Carfilzomib (CFZ) is an FDA-approved proteasome inhibitor with antineoplastic properties against various cancers, yet its short blood retention time after intravenous injection (< 30 min) makes clinical applications limited to multiple myeloma. We previously developed ternary polypeptide nanoparticles (tPNPs) as a new nanoparticle formulation of CFZ to overcome these limitations. The formulation was prepared by polyion complexation between poly(ethylene glycol)-poly(L-glutamate) block copolymers (PEG-PLE) and CFZ-cyclodextrin (CD) inclusion complexes, where CDs were positively charged with 7 primary amines attached while PEG-PLE carried 100 carboxