2025
J Control Release 2025 Oct 9;388(Pt 1):114299. doi: 10.1016/j.jconrel.2025.114299. Online ahead of print.
Polymeric-lipid nanoparticles that leverage cationic helper lipids and the protein corona for lung-targeted delivery of a novel anti-cancer drug
Centre for Pharmaceutical Innovation, University of South Australia, UniSA Clinical and Health Sciences, SA 5000, Australia. Centre for Pharmaceutical Innovation, University of South Australia, UniSA Clinical and Health Sciences, SA 5000, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, SA 5000, Adelaide, Australia. Centre for Cancer Biology, SA Pathology and University of South Australia, SA 5000, Adelaide, Australia. Centre for Pharmaceutical Innovation, University of South Australia, UniSA Clinical and Health Sciences, SA 5000, Australia. Electronic address: Paul.Joyce@unisa.edu.au.
Service type: Stock strains
Abstract
Lung cancer remains one of the leading causes of cancer-related mortality worldwide, highlighting the urgent need for more effective therapeutic strategies. Nanomedicine offers a promising avenue to improve treatment outcomes by enabling localised drug delivery within the lungs. Drawing inspiration from the recent success of mRNA lipid nanoparticles, we developed a novel class of polymeric-lipid nanoparticles (P-LNPs) designed to encapsulate RB-012, an anticancer compound that inhibits 14-3-3 protein function but is rapidly cleared from systemic circulation due to its cationic and amphiphilic properties. RB-012 was co-assembled with the anionic polymer polyacrylic acid (PAA) and various combinations of cholesterol, pegylated, and charged helper lipids to form stable P-LNPs that significantly impeded in vitro premature drug release. This approach resulted in >30-fold increase in bioavailability following intravenous administration (2 mg/kg) to Sprague-Dawley rats. Varying the helper lipid composition, through the inclusion of 16-32 mol% of the cationic lipid, DOTAP, yielded a > 50-fold increase in pulmonary drug exposure compared to unformulated RB-012. These biodistribution enhancements were linked to altered protein corona profiles on the nanoparticle surface, with P-LNPs formulated with DOTAP increasing the degree of protein corona adsorption in a concentration-dependent manner, compared to P-LNPs prepared with the anionic helper lipid, DOPE. In vitro and in ovo assays confirmed that the P-LNPs significantly improved the anti-tumour efficacy of RB-012, supporting their potential as a targeted therapeutic platform for lung cancer treatment.
Keywords: Cationic amphiphilic drugs; Hybrid nanoparticles; Lung cancer; Protein corona; Pulmonary delivery.
