Nano-micelle generating dissolving microneedles for enhanced lymphatic delivery of hydrophobic TLR agonist molecules Nak Won Kim1, Sun Young Kim2, Min Sang Lee1, Jung Eun Lee1, Yue Yin1, Jong Han Lee1, Su Yeon Lim1, Hong Kee Kim3, Yong Taik Lim*,2, Ji Hoon Jeong*,1, 1School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea; 2SKKU Advanced Institute of Nanotechnology (SAINT), School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea; 3Raphas Co. Ltd. Seoul 03920, Republic of Korea *Corresponding Authors
Dissolving microneedle has been considered as an attractive method for transcutaneous immunization due to its superior ability to deliver vaccines and adjuvant through the stratum corneum with minimally invasive manner. However, since dissolving microneedles are mostly prepared using water-soluble sugars or polymers for their rapid dissolution in the intradermal fluid after administration, it is often difficult to formulate with poorly water-soluble drugs or adjuvant. In this study, we develop a micelle-forming tri-block copolymer-based dissolving microneedle which can be fabricated in both aqueous and organic solvent, so that a hydrophilic antigen and hydrophobic TLR agonist can be readily loaded in the microneedle matrix. Furthermore, upon its dissolution after cutaneous application, the microneedle can generate nano-micelle containing hydrophobic TRL agonist. The size of nano-micelle ranged from 30 to 40 nm enables the efficient transition of the nano-micelle to lymph node where it can effectively stimulate the resident antigen presenting cells (APCs), leading to enhanced induction of antigen specific humoral and cellular immunity. When the microneedle containing OVA antigen and a poorly water-soluble TLR agonist, resiquimod (R848), was applied on the skin of tumor bearing mice, a significant level of antigen-specific humoral and cellular immunity can be induced, resulting in a remarkable anti-tumor activity.
Funding The authors acknowledge the financial support from the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (2016R1A2B4015056 and 2014R1A2A1A10049960).