Carfilzomib-Loaded Ternary Polypeptide Nanoparticles Stabilized by Polycationic Complexation
Article
Agbana, P, Park, JE, Rychahou, P et al. (2024). Carfilzomib-Loaded Ternary Polypeptide Nanoparticles Stabilized by Polycationic Complexation
. 113(3), 711-717. 10.1016/j.xphs.2023.08.026
Agbana, P, Park, JE, Rychahou, P et al. (2024). Carfilzomib-Loaded Ternary Polypeptide Nanoparticles Stabilized by Polycationic Complexation
. 113(3), 711-717. 10.1016/j.xphs.2023.08.026
Carfilzomib (CFZ) is a second-generation proteasome inhibitor showing great efficacy in multiple myeloma treatment, yet its clinical applications for other diseases such as solid cancers are limited due to low aqueous solubility and poor biostability. Ternary polypeptide nanoparticles (tPNPs) are drug carriers that we previously reported to overcome these pharmaceutical limitations by entrapping CFZ in the core of the nanoparticles and protecting the drugs from degradation in biological media. However, preclinical studies revealed that tPNPs would require further improvement in particle stability to suppress initial burst drug release and thus achieve prolonged inhibition of proteasome activity with CFZ against tumor cells in vivo. In this study, CFZ-loaded tPNPs are stabilized by polycations which have varying pKa values and thus differently modulate nanoparticle stability in response to solution pH. Through polyion complexation, the polycations appeared to stabilize the core of tPNPs entrapping CFZ-cyclodextrin inclusion complexes while allowing for uniform particle size before and after freeze drying. Interestingly, CFZ-loaded tPNPs (CFZ/tPNPs) showed pH-dependent drug release kinetics, which accelerated CFZ release as solution acidity increased (pH < 6) without compromising particle stability at the physiological condition (pH 7.4). In vitro cytotoxicity and proteasome activity assays confirmed that tPNPs stabilized with cationic polymers improved bioactivity of CFZ against CFZ-resistant cancer cells, which would be greatly beneficial in combination with pH-dependent drug release for treatment of solid cancers with drug resistance and tumor microenvironment acidosis by using CFZ and other proteasome inhibitors.
