TY - JOUR
T1 - A lipid nanoparticle platform for mRNA delivery through repurposing of cationic amphiphilic drugs
AU - Bogaert, Bram
AU - Sauvage, Félix
AU - Guagliardo, Roberta
AU - Muntean, Cristina
AU - Nguyen, Van Phuc
AU - Pottie, Eline
AU - Wels, Mike
AU - Minnaert, An Katrien
AU - De Rycke, Riet
AU - Yang, Qiangbing
AU - Peer, Dan
AU - Sanders, Niek
AU - Remaut, Katrien
AU - Paulus, Yannis M.
AU - Stove, Christophe
AU - De Smedt, Stefaan C.
AU - Raemdonck, Koen
N1 - Funding Information:
B. Bogaert and A-K. Minnaert are doctoral fellows of the Research Foundation-Flanders (grant numbers 1S75019N , S28420N , FWO, Belgium). C. Muntean and K. Raemdonck additionally acknowledge the FWO for funding through research grant 3G039419 . R. Guagliardo and M. Wels are doctoral fellows within the NANOMED project, which has received funding from the European Union's Horizon 2020 Research and Innovation Programme Marie Skłodowska Curie Innovative Training Networks (ITN) under grant number 676137 . This project has additionally received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. 101002571 ). We acknowledge the donation of New Zealand White rabbits from the Center for Advanced Models and Translational Sciences and Therapeutics (CAMTraST) at the University of Michigan. Y.M. Paulus acknowledges funding support from the NIH National Eye Institute (NEI) (award number 1K08EY027458 ) along with the Alcon Research Institute Young Investigator Grant and unrestricted departmental support from Research to Prevent Blindness . This work used the Vision Research Core Center funded by P30EY007003 from the NEI . The authors thank the Centre for Advanced Light Microscopy at Ghent University (Belgium) for the use and support of microscopy experiments, the Laboratory of Toxicology at Ghent University (Belgium) for the use of the NanoBiT® Assay and the Department of Ophthalmology and Visual Sciences at the University of Michigan for the collaboration on the in vivo rabbit model.
Funding Information:
B. Bogaert and A-K. Minnaert are doctoral fellows of the Research Foundation-Flanders (grant numbers 1S75019N, S28420N, FWO, Belgium). C. Muntean and K. Raemdonck additionally acknowledge the FWO for funding through research grant 3G039419. R. Guagliardo and M. Wels are doctoral fellows within the NANOMED project, which has received funding from the European Union's Horizon 2020 Research and Innovation Programme Marie Skłodowska Curie Innovative Training Networks (ITN) under grant number 676137. This project has additionally received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. 101002571). We acknowledge the donation of New Zealand White rabbits from the Center for Advanced Models and Translational Sciences and Therapeutics (CAMTraST) at the University of Michigan. Y.M. Paulus acknowledges funding support from the NIH National Eye Institute (NEI) (award number 1K08EY027458) along with the Alcon Research Institute Young Investigator Grant and unrestricted departmental support from Research to Prevent Blindness. This work used the Vision Research Core Center funded by P30EY007003 from the NEI. The authors thank the Centre for Advanced Light Microscopy at Ghent University (Belgium) for the use and support of microscopy experiments, the Laboratory of Toxicology at Ghent University (Belgium) for the use of the NanoBiT® Assay and the Department of Ophthalmology and Visual Sciences at the University of Michigan for the collaboration on the in vivo rabbit model.
