Modular Lipid Nanoparticle Platform Technology for siRNA and Lipophilic Prodrug Delivery. Issue 37 (1st August 2021)

• Record Type: Journal Article
• Authors: van der Meel, Roy; Chen, Sam; Zaifman, Josh; Kulkarni, Jayesh A.; Zhang, Xu Ran S.; Tam, Ying K.; Bally, Marcel B.; Schiffelers, Raymond M.; Ciufolini, Marco A.; Cullis, Pieter R.; Tam, Yuen Yi C.
• Is Part Of: Small. Volume 17:Issue 37(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-08-01
• Subjects: androgen receptor -- combination treatment -- lipid nanoparticles -- modularity -- platform technology -- prodrug -- prostate cancer -- siRNA; Nanotechnology -- Periodicals; Nanoparticles -- Periodicals; Microtechnology -- Periodicals; 620.5
• DOI: 10.1002/smll.202103025
• Languages: English
• ISSNs: 1613-6810

Abstract

Abstract: 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. Abstract : Lipid nanoparticles (LNPs) are the most advanced nanocarriers for nucleic acid therapeutics such as small interfering RNA (siRNA). Here, it is showcased how LNP technology's modularity and the ability to stably incorporate lipophilic small molecule prodrugs provide ample opportunities to develop combination therapies by co‐encapsulating multiple therapeutic agents in a single formulation.