role of CADs may help to explain how alterations in the lipid or protein composi-tion of lysosomal membranes lead to transient and enzyme-specific lysosomal leakage.

Despite these remaining questions, Petersen and colleagues’ findings argue for an in-depth pharmacological and epidemiological study of the effect of CAD treatment on cancer outcomes. CADs are relatively cheap drugs that have limited side effects, but their activ-ity in lysosomal killing pathways is probably not sufficient for effective cancer therapy when used alone, so combination treatments with other chemotherapeutic compounds might be advisable. Future research might also reveal specific and potent modulators of

lysosomal-sphingolipid metabolism that are even more effective than CADs at inducing the death of cancer cells through this pathway. ■

Paul Saftig is at the Biochemisches Institut, Christian Albrechts-Universität Kiel, 24118 Kiel, Germany. Konrad Sandhoff is at the Life and Medical Sciences Institute, Universität Bonn, 53121 Bonn, Germany.e-mail: psaftig@biochem.uni-kiel.de

1. Petersen, N. H. T. et al. Cancer Cell 24, 379–393 (2013).

2. Saftig, P. & Klumperman, J. Nature Rev. Mol. Cell Biol. 10, 623–635 (2009).

3. Mohamed, M. M. & Sloane, B. F. Nature Rev. Cancer 6, 764–775 (2006).

4. Boya, P. & Kroemer, G. Oncogene 27, 6434–6451 (2008).

5. Fehrenbacher, N. et al. Cancer Res. 68, 6623–6633 (2008).

6. Kirkegaard, T. et al. Nature 463, 549–553 (2010).7. Linke, T. et al. Biol. Chem. 382, 283–290 (2001).8. Hurwitz, R., Ferlinz, K. & Sandhoff, K. Biol. Chem.

375, 447–450 (1994).9. Kornhuber, J. et al. Cell Physiol. Biochem. 26, 9–20

(2010).10. Abdul-Hammed, M. et al. J. Lipid Res. 51, 1747–1760

(2010).

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to bind to cells end-on — that is, the particles’ chemical properties control their orientation upon interaction with the cells. Conversely, the authors also made microtubes that have adhesive molecules along their outer length but not on the ends; these tend to bind to cells side-on.

Much of our knowledge about particle interactions with cells originates from stud-ies of spherical particles that have uniform surface chemistry. However, it has become clear that particle shape has a major role in these interactions. For example, two particles made of the same polymer may have differ-ent rates of uptake by cells, solely because of differences in their shape and in their orien-tation relative to the cells2. Furthermore, dif-ferent surface patterns on particles can have distinctively different effects on the particles’ interactions with cells3. These effects are important for many potential medical applica-tions of nano- and microparticles, particularly drug delivery.

Particles that have tunable orientations for cell attachment, like those developed by Gilbert et al., might provide another level of control over drug delivery into targeted cells. Cell-binding ‘patches’ on particles could regu-late how those particles bind to cells, and even which cells they bind to, if biochemical mol-ecules that target particular proteins or recep-tors are added to the patches. Furthermore, the other key properties of such particles, includ-ing their size, aspect ratio (the ratio of width to length) and stiffness, could be used to influ-ence rates of particle binding and uptake into the cells.

It can also be envisaged that new biomater-ial–cell constructs could be created by using such particles to connect cells into a network whose properties are highly tunable, for exam-ple by changing the numbers, dimensions and cell-binding tendencies of the particles. This could facilitate the formation of biomimetic or tissue-like hybrid materials that contain living cells in an environment more like their native milieu than the current commonly used in vitro supports.

Furthermore, regulation of the cellular microenvironment can alter cell functions such as differentiation of stem cells, cell-growth rates and gene expression4. So, if cells bind particles in a selective orientation, the particles could potentially also shape how these functions are organized in three dimen-sions within a tissue construct. Such orienta-tion-specific interactions could be valuable for generating scaffold-free constructs for tissue engineering. In the future, it might also be possible to form cell-based ‘polymers’, using microtubes with engineered regions to link cells to form different architectures, including linear and branched systems.

