Modular lipid nanoparticle platform technology for siRNA and lipophilic prodrug delivery

Abstract

Successfully employing therapeutic nucleic acids, such as small interfering RNA (siRNA), requires chemical modifications or the use of nanocarrier technology to prevent their degradation in the circulation and to facilitate intracellular delivery. Lipid nanoparticles (LNP) are among the most advanced nanocarriers culminating in the first siRNA therapeutics clinical translation and approval. At the same time, their applicability as modular platform technology due to the interchangeable building blocks and siRNA payload hallmarks one of LNPs major advantages. In addition, drug derivatization approaches to synthesize lipophilic small molecule prodrugs enable stable incorporation in LNPs. This provides ample opportunities to develop combination therapies by co-encapsulating multiple therapeutic agents in a single formulation. Here, we describe how the modular LNP platform can be applied for combined gene silencing and chemotherapy to induce additive anti-cancer effects. We show 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. In addition, we demonstrate that prodrug incorporation does not affect LNPs gene silencing ability and that the combination therapy induces additive therapeutic effects in vitro. Using a double-radiolabeling approach, we quantitively determined the LNPs and prodrugs pharmacokinetic properties and biodistribution following systemic administration in tumor-bearing mice. Our results indicate that co-encapsulation of siRNA and lipophilic prodrugs into LNPs is an attractive and straightforward approach for combination therapy development. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/907394v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@b61be4org.highwire.dtl.DTLVardef@1e130c5org.highwire.dtl.DTLVardef@148e5dcorg.highwire.dtl.DTLVardef@eb0cb9_HPS_FORMAT_FIGEXP M_FIG C_FIG