High drug-loaded microspheres enabled by controlled in-droplet precipitation promote functional recovery after spinal cord injury

Wei Li, Jian Chen, Shujie Zhao, Tianhe Huang, Huiyan Ying, Claudia Trujillo, Giuseppina Molinaro, Zheng Zhou, Tao Jiang, Wei Liu, Linwei Li, Yuancheng Bai, Peng Quan, Yaping Ding, Jouni Hirvonen, Guoyong Yin (), Hélder A. Santos (), Jin Fan () and Dongfei Liu ()
Additional contact information
Wei Li: University of Helsinki
Jian Chen: The First Affiliated Hospital of Nanjing Medical University
Shujie Zhao: The First Affiliated Hospital of Nanjing Medical University
Tianhe Huang: China Pharmaceutical University
Huiyan Ying: University of Helsinki
Claudia Trujillo: University of Helsinki
Giuseppina Molinaro: University of Helsinki
Zheng Zhou: The First Affiliated Hospital of Nanjing Medical University
Tao Jiang: The First Affiliated Hospital of Nanjing Medical University
Wei Liu: The First Affiliated Hospital of Nanjing Medical University
Linwei Li: The First Affiliated Hospital of Nanjing Medical University
Yuancheng Bai: China Pharmaceutical University
Peng Quan: University of Helsinki
Yaping Ding: University of Helsinki
Jouni Hirvonen: University of Helsinki
Guoyong Yin: The First Affiliated Hospital of Nanjing Medical University
Hélder A. Santos: University of Helsinki
Jin Fan: The First Affiliated Hospital of Nanjing Medical University
Dongfei Liu: University of Helsinki

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Drug delivery systems with high content of drug can minimize excipients administration, reduce side effects, improve therapeutic efficacy and/or promote patient compliance. However, engineering such systems is extremely challenging, as their loading capacity is inherently limited by the compatibility between drug molecules and carrier materials. To mitigate the drug-carrier compatibility limitation towards therapeutics encapsulation, we developed a sequential solidification strategy. In this strategy, the precisely controlled diffusion of solvents from droplets ensures the fast in-droplet precipitation of drug molecules prior to the solidification of polymer materials. After polymer solidification, a mass of drug nanoparticles is embedded in the polymer matrix, forming a nano-in-micro structured microsphere. All the obtained microspheres exhibit long-term storage stability, controlled release of drug molecules, and most importantly, high mass fraction of therapeutics (21.8–63.1 wt%). Benefiting from their high drug loading degree, the nano-in-micro structured acetalated dextran microspheres deliver a high dose of methylprednisolone (400 μg) within the limited administration volume (10 μL) by one single intrathecal injection. The amount of acetalated dextran used was 1/433 of that of low drug-loaded microspheres. Moreover, the controlled release of methylprednisolone from high drug-loaded microspheres contributes to improved therapeutic efficacy and reduced side effects than low drug-loaded microspheres and free drug in spinal cord injury therapy.

Date: 2022
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DOI: 10.1038/s41467-022-28787-7

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