2024 AIChE Annual Meeting

Local Delivery of an Adenosine Signaling Agonist Via Polymeric Microparticles for Suppression of Inflammation in Allergic Contact Dermatitis

Vascular composite allotransplantation (VCA) involves transplantation of multiple tissue types, including skin, making these transplants highly prone to rejection [1, 2]. One potential way of developing new strategies for immunosuppression in VCA is to study a disease with similar characteristics to skin transplant rejection, such as allergic contact dermatitis (ACD) [3]. In ACD, activated immune cells release extracellular ATP (eATP), which promotes inflammatory signaling. eATP is naturally converted to adenosine (Ado), which promotes anti-inflammatory signaling [4]. Therefore, it is possible that blocking eATP signaling and/or amplifying Ado signaling may lead to immunosuppression in ACD.

This study aimed to determine if polymeric microparticles could be used to encapsulate and locally deliver three eATP or Ado signaling modifiers in vivo to reduce the innate immune response associated with ACD. The three drugs of interest for this study, chosen for their success in clinical trials, mechanism of action, and hydrophobicity, were IBMECA (adenosine receptor agonist), Regadenoson (adenosine receptor agonist), and JNJ-55308942 (eATP receptor antagonist). In this study, the aforementioned drugs were encapsulated in poly(lactic-co-glycolic-acid) (PLGA) microparticles (MPs) using a single emulsion solvent evaporation method [5]. Microparticles were characterized for release kinetics and size distribution. To study the effects of drug-loaded MPs in ACD, a murine contact hypersensitivity (CHS) model was used [6]. In this model, ear thickness measurements are taken as a method to quantify inflammation (indicative of swelling) [6]. To induce ACD-like symptoms, mice were sensitized topically with 1-fluoro-2,4-dinitrobenzene (DNFB), a known chemical allergen. Prior to sensitization, ear thickness was measured, and drug-loaded-MPs or Blank-MPs (containing no drug) were injected subcutaneously at the base of the ear. 24 hours after sensitization, ear thickness was re-measured, and mice were sacrificed to harvest cervical draining lymph nodes for flow cytometry.

It was found that IBMECA-MPs significantly reduced the change in ear thickness when compared to Blank-MPs. Regadenoson-MPs and JNJ-MPs did not reduce change in ear thickness when compared to Blank-MPs. Flow cytometry analysis of dendritic cell populations showed that IBMECA-MPs altered expression of several surface markers related to inflammatory responses. More specifically, IBMECA-MPs significantly reduced CD40 expression across multiple dendritic cell subtypes. Together, these results suggest that treatment with IBMECA-MPs could have a therapeutic effect in ACD.

References:

[1] Uluer, Mehmet C., et al. “Vascularized composite allotransplantation: Medical complications.” Current Transplantation Reports, vol. 3, no. 4, 15 Aug. 2016, pp. 395–403. doi: 10.1007/s40472-016-0113-x.

[2] Abdallah, Florence, et al. “Skin immune landscape: Inside and outside the organism.” Mediators of Inflammation, vol. 2017, 2017, pp. 1–17. doi: 10.1155/2017/5095293.

[3] Starzl, Ravi, et al. “Review of the early diagnoses and assessment of rejection in vascularized composite allotransplantation.” Clinical and Developmental Immunology, vol. 2013, 2013, pp. 1–9. doi: 10.1155/2013/402980.

[4] Faas, M.M., et al. “Extracellular ATP and adenosine: The Yin and Yang in immune responses?” Molecular Aspects of Medicine, vol. 55, June 2017, pp. 9–19. doi: 10.1016/j.mam.2017.01.002.

[5] Jhunjhunwala, Siddharth, et al. “Controlled release formulations of IL-2, TGF-β1 and rapamycin for the induction of regulatory T cells.” Journal of Controlled Release, vol. 159, no. 1, Apr. 2012, pp. 78–84. doi: 10.1016/j.jconrel.2012.01.013.

[6] Balmert, Stephen C., et al. “In vivo induction of regulatory T cells promotes allergen tolerance and suppresses allergic contact dermatitis.” Journal of Controlled Release, vol. 261, Sept. 2017, pp. 223–233. doi: 10.1016/j.jconrel.2017.07.006.