Several obstacles need to be overcome to apply the microtubes therapeutically. These include the formation of microtubes that are

biocompatible and which can respond to, and degrade in, cellular or physiological condi-tions. It is likely that Gilbert and colleagues’ work will trigger research into optimizing the efficiency with which such particles can be produced and attached to cells, and also into what happens to the particles and cells when they interact over extended times in vitro and in vivo. This will be well worth it, because the prospect of being able to design particles to deliver payloads of drugs and organize cells in new ways is exciting. ■

Andrea J. O’Connor and Frank Caruso are in the Department of Chemical and Biomolecular Engineering, University of Melbourne, Victoria 3010, Australia.e-mail:  fcaruso@unimelb.edu.au

1. Gilbert, J. B., O’Brien, J. S., Suresh, H. S., Cohen, R. E. & Rubner, M. F. Adv. Mater. http://dx.doi.org/10.1002/adma.201302673 (2013).

2. Mitragotri, S. & Lahann, J. Nature Mater. 8, 15–23 (2009).

3. Verma, A. et al. Nature Mater. 7, 588–595 (2008).4. Discher, D. E., Janmey, P. & Wang, Y. L. Science 310,

1139–1143 (2005).

M U LT I P L E S C L E R O S I S

An old drug plays a new trickA drug already used to treat Parkinson’s disease induces repair of the damage that occurs to the myelin sheath around nerve fibres during multiple sclerosis. The finding offers new therapeutic avenues for this disease. See Article p.327

H A R T M U T W E K E R L E & E D G A R M E I N L

What a change: just 20 years ago, multiple sclerosis was a disease without any promising treatment.

Today, it has become treatable. Indeed, the number of drugs that effectively mitigate, although unfortunately do not cure, the dis-ease is impressive, and is growing. But these drugs work well only in blunting the early inflammatory phase of multiple sclerosis, they do not help to restore myelin1 — the protec-tive sheath surrounding the axons of neurons in the brain and spinal cord that is damaged in the disease. In this issue, Deshmukh et al.2 (page 327) identify a drug, benztropine, that may finally raise the hope of myelin repair*.

The authors show that benztropine pro-motes the differentiation of oligodendrocytes (the myelin-forming cells in the brain) in vitro and supports remyelination in animal models of multiple sclerosis (MS). What’s more, the drug is an old acquaintance: benztropine is well established as an approved treatment for Parkinson’s disease3.

The finding came from a monumental experimental effort that was organized in three stages. First, in a high-throughput set-up, the researchers exposed immature oligodendro-cyte progenitor cells to 100,000 different small molecules in individual culture wells (Fig 1a). The progenitors came from the optic nerves of newborn rats, in which myelin formation was just about to start. After 6 days of exposure, the cultures were screened for production of intracellular myelin basic protein (MBP), a key

product of myelin-forming cells. This process identified compounds in more than a dozen functional classes that drove MBP forma-tion; these molecules were then considered further.

MBP production is necessary but not suf-ficient for the formation of intact, compacted, myelin sheaths. To test the effects of their com-pounds on this latter process, the authors used a second, medium-throughput step to examine effects on the myelination of axons of neurons co-cultured with oligodendrocyte precursors (Fig. 1b). In the presence of one of the com-pounds, benz tropine, more myelin wraps appeared around the axons than in untreated cultures. Additional pharmacological experi-ments revealed that the benztropine-driven myelination involved blocking the activity of muscarinic cholinergic receptors, extending a previous observation about the function of these receptors on oligodendrocytes4.

These findings were made using cultures of rodent cells, but, as readers (and drug- regulatory agencies) would ask, could the drug promote myelin repair in live animals with an MS-like disease? In the third, low-throughput, stage (Fig. 1c), the investigators tested benztro-pine in two mouse models of demyelinating disease. The first, called experimental auto-immune encephalomyelitis, involves induc-ing an autoimmune response against myelin by immunizing the animals with a myelin auto-antigen. This condition recapitulates in vivo some essential features of human MS, such as large-scale demyelinated lesions accompanied by axonal damage5. Benztropine substantially mitigated ongoing disease and promoted remyelination in these mice. But these findings

*This article and the paper under discussion2 were published online on 9 October 2013.

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