Abstract

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 previ- ously reported to overcome these pharmaceutical limitations by entrapping CFZ in the core of the nanopar- ticles 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 par- ticle 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.

Document Type

Article

Publication Date

2024

Notes/Citation Information

© 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.xphs.2023.08.026

Funding Information

This study was supported by the University of Kentucky (UK) Cen- ter for Clinical and Translational Science (CCTS), the National Center for Advancing Translational Sciences (UL1TR001998), National Insti- tute on Aging (1R01AG073122-01), and NCI grant (P30 CA177558) for the Radiopharmaceutical Alliance of UK College of Medicine and Markey Cancer Center. The authors also thank Ms. Kaysi Lee for her assistance in cell culture.

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