Modular Lipid Nanoparticle Platform Technology for siRNA and Lipophilic Prodrug Delivery

Roy van der Meel (Corresponding author), Sam Chen, Josh Zaifman, Jayesh A. Kulkarni, Xu Ran Sabrina Zhang, Ying K. Tam, Marcel B. Bally, Raymond M. Schiffelers, Marco A. Ciufolini, Pieter R. Cullis, Yuen Yi C. Tam

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)
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Successfully employing small interfering RNA (siRNA) therapeutics requires the use of nanotechnology for efficient intracellular delivery. Lipid nanoparticles (LNPs) have enabled the approval of various nucleic acid therapeutics. A major advantage of LNPs is the interchangeability of its building blocks and RNA payload, which allow it to be a highly modular system. In addition, drug derivatization approaches can be used to synthesize lipophilic small molecule prodrugs that stably incorporate in LNPs. This provides ample opportunities to develop combination therapies by co-encapsulating multiple therapeutic agents in a single formulation. Here, it is described how the modular LNP platform is applied for combined gene silencing and chemotherapy to induce additive anticancer effects. It is shown that various lipophilic taxane prodrug derivatives and siRNA against the androgen receptor, a prostate cancer driver, can be efficiently and stably co-encapsulated in LNPs without compromising physicochemical properties or gene-silencing ability. Moreover, it is demonstrated that the combination therapy induces additive therapeutic effects in vitro. Using a double-radiolabeling approach, the pharmacokinetic properties and biodistribution of LNPs and prodrugs following systemic administration in tumor-bearing mice are quantitatively determined. These results indicate that co-encapsulating siRNA and lipophilic prodrugs into LNPs is an attractive and straightforward plug-and-play approach for combination therapy development.
Original languageEnglish
Article number2103025
Issue number37
Early online date1 Aug 2021
Publication statusPublished - 16 Sep 2021


  • androgen receptor
  • combination treatment
  • lipid nanoparticles
  • modularity
  • platform technology
  • prodrug
  • prostate cancer
  • siRNA


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