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Modular Lipid Nanoparticle Platform Technology for siRNA and Lipophilic Prodrug Delivery
Author(s) -
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.
Publication year - 2021
Publication title -
small
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.785
H-Index - 236
eISSN - 1613-6829
pISSN - 1613-6810
DOI - 10.1002/smll.202103025
Subject(s) - prodrug , small interfering rna , chemistry , pharmacology , gene silencing , biodistribution , nucleic acid , small molecule , nanotechnology , rna , in vitro , biochemistry , materials science , biology , gene
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.