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Published on: February 9, 2019
Ionizable lipid nanoparticles for RAS protease delivery to inhibit cancer cell proliferation
Ella Atsavapranee1, Rebecca M Haley1, Margaret M Billingsley1
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Abstract:
Mutations in RAS, a family of proteins found in all human cells, drive a third of cancers, including many pancreatic, colorectal, and lung cancers. However, there is a lack of clinical therapies that can effectively prevent RAS from causing tumor growth. Recently, a protease was engineered that specifically degrades active RAS, offering a promising new tool for treating these cancers. However, like many other intracellularly acting protein-based therapies, this protease requires a delivery vector to reach its site of action within the cell. In this study, we explored the incorporation of cationic lipids into ionizable lipid nanoparticles (LNPs) to develop a RAS protease delivery platform capable of inhibiting cancer cell proliferation in vitro and in vivo. A library of 13 LNPs encapsulating RAS protease was designed, and each formulation was evaluated for in vitro delivery efficiency and toxicity. A subset of four top-performing LNP formulations was identified and further evaluated for their impact on cancer cell proliferation in human colorectal cancer cells with mutated KRAS in vitro and in vivo, as well as their in vivo biodistribution and toxicity. In vivo, both the concentration of cationic lipid and type of cargo influenced LNP and cargo distribution. All lead candidate LNPs showed RAS protease functionality in vitro, and the top-performing formulation achieved effective intracellular RAS protease delivery in vivo, decreasing cancer cell proliferation in an in vivo xenograft model and significantly reducing tumor growth and size. Overall, this work demonstrates the use of LNPs as an effective delivery platform for RAS proteases, which could potentially be utilized for cancer therapies.
Insights
Ionizable lipid nanoparticles (LNPs) deliver engineered RAS proteases to inhibit cancer cell proliferation. This LNP platform shows promise for developing novel cancer therapies targeting RAS mutations.
Area of Science:
- Biotechnology
- Oncology
- Nanomedicine
Background:
- RAS protein mutations drive approximately one-third of all human cancers.
- Effective clinical therapies targeting oncogenic RAS proteins remain limited.
- Intracellular protein-based therapies require efficient delivery systems.
Purpose of the Study:
- To develop and evaluate ionizable lipid nanoparticles (LNPs) as a delivery platform for RAS proteases.
- To assess the efficacy of LNP-delivered RAS proteases in inhibiting cancer cell proliferation in vitro and in vivo.
- To optimize LNP formulations for enhanced delivery, biodistribution, and reduced toxicity.
Main Methods:
- Designed and synthesized a library of 13 cationic lipid-containing LNPs encapsulating RAS protease.
- Evaluated LNP formulations for in vitro delivery efficiency and cytotoxicity.
- Assessed the anti-proliferative effects of top-performing LNP formulations in KRAS-mutated colorectal cancer cells.
- Conducted in vivo studies using a xenograft model to evaluate LNP biodistribution, tumor growth inhibition, and toxicity.
Main Results:
- Identified four top-performing LNP formulations with efficient in vitro delivery and RAS protease functionality.
- Demonstrated that both cationic lipid concentration and cargo type influenced in vivo LNP and cargo distribution.
- Showcased significant reduction in cancer cell proliferation and tumor growth in vivo with the lead LNP formulation.
- Confirmed effective intracellular delivery of RAS protease in vivo.
Conclusions:
- Ionizable lipid nanoparticles serve as a viable and effective delivery platform for intracellular RAS proteases.
- This LNP-based approach holds potential for the development of novel cancer therapeutics targeting RAS-driven tumors.
- Further development of this platform could lead to new treatment strategies for various cancers, including colorectal, pancreatic, and lung cancers.
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