Nanoparticle Drug Delivery Could Offer More Effective Pain Relief Than Opioids
Nanoparticle Drug Delivery Could Offer More Effective Pain Relief Than Opioids
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Historically, efforts to target the substance P (SP) neurokinin 1 receptor (NK1R), for the treatment of pain have failed. These studies had one critical flaw, whilst they were targeting the right receptor, they were focusing on the wrong location.
I recently had the pleasure of speaking with Nigel Bunnett, PhD., Chair of the Department of Basic Science and Craniofacial Biology at New York University (NYU) College of Dentistry, to learn about the development and testing of a nanoparticle, designed to deliver a drug called aprepitant to the receptor within endosomes, to disrupt pain signaling.
Findings from their recent study, published in Nature Nanotechnology showed that the nanoparticles were actually more effective than opioids in models of acute pain, chronic inflammatory pain, and neuropathic pain. In future, this could present patients, with an alternative to opioid medications – and their adverse effects.
Laura Lansdowne (LL): What therapeutic options are currently available for chronic pain and what are some of the common side effects associated with these medications? (opioid addiction) corticosteroids, antidepressants etc anticonvulsants?
Nigel Bunnett (NB): One therapeutic option is over the counter medicines – non-steroidal anti-inflammatory drugs that people commonly take and the side effects of taking those long term are gastric ulcer disease because they cause bleeding in the stomach. The prescribed types of drugs used for pain are opioids.
Opioids have major problems. The fundamental problem is that opioids not only inhibit pain, they also inhibit respiration – they stop your breathing. They also cause severe constipation. The difficulty is that with continued use, the effectiveness of opioids for treating pain diminishes and they also cause addiction.
However, the effects on respiratory depression and constipation remain. As a result, patients take higher and higher doses because they're addicted and because a larger dose is needed to treat the pain. At a high enough dose, opioids can stop your breathing and kill you.
That's the problem with the opioid crisis – in the United States, opioid-related overdose is responsible for almost 80,000 deaths last year. It's a global problem – it’s not confined to the United States.
LL: What are some of the key properties of nanoparticles and why do these features make them well suited to being drug delivery vehicles?
NB: Nanoparticles are microscopical particles that can be used to encapsulate drugs. You can encapsulate into a nanoparticle, multiple different drugs, which will affect different pathways. You can design the particle to deliver the drug to a particular cell type.
And so, if you could imagine, in the context of pain, pain is a normal process that is necessary for survival. If you can't detect painful stimuli, you won't know that you have injured yourself. There are patients who have genetic abnormalities which prevent them from detecting pain and they can suffer from fatal injuries.
Because pain is so important, there are many redundant pathways that transmit pain and many redundant messages. Because of this, you need to be able to antagonize more than one at the same time – you can do that with nanoparticles. If you have a conventional drug and you give it to a patient, the drug could distribute all over the body.
In contrast, nanoparticles can be designed to deliver the drug to a specific cell or neuron type, which in this case, is involved in pain transmission, allowing for much lower doses of drugs to be used because they're not diluted throughout the entire body.
You can deliver combinations of drugs and you can deliver them to the right cell type enhancing their efficacy.
LL: Could you highlight some of the different mechanisms for the controlled release of drugs?
NB: There are several different ways in which you can get the drug to be released. It can be pH, it can be reducing conditions, it can be protease activity. In our paper we focused on pH-dependent release, but we are also investigating other stimuli to trigger the release of a drug, particularly within endosomes of neurons.
LL: Could you tell us more about the current use of nanoparticles?
NB: There has been great interest in using nanoparticles for the treatment of cancer. You can put multiple therapeutic agents into a nanoparticle. If you administered these agents to patients using conventional drug delivery routes, it could kill them. Nanoparticles allow you to target these chemotherapeutic agents to the correct cell type, meaning you can use them at lower doses and simultaneously, which could have a therapeutic advantage for cancer. Whilst there is a major interest in the use of nanoparticles for cancer therapeutics, we, of course, are using them uniquely for pain.
LL: Could you tell us more about your recent Nature Nanotechnology study and talk us through the design and testing of the nanoparticle that you developed?
NB: We were targeting a receptor called the substance P (SP) neurokinin 1 receptor (NK1R). This is the “poster child” for failures in drug discovery for the treatment of pain. Most major pharmaceutical companies in the 1990s and early 2000s had programs for the NK1R for pain and chronic neurological diseases such as depression, and also inflammatory diseases – but the trials failed. The drugs weren't effective and currently the only drug clinically available is aprepitant, an antagonist to this receptor, used to treat nausea and vomiting related to chemotherapy in cancer patients.
Now, all of these drugs were designed to target a receptor at the surface of cells. However, we've learned that once activated, this receptor moves from the surface of cells to the endosome – this has been known for almost 30 years.
It used to be thought that endosomes were just a conduit that would take the receptor either back to the plasma membrane or to be degraded, but we've discovered that the receptor actually continues to signal from endosomes for prolonged periods and this signaling is important for controlling the excitability of nerve cells that transmit pain.
Therefore, we reasoned that the ideal drug would not target the receptor at the surface of cells – but would instead target the receptor in endosomes.
We generated nanoparticles which were designed to enter endosomes by clathrin-mediated endocytosis, which disassemble in the acidic endosomal environment and slowly release aprepitant right inside the compartment of the cell, where the receptor is functioning and where the receptor is signaling pain – this is where we want to inhibit the receptor.
We showed that the nanoparticles released aprepitant (which is the drug that previously failed trials for pain but is approved for use to prevent chemotherapy-induced nausea).
We showed that the particles disassemble in a test tube and can release the drug in a pH- dependent way. We demonstrated, using fluorescently labeled particles, that the nanoparticles are taken up by cells and they release the drug in cells in a pH-dependent fashion. We found that the particles have a sustained inhibitory effect on signaling of the receptor in endosomes and have a sustained inhibitory action on excitability of neurons.
We also tested the nanoparticles in different preclinical models of pain (mice and rats) and found that the particles were far more effective than conventional, non-encapsulated aprepitant and more effective than opioids in models of acute pain, chronic inflammatory pain, and neuropathic pain.
LL: Can you tell us more about next steps, what follow-up research are you conducting?
NB: Firstly, we are encapsulating antagonists of several different receptors into the same nanoparticle and are looking at the substance P receptor and the receptor for a peptide called calcitonin gene-related peptide (CGRP).
Secondly, we are coating the nanoparticles with a drug that will target it specifically to those neurons that transmit pain. This is a drug which would also inhibit the activity of neurons. So potentially, in one particle, we would have three different drugs which would inhibit pain signaling and would work only in those neurons that transmit pain.
We're working with an entity in the US called the National Center for Advancing Translational Science, a branch of the NIH. They are working with us to take these particles all the way up to human clinical trials. I think there's great potential in this technology.
Nigel Bunnett was speaking with Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.