Nanoparticle drug delivery targets an intracellular source of pain

Sensing and responding to pain is a mechanism, and when exposed to a painful stimulus, our body initiates responses to avoid further damage and initiate appropriate wound healing processes. However, damaged tissue or chronic conditions (e.g. arthritis or diabetic neuropathy) can dysregulate pain pathways, resulting in chronic pain, which is both debilitating and difficult to treat. While opioids remain the most effective treatment, there are many unwanted side-effects including tolerance (analgesic effect diminishes over time) and dependence, which are major contributors to the present, the growing global opioid epidemic.

G protein-coupled receptors are cell-surface sensors that play Vital roles in responding to painful stimuli and relaying these pain signals from sensory neurons to the spinal cord and brain. curiously, we and others have previously demonstrated that when GPCRs such as the Neurokinin 1 receptor are stimulated during pain, they undergo endocytosis and relocate to intracellular organelles such as the endosomal network.

This study was done as a multi-disciplinary international team, combining expertise in nanotechnology, neuroscience, and GPCR pharmacology. We have developed pH-responsive, self-assembling soft polymeric nanoparticles that can be loaded with small molecule drugs for intracellular drug delivery when exposed to the acidic environment of endosomes. The choice of drug was the antagonist aprepitant, currently used in the clinic for emesis (and previously failed for the treatment of pain). To determine the efficacy of endosomal drug delivery for pain, we compared these nanoparticles to non-pH-responsive control particles or ‘free’ drugs, and tracked fluorescently labeled particles in cells and animals. We then tested their efficacy in neurons, spinal cord slices followed by pre-clinical pain case studies. Only pH-sensitive delivery improved aprepitant efficacy and provided.

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