Safety of the use of gold nanoparticles conjugated with proinsulin peptide and administered by hollow microneedles as an immunotherapy in type 1 diabetes

Abstract

Antigen-specific immunotherapy is immunomodulatory strategy for autoimmune diseases, such as Type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, stop autoimmune beta-cell destruction and prevent permanent dependence on exogenous insulin. In this study, human proinsulin peptide C19-A3 (known for its positive safety profile) was conjugated to ultrasmall gold nanoparticles (GNP), an attractive drug delivery platform due to the potential anti-inflammatory properties of gold. We hypothesised that microneedle intradermal delivery of C19-A3 GNP may improve peptide pharmacokinetics and induce tolerogenic immunomodulation and proceeded to evaluate its safety and feasibility in a first-in-human trial. Allowing for the limitation of the small number of participants, intradermal administration of C19-A3 GNP appears safe and well-tolerated in participants with Type 1 diabetes. The associated prolonged skin retention of C19-A3 GNP after intradermal administration offers a number of possibilities to enhance its tolerogenic potential, which should be explored in future studies.

Recent advances in nano-targeting drug delivery systems for rheumatoid arthritis treatment

“…In addition, clinical trials have tested the coupling of human proinsulin peptide (C19-A3) with AuNPs (C19-A3-AuNPs) for the treatment of type 1 diabetes. In a phase I clinical trial, the safety of intradermal administration of C19-A3-AuNP through microneedles has been explored [93]. Patients with type 1 diabetes have shown good tolerance to C19-A3-AuNPs with no signs of systemic allergy.…”

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“…This formulation has showed significant positive results regarding the diseases’ progression [ 45 ]. Another nanoformulation, C19A3-GNP, comprises ultrasmall-AuNPs (size smaller than 5 nm) loaded with a proinsulin-derived peptide (C19A3), and has been investigated for immunotherapy delivery to treat type 1 diabetes (NCT02837094) [ 46 ]. Recently (2022), a new clinical trial involving AuNPs of size 8–28 nm in diameter with varying shapes, denominated as the Gold Factor, was initiated aiming to determine the clinical value of this gold-based nanoformulation for improving joint health, function, and quality of life for arthritis patients (NCT05347602).…”

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“…Thus, ultrasmall AuNP (< 5 nm) were proposed as delivery carriers of C19-A3, as they can be easily functionalized and present higher uptake by antigen-presenting cells than free peptides. The safety profile of C19-A3-conjugated AuNP intradermally administered via microneedles (three doses at 4-week intervals) was explored in a phase I clinical trial, starting in 2016 [28]. The type 1 diabetes patients tolerated the C19-A3-AuNP doses well, and no signs of systemic hypersensitivity were observed.…”