Dalargin is an enkephalin-type peptide that has analgesic (pain-reducing) effects when injected directly into the brain. However, when given intravenously, it does not cross the BBB and no analgesia occurs [59, 102]. Studies to investigate the targeting of dalargin to the brain were carried out using the tail-flick test [59, 102] as well as the hot-plate test [61, 103]. Both tests are useful to quantify pain perception as a behavioral model of drug activity in the brain. When the rat tail is lightly pinched, the rat withdraws the tail by flicking it to the side. If an effective analgesic is given, the flicking does not occur because the rat feels no pain. Thus, one can quantify experimentally analgesic effects of a drug. In the hot-plate test the situation is similar: when placed on a hot plate, the animals will lick their paws. Time to tail flicking and time to paw withdrawal are very sensitive and reliable measures of pain perception and can thus be used to quantify analgesia.
To evaluate the usefulness of nanoparticles crossing the BBB, dalargin was bound to nanoparticles and injected into animals, which were then tested for analgesia. To be sure that drug alone or nanoparticles alone had no analgesic effect, groups of animals that received different treatments were compared: (1) dalargin alone; (2) polysorbate 80 alone; (3) poly(butylcyanoacrylate) nanoparticles alone; (4) a mixture of dalargin and polysorbate 80; (5) a mixture of dalargin and poly(butylcyanoacrylate); (6) a mixture of all three components, dalargin, polysorbate 80, and nanoparticles, mixed immediately before injection; and (7) a suspension of dalargin bound to nanoparticles without coating. After intravenous (i.v.) injection into mice, none of the groups showed an analgesic effect. Only dalargin bound to poly(butylcyanoacrylate) nanoparticles coated with polysorbate 80 produced a significant antinociceptive effect [59, 61, 102, 103]. This clearly showed that dalargin had crossed the BBB. Figure 8 shows the antinociceptive effect after i.v. administration of polysorbate 80-coated nano-particles loaded with dalargin using the hot-plate test . Apparently the coating with polysorbate 80 was the critical step in achieving the effect. This finding raised the question whether any other coating material may be useful as well.
Therefore, different coating materials in combination with the nanoparticles were used to study the specificity of the coating effect to deliver dalargin to the brain. It was found that polysorbate 20, 40, and 60 coatings have similar, but weaker, analgesic effects compared with polysorbate 80 coating. Poloxamers and poloxamines as well as surfactants of the Cremophor and Brij series [polyoxyethylene-(23)-laurylether] had no effect . Thus, with a particular set of coating materials nanoparticles effectively delivered drugs to the brain after i.v. injection.
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