Wen Ping, Wang Yunyang, Zhang Chenghao, He Peng, Lin Zhuming, Hu Zhongyu, Lu Weiyue
Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China; Advanced Institute of Pharmaceutical Innovative Technology, Prinbury Biopharm Co, Ltd, Shanghai 201203, China.
Beijing Institute of Biological Products Co., Ltd, Beijing 100176, China.
Int J Pharm. 2025 Jan 25;669:125023. doi: 10.1016/j.ijpharm.2024.125023. Epub 2024 Dec 3.
The aim of this study was to improve the efficacy of Hepatitis B surface antigen (HBsAg) vaccination via liposome-loaded dissolvable microneedle (Lipo-dMN) patches. HBsAg liposomes were prepared using the thin-film hydration method and subsequently incorporated into dissolvable microneedle patches via a pre-vacuum approach. Liposomes, dissolvable microneedle patches (dMN), and Lipo-dMN were characterized for encapsulation efficiency, mechanical properties, morphology, skin insertion, in vitro release, cellular uptake, and in vivo vaccination studies. The HBsAg was encapsulated into liposomes with encapsulation efficiencies around 50 %, particle size around 160 nm, and zeta potential around -20 mV. HBsAg can maintain its activity during the preparation of dMN and Lipo-dMN. The intact pyramid microneedle has a sharp end and strong mechanical properties that allow easy insertion into the ex vivo pig skin. The dMN and Lipo-dMN, with a mechanical property of 1.6 N, readily penetrate the epidermis and release the HBsAg and HBsAg liposome to modulate the immune response. A comprehensive comparison of HBsAg subcutaneous injection and intradermal delivery of HBsAg and HBsAg liposome by dMN revealed different levels of anti-HBsAg IgG antibody. Inoculation with dMN and Lipo-dMN resulted in significantly higher levels of anti-HBsAg IgG antibodies (p < 0.01) compared to subcutaneous injection of HBsAg. In addition, we found that IgG levels increased significantly (P < 0.05) with increased dose of subcutaneous injection of HBsAg and intradermal delivery of dMN, but the opposite effect was observed in Lipo-dMN. The possible mechanism for this observation may be the increased cellular uptake of liposomes by BMDCs upon long-term incubation. In summary, this study presents a promising approach to enhance HBsAg vaccination efficacy through the synergistic combination of liposomes and dissolvable microneedles at reduced vaccine doses.
本研究的目的是通过负载脂质体的可溶微针（Lipo-dMN）贴片提高乙型肝炎表面抗原（HBsAg）疫苗接种的效果。采用薄膜水化法制备HBsAg脂质体，随后通过预真空方法将其掺入可溶微针贴片中。对脂质体、可溶微针贴片（dMN）和Lipo-dMN进行了包封效率、机械性能、形态、皮肤插入、体外释放、细胞摄取和体内疫苗接种研究。HBsAg被包封在脂质体中，包封效率约为50%，粒径约为160nm，zeta电位约为-20mV。HBsAg在dMN和Lipo-dMN的制备过程中能够保持其活性。完整的金字塔形微针尖端尖锐，机械性能强，易于插入离体猪皮肤。机械性能为1.6N的dMN和Lipo-dMN能够轻易穿透表皮，释放HBsAg和HBsAg脂质体以调节免疫反应。对HBsAg皮下注射以及通过dMN进行HBsAg和HBsAg脂质体皮内递送的全面比较显示，抗HBsAg IgG抗体水平不同。与皮下注射HBsAg相比，用dMN和Lipo-dMN接种导致抗HBsAg IgG抗体水平显著更高（p<0.01）。此外，我们发现随着皮下注射HBsAg剂量的增加以及dMN皮内递送剂量的增加，IgG水平显著升高（P<0.05），但在Lipo-dMN中观察到相反的效果。这一观察结果的可能机制可能是长期孵育后骨髓来源的树突状细胞（BMDCs）对脂质体的细胞摄取增加。总之，本研究提出了一种有前景的方法，即通过在降低疫苗剂量的情况下将脂质体和可溶微针协同组合来提高HBsAg疫苗接种效果。