Publisher Copyright:
© 2022
PY - 2022/10
Y1 - 2022/10
N2 - Since the recent clinical approval of siRNA-based drugs and COVID-19 mRNA vaccines, the potential of RNA therapeutics for patient healthcare has become widely accepted. Lipid nanoparticles (LNPs) are currently the most advanced nanocarriers for RNA packaging and delivery. Nevertheless, the intracellular delivery efficiency of state-of-the-art LNPs remains relatively low and safety and immunogenicity concerns with synthetic lipid components persist, altogether rationalizing the exploration of alternative LNP compositions. In addition, there is an interest in exploiting LNP technology for simultaneous encapsulation of small molecule drugs and RNA in a single nanocarrier. Here, we describe how well-known tricyclic cationic amphiphilic drugs (CADs) can be repurposed as both structural and functional components of lipid-based NPs for mRNA formulation, further referred to as CADosomes. We demonstrate that selected CADs, such as tricyclic antidepressants and antihistamines, self-assemble with the widely-used helper lipid DOPE to form cationic lipid vesicles for subsequent mRNA complexation and delivery, without the need for prior lipophilic derivatization. Selected CADosomes enabled efficient mRNA delivery in various in vitro cell models, including easy-to-transfect cancer cells (e.g. human cervical carcinoma HeLa cell line) as well as hard-to-transfect primary cells (e.g. primary bovine corneal epithelial cells), outperforming commercially available cationic liposomes and state-of-the-art LNPs. In addition, using the antidepressant nortriptyline as a model compound, we show that CADs can maintain their pharmacological activity upon CADosome incorporation. Furthermore, in vivo proof-of-concept was obtained, demonstrating CADosome-mediated mRNA delivery in the corneal epithelial cells of rabbit eyes, which could pave the way for future applications in ophthalmology. Based on our results, the co-formulation of CADs, helper lipids and mRNA into lipid-based nanocarriers is proposed as a versatile and straightforward approach for the rational development of drug combination therapies.
AB - Since the recent clinical approval of siRNA-based drugs and COVID-19 mRNA vaccines, the potential of RNA therapeutics for patient healthcare has become widely accepted. Lipid nanoparticles (LNPs) are currently the most advanced nanocarriers for RNA packaging and delivery. Nevertheless, the intracellular delivery efficiency of state-of-the-art LNPs remains relatively low and safety and immunogenicity concerns with synthetic lipid components persist, altogether rationalizing the exploration of alternative LNP compositions. In addition, there is an interest in exploiting LNP technology for simultaneous encapsulation of small molecule drugs and RNA in a single nanocarrier. Here, we describe how well-known tricyclic cationic amphiphilic drugs (CADs) can be repurposed as both structural and functional components of lipid-based NPs for mRNA formulation, further referred to as CADosomes. We demonstrate that selected CADs, such as tricyclic antidepressants and antihistamines, self-assemble with the widely-used helper lipid DOPE to form cationic lipid vesicles for subsequent mRNA complexation and delivery, without the need for prior lipophilic derivatization. Selected CADosomes enabled efficient mRNA delivery in various in vitro cell models, including easy-to-transfect cancer cells (e.g. human cervical carcinoma HeLa cell line) as well as hard-to-transfect primary cells (e.g. primary bovine corneal epithelial cells), outperforming commercially available cationic liposomes and state-of-the-art LNPs. In addition, using the antidepressant nortriptyline as a model compound, we show that CADs can maintain their pharmacological activity upon CADosome incorporation. Furthermore, in vivo proof-of-concept was obtained, demonstrating CADosome-mediated mRNA delivery in the corneal epithelial cells of rabbit eyes, which could pave the way for future applications in ophthalmology. Based on our results, the co-formulation of CADs, helper lipids and mRNA into lipid-based nanocarriers is proposed as a versatile and straightforward approach for the rational development of drug combination therapies.
KW - Cationic amphiphilic drugs
KW - Cellular delivery
KW - Drug repurposing
KW - Lipid nanoparticles
KW - Messenger RNA
KW - Nanomedicine
KW - RNA therapeutics
KW - Nortriptyline
KW - Rabbits
KW - COVID-19 Drug Treatment
KW - Humans
KW - RNA, Small Interfering/genetics
KW - Lipids/chemistry
KW - Drug Repositioning
KW - RNA, Messenger/genetics
KW - Animals
KW - Cattle
KW - Antidepressive Agents, Tricyclic
KW - Nanoparticles/chemistry
KW - Cations
KW - HeLa Cells
KW - Liposomes
KW - Drug Combinations
UR - http://www.scopus.com/inward/record.url?scp=85136526402&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85136526402&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2022.08.009
DO - 10.1016/j.jconrel.2022.08.009
M3 - Article
C2 - 35963467
AN - SCOPUS:85136526402
SN - 0168-3659
VL - 350
SP - 256
EP - 270
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -