(181ab) Rapid and Complete Implantation of Layer-By-Layer Microneedle Drug Films for Enhanced Transdermal Vaccination

Yanpu He^1,2,#, Celestine Hong^1,2,#, Jiahe Li^1,2, MayLin T Howard^1,2, Yingzhong Li^1,3, Michelle E Turvey⁴, Divakara SSM Uppu⁴, John R Martin^1,2, Ketian Zhang^1,5, Darrell J Irvine^1,3,5,6, and Paula T Hammond^1,2*

¹Koch Institute for Integrative Cancer Research, ²Department of Chemical Engineering, ³Department of Biological Engineering, ⁵Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States. ⁴Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), Singapore, Singapore. ⁶Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, United States.

Abstract

The utility of layer-by-layer (LbL) coated microneedle (MN) skin patches for transdermal drug delivery has been proven a promising approach, with advantages over hypodermal injection due to painless and easy self-administration. However, the long epidermal application time required for drug implantation by existing LbL MN strategies (15 to 90 minutes) can lead to potential medication noncompliance. Here, we developed a MN platform to shorten the application time in MN therapies based on a synthetic pH-induced charge-invertible polymer, requiring only 1-minute skin insertion time to implant LbL films in vivo. Following MN-mediated delivery of 0.5 μg model antigen chicken ovalbumin (OVA) in the skin of mice, this system achieved sustained release over 3 days and led to an elevated immune response as demonstrated by significantly higher humoral immunity compared with OVA administration via conventional routes (subcutaneously and intramuscularly). Serum OVA-specific IgG₁ level of the microneedle vaccinated group was 9-fold and 160-fold higher than that in intramuscular and subcutaneous injection groups, respectively. Moreover, in an ex vivo experiment on human skin surgical samples, we achieved efficient immune activation through MN-delivered LbL films, demonstrated by a rapid uptake of vaccine adjuvants by the antigen presenting cells, suggesting the potential of applying this technology to human transdermal vaccination. In addition, future work may also incorporate nucleic acid-based vaccines (e.g., mRNA), immune adjuvants (e.g., CpG oligodeoxynucleotides), or immune checkpoint inhibitors (e.g., anti-programmed cell death protein 1) into this system to compare against current delivery technologies.

References:

1. He, Y., Hong, C., Li, J., Howard, M. T., Li, Y., Turvey, M. E., ... & Hammond, P. T. (2018). Synthetic Charge-Invertible Polymer for Rapid and Complete Implantation of Layer-by-Layer Microneedle Drug Films for Enhanced Transdermal Vaccination. ACS nano, 12(10), 10272-10280.
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