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Science1 publisher2 min readPublished

Double-bond-rich liposomes held a rat nerve block for two to three weeks

Formulators expected fluid lipid membranes to leak fastest. With the water-soluble neurotoxin tetrodotoxin inside, the most unsaturated liposomes released it slowest and numbed a rat's leg for weeks.

The Scientist · Science desk

Photograph accompanying Double-bond-rich liposomes held a rat nerve block for two to three weeks
Photo: stanford.edu

What happened

  • Rats injected near a leg nerve with a new liposome formulation stayed numb for two to three weeks, while a commercial formulation used for comparison gave about four to eight hours.
  • The work is published in Nature Biomedical Engineering under the title "Ultra-slow release of hydrophilic drugs via multilamellar-multivesicular liposomes formed by unsaturated phospholipids".
  • Liposome researchers had until now expected drug molecules to escape fastest from particles built of the most fluid lipids. This result inverts that expectation.
  • The liposomes made with many double bonds came out with multiple internal compartments, while those made without them formed a simple single sphere.

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Why it matters

  • constraint The longest-duration evidence belongs to a drug with no commercial clinical use, so anyone wanting weeks of nerve block from a licensed anesthetic has to establish the release profile again with a different molecule.
  • capability If Kohane's wider claim holds, multi-week release of a hydrophilic drug becomes a matter of choosing phospholipids for a molecule that already exists, with no new active compound to develop.
  • decision Prior practice treated the fluid end of the lipid range as the leaky one. Formulators working on sustained release of water-soluble drugs now have reason to test it.
  • precedent Wang states the onion-like geometry as a possibility, so a group copying this design is copying an empirical release rule. Follow-up structural work would turn it into a predictable one.

Fluidity here is a packing property. Add double bonds to a phospholipid's tails and the tails cannot sit tightly against one another [7]. Composition sets how fast the contents leak, and a faster leak gives a more potent effect over a shorter window, with more risk of toxicity [23]. For a hydrophilic payload, Yuan Wang found the fluid liposomes released most slowly [6].

The reason offered is a count of barriers. A water-soluble drug in the multi-compartment particles has more lipid layers between it and the tissue [9].

"The more fluid membranes in liposomes with many double bonds may be easier to cross, but the greater number of barriers slow down the drug's release," Wang said [10]. The shape itself is given as a possibility. "The more fluid liposomes with more double bonds may form concentric spheres that are like onions with many layers or could even potentially be even spheres within spheres," Wang said [11].

Converted to one unit, the reported block runs 336 to 504 hours. Set against a commercial formulation lasting about four to eight hours [3], that is 42 to 126 times longer [20]. Against the eight to 12 hours most local anesthetics in clinical use provide [4], it is 28 to 63 times [21].

The comparison has gaps. The paper does not report how many rats were treated, and it does not name the commercial formulation used as the comparator [22]. Safety rests on a negative result, no toxicity at the injection site or elsewhere in the animal [13]. The team argues that the release is slow enough for the body to clear the drug while enough remains to block the nerve [14].

GEN, reporting the work, notes that nerve blocks in humans tend to last longer than in rats and argues the formulation could therefore far exceed the duration of anesthetics now in use [19], an argument about direction inferred from rat physiology.

Tetrodotoxin carried the result. The liposomes were loaded with the neurotoxin found in pufferfish and blue-ringed octopuses [12], which is not used commercially in patients [15]. Daniel Kohane, who directs the Laboratory for Biomaterials and Drug Delivery and is senior associate in pediatric critical care at Boston Children's [17], said the combination "could be used for longer term perioperative pain instead of opioids, and we are starting to consider using these potentially for chronic pain, as well" [16]. He also said, "These liposomes can also provide slow release of a wide range of hydrophilic molecules" [18]. The work so far covers one hydrophilic drug injected near one nerve in rats [12][13].

What to watch

  • Whether the same unsaturated liposomes stretch the duration of an anesthetic already approved for use in patients.
  • Whether imaging in the paper confirms the onion-like or sphere-within-sphere structure that Wang describes as a possibility.
  • Whether hydrophilic drugs other than tetrodotoxin show the same ultra-slow release, as Kohane claims they can.
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