755: Nanocarrier Technology for Peripheral Pain Treatment: Proof of Concept and Safety Studies in Vivo

Topic: Experimental (Non-clinical) Human Studies
Subtopic: Pain Category (ICD-11), Acute postsurgical pain, Developing methodology/technology, Pharmacological treatments, Drug development

Background and Aims: Dendritic nanocarriers based on functionalized polyglycerol were loaded with κ-opioid agonist / µ-antagonist Nalbuphine, aiming to target exclusively peripheral opioid receptors. This strategy offers a promising approach for managing post-operative and neuropathic pain while minimising central adverse effects. Peripherally restricted agonists can provide effective analgesia at the site of tissue injury by reducing nociceptor excitability and inflammatory signalling without significantly crossing the blood–brain barrier (Stein,C, 2009, 2016). This approach may decrease risks such as respiratory depression, sedation, and addiction associated with centrally acting opioids. Additionally, κ-receptor agonists may reduce visceral and inflammatory pain with lower abuse potential. (Vadivelu N. 2010; Spetea M. 2012; Zöllner C. and Stein C. 2007, Kalso, E. 2025)
Fluorescence marked carriers exhibited a preferential accumulation of opioid nano pro-drugs in inflamed peripheral tissue. Safety studies in mini-pig and rodents were carried out to demonstrate that dendritic nanocarriers loaded with opioids can be a safe approach to developing drugs for peripheral pain treatment.

Methods: Dendritic polyglycerol nanocarriers were synthesized and loaded with Nalbuphine (Fleige, 2016). Carriers were characterised using dynamic light scattering, NMR, and SEC-MALS chromatography. Pro-drug stability was determined with HPLC and NMR spectroscopy.
Rodent and mini-pig safety study according to GLP (Good laboratory practice) were carried out to evaluate the pro-drugs´drug toxicity, tolerability, and pharmacokinetics. Animals received repeated doses for 28 days in 3 dosis groups plus one recovery group, with monitoring of clinical signs, body weight, blood chemistry, and organ function. Additionally acute toxicity studies were carried out in mini-pigs.
Fluorescence marked carriers were synthesized using ICC dye. The fluorescence marked pro-drug was injected into Wistar rats. Concentration of two different metabolites of the carrier plus free dye were assessed for spleen, kidney, lung, brain, inflamed and non-inflamed muscle tissue and compared with saline solution.
The data was compared to efficacy data using the paw pressure model (González-Rodríguez, 2017).

Results: The florescence marked carriers accumulated in inflamed tissue, while non-inflamed tissue exhibited only autofluorescence. No signals were found in brain tissue, proving that the carrier did not cross the blood brain barrier.
Partial renal clearance was observed for the carriers in the first hour of experiment. Pharmacokinetic assessment demonstrated that free Nalbuphine was only present in the highest dosing group, but not in the therapeutic regime. Data of pro-drug was compared with data of the free drug in in-vivo tests. Furthermore, the data was in alignment with the stability of the pro-drug at shelf life and under physiological conditions.
The acute toxicity study in mini-pig resulted in no decreased vitality even at dosages exceeding the highest dose used in the subchronic 28 day GLP study by a factor of three.
Histopathology and blood values were investigated to provide a risk assessment before human clinical trials.

Conclusions: The results validate data from efficacy studies. It is demonstrated that dendritic nanocarriers synthesized from functionalized polyglycerol can serve as a platform technology for targeted drug-delivery into inflamed tissue. The platform technology presented is efficient in preventing drugs from crossing the blood brain barrier.
No severe side effects were found in non-clinical studies, suggesting that clinical trials in human volunteers and patients are feasible. The combination of dendritic nanocarriers with Nalbuphine results in a pro-drug with less side effects than the parent drug and provides a safe alternative to current µ-agonists for post-operative pain treatment.

Peripherical acting nano-pro-drugs have the capability to reduce the risks of post-surgical opioid addiction and thus may play a role in fighting the opioid crisis.

References: Fleige E, MORE S., Unbehauen M, Haag R., Stein C., Machelska H, Paulus, F., (2016) Analgesic preparation with nanocarriers and use thereof, WO2017097291A1

González-Rodríguez, G., Quadir M.A, Shilpi Gupta, Walker K.A, Xuejiao Zhang, Spahn V., Labuz D., Rodriguez-Gaztelumendi A, Schmelz M., Parr J.M., Machelska H., Haag R., Stein C. (2017) Polyglycerol-opioid conjugate produces analgesia devoid of side effects eLife 6:e27081

Kalso, E. (2005). Opioids for persistent non-cancer pain: Research and clinical implications. British Journal of Anaesthesia, 95(1), 95–101. https://doi.org/10.1093/bja/aei010

Spetea, M., & Schmidhammer, H. (2012). The kappa opioid receptor: Therapeutic potential for pain and addiction. British Journal of Pharmacology, 167(5), 960–974. https://doi.org/10.1111/j.1476-5381.2012.02082.x

Stein, C. (2016). Opioid receptors. Annual Review of Medicine, 67, 433–451. https://doi.org/10.1146/annurev-med-062613-093100

Stein, C., & Lang, L. J. (2009). Peripheral mechanisms of opioid analgesia. Current Opinion in Pharmacology, 9(1), 3–8. https://doi.org/10.1016/j.coph.2008.12.009

Vadivelu, N., Mitra, S., & Narayan, D. (2010). Recent advances in postoperative pain management. Yale Journal of Biology and Medicine, 83(1), 11–25.

Zöllner, C., & Stein, C. (2007). Opioids. Handbook of Experimental Pharmacology, 177, 31–63. https://doi.org/10.1007/978-3-540-33823-9_2

Presenting Author: Dr. Sam Dylan Moré
Submitting Author: Sam Dylan Moré

Senior Author: Dr. Sam Dylan Moré

IASP 2026 Global Year theme of Neuropathic Pain: No

• Muhammad Imtiaz Ashraf: PhD - Charite University Hospital, Berlin, Germany
• Piotr Ziemconek: PhD - Polish Accademy of Sciences, Lodz, Poland