news and views histamine, serotonin and calcium. These ions and can also leak through the porous capillary Daedalus bind tightly to and neutralize the fixed charge walls of tumours, providing targeted delivery groups, causing the granule network to of anticancer agents. The practicality of the A chance of justice shrink. Shrinking is favoured when the coun- system might be further improved by tether- terion is polyvalent or partially hydrophobic. ing certain molecules, ones which bind specif- A legal verdict, says Daedalus, pretends to If a secretory granule consisted only of ically or nonspecifically to target cells or extra- be a certainty; but in truth it is merely a a charged network, it would not hold its cellular matrix, to the lipid coating, thus local- probability. Consider, for example, those payload very long in the intracellular or izing the microspheres at a particular site and plaintiffs who claim to have been made ill the extracellular environment. Sodium and perhaps preventing side-effects. Collagen, by silicone breast-implants, radioactivity potassium ions would invade the granules peptides containing arginine–glycine–aspar- or tobacco. Clearly it is impossible to be and rapidly ‘exchange out’ the incorporated tate sequences and Fab fragments of antibod- sure that they would not have got just as species. Because these metal ions do not bind ies are logical candidates. This strategy has ill if they had never encountered these to the fixed negative-charge groups, they been investigated with liposomes, another perils. would establish an osmotic pressure inside type of drug carrier6. So Daedalus is musing on the character the granule, causing it to swell and release its Needham and colleagues’ prototype sys- and process of a truly scientific court. If, contents. To prevent this, the granule is coat- tem triggers drug release by electroporation, for example, epidemiological evidence ed with a lipid membrane that blocks ion which may be difficult to effect in situ, and shows that passive smoking in the transport. Secretion of the stored contents the authors point out that modifications to workplace increases your chance of getting requires electrochemically stimulated fusion the lipid coating may make it sensitive to lung cancer by 1%, then the judge could of the granule’s membrane with the cell stimuli such as temperature or ultrasound. decide the case won if the number 100 membrane, which exposes the matrix to Work with liposomes also points to a second, turns up on his random number generator, the extracellular medium, triggering ion potentially powerful, refinement of the but lost if 1–99 turn up. Chancy or exchange and swelling. system7,8. By anchoring suitable stimulus- vexatious litigants would be strongly If nature can do this, why can’t we? That sensitive polymers in the membrane, one can discouraged. was the question asked by Needham and col- destabilize the lipid coating, and therefore It might be fairer, however, to allow an leagues, and their response is outlined in Fig. trigger drug release, by changes in local tem- openly statistical verdict. A defendant 2 of the paper on page 459. Using technology perature, pH and glucose concentration, or found ‘probably guilty’ (perhaps set at that had already been developed5, they syn- by illumination at a particular wavelength. 91.7% if 11 jurors out of 12 reckon he did thesized crosslinked polymethacrylic-acid Even more sophisticated systems can be it) might incur a fine or punishment microgels that had a swollen diameter of 6.5 envisaged in which lipid-coated, bioadhesive reduced in proportion. A defendant found m m at pH 7.4. They then incorporated the microgels that respond to different stimuli, ‘probably innocent’ (say, 8.3% or 16.7%) hydrophobic, cationic, anticancer drug dox- each type of microgel containing a different might leave the court unpunished, but orubicin hydrochloride at pH 5.0, which agent, are mixed together and delivered with a definite ‘stain’ on his character. neutralized the acid groups, causing the gel locally or regionally. Such a system could Thereafter, until the stain was declared to shrink. As a final step, they used a newly permit localized combination therapies, in spent, or expunged by good behaviour, he devised process to coat the collapsed gel with which the delivery of the different agents would be literally ‘a suspicious character’ a lipid bilayer, and showed that the lipid occurs according to a predetermined —which would tell against him if he came was present exclusively at the surface. The sequence. up again on a similar charge. lipid coating all but prevents dissipation of These kinds of elaborations would add This approach would fit well into pH gradients, and the acidified construct further complexity to Needham and col- British society. British motorists already remains stable in pH 7.4 phosphate-buffered leagues’ system — the combinatorial possi- accumulate ‘stains’ on their driving saline, a proxy for body fluids, for at least 48 bilities are numerous, and would require a licences for each small offence. Enough hours. By this means they mimic the storage great deal of further development and test- staining cancels the licence. The British aspect of a granule. ing. Moreover, the effectiveness of the origi- honours system awards a ‘shine’ on the To demonstrate ‘quick release’, the nal concept needs to be tried out in an animal character of good eggs and praiseworthy authors exposed microspheres in phos- model. At the least, however, the authors types; if they later go to the bad, the shine phate-buffered saline at pH 7.4 to electro- have succeeded in showing how some can be withdrawn again. Affirmative poration fields that were strong enough to cunning chemistry can be used to emulate a action gives whole groups a collective breach the lipid coatings. A brief electro- physiological process for the purposes of shine, entitling them to jobs, presumptions poration pulse led to rapid swelling of the improved drug delivery. of virtue or innocence, and so on. gels which was complete within seconds, Ronald A. Siegel is in the Departments of Such an open system of honours and and all the incorporated doxorubicin was Biopharmaceutical Sciences and of Pharmaceutical dishonours is much fairer than the ‘dossier released within minutes. Although these Chemistry, School of Pharmacy S-926, University of societies’ run by dictators. Secret dossiers, processes take somewhat longer than they do California at San Francisco, San Francisco, for some reason possibly connected with in nature, the times concerned are more than California 94143-0446, USA. the second law of thermodynamics, only acceptable for many drug-release purposes. e-mail: [email protected] accumulate evidence against their subjects. How might such a system be used in prac- 1. Kiser, P. F., Wilson, G. & Needham, D. Nature 394, 459–462 Only those faceless apparatchiks who tice? The particles are of such size that they will (1998). never put a foot wrong or do anything be rapidly cleared by the reticuloendothelial 2. Langer, R. S. & Peppas, N. A. Biomaterials 2, 201–214 (1981). original, flourish under them. Ominously, system, which consists of scavenger cells that 3. Tanaka, T. & Fillmore, D. J. Chem. Phys. 70, 1214–1218 (1979). dossiers are now growing fast even in the 4. Fernandez, J. M., Villalon, M. & Verdugo, P. Biophys. J. 59, continually patrol the body. So, without mod- 1022–1027 (1991). democracies, in the form of credit ratings, ification, the system is probably best suited 5. Kashiwabara, M., Fujimoto, K. & Kawaguchi, H. Coll. Polym. referees’ reports, compulsory secret for local administration, be it subcutaneous, Sci. 273, 339–345 (1995). reporting of ‘suspicious’ bank deposits, intramuscular or intraperitoneal. The 6. Yerushalmi, N. & Margalit, R. Archiv. Biochem. Biophys. 349, and so on. An open, numerical ‘stains and authors suggest, however, that the synthesis 21–26 (1998). shines’ system might just stop the rot. 7. You, H. & Tirrell, D. J. Am. Chem. Soc. 113, 4022–4023 (1991). can be altered to make much smaller particles 8. Meyer, O., Papahadjopoulos, D. & Leroux, J. FEBS Lett. 421, David Jones that will avoid the reticuloendothelial system 61–64 (1998). 428 NATURE | VOL 394 | 30 JULY 1998 © 1998 Macmillan Magazines Ltd.