John Garner

PLGA from PolySciTech used in development of nanoparticle-based antisense oligonucleotide delivery system

Blog Post created by John Garner on Jan 17, 2019

Foged 2019 antisense oligonucleotide.jpg

Antisense oligonucleotides (AS)=O) are synthetic polymers that are short-chain derivatives of DNA or RNA. They can potentially be applied to treating a wide range of diseases by blocking or modifying the synthesis of specific proteins involved in pathological states. However, transporting ASO into the cell where it would work is not easily accomplished. Recently, researchers at University of Copenhagen used PLGA (AP030, AP085, AP054, AP199) from PolySciTech ( as part of designing a nanoparticle system for delivery of antisense oligonucleotides. This research holds promise to enable drug delivery for this class of molecules. Read more: Thanki, Kaushik, Simon Papai, Abhijeet Lokras, Fabrice Rose, Emily Falkenberg, Henrik Franzyk, and Camilla Foged. "Application of a Quality-By-Design Approach to Optimise Lipid-Polymer Hybrid Nanoparticles Loaded with a Splice-Correction Antisense Oligonucleotide: Maximising Loading and Intracellular Delivery." Pharmaceutical Research 36, no. 3 (2019): 37.

“Background: Antisense oligonucleotides (ASOs) are promising therapeutics for specific modulation of cellular RNA function. However, ASO efficacy is compromised by inefficient intracellular delivery. Lipid-polymer hybrid nanoparticles (LPNs) are attractive mediators of intracellular ASO delivery due to favorable colloidal stability and sustained release properties. Methods: LPNs composed of cationic lipidoid 5 (L5) and poly(DL-lactic-co-glycolic acid) were studied for delivery of an ASO mediating splice correction of a luciferase gene transcript (Luc-ASO). Specific purposes were: to increase the mechanistic understanding of factors determining the loading of ASO in LPNs, and (ii) to optimise the LPNs and customise them for Luc-ASO delivery in HeLa pLuc/705 cells containing an aberrant luciferase gene by using a quality-by-design approach. Critical formulation variables were linked to critical quality attributes (CQAs) using risk assessment and design of experiments, followed by delineation of an optimal operating space (OOS). Results: A series of CQAs were identified based on the quality target product profile. The L5 content and L5:Luc-ASO ratio (w/w) were determined as critical formulation variables, which were optimised systematically. The optimised Luc-ASO-loaded LPNs, defined from the OOS, displayed high loading and mediated splice correction at well-tolerated, lower doses as compared to those required for reference L5-based lipoplexes, L5-modified stable nucleic acid lipid nanoparticles or LPNs modified with dioleoyltrimethylammonium propane (conventional cationic lipid). Conclusions: The optimal Luc-ASO-loaded LPNs represent a robust formulation that mediates efficient intracellular delivery of Luc-ASO. This opens new avenues for further development of LPNs as a broadly applicable technology platform for delivering nucleic acid cargos intracellularly. Key Words: antisense oligonucleotides in vitro splice correction HeLa pLuc/705 cells lipidoids lipid-polymer hybrid nanoparticles (LPNs) quality-by-design statistical optimization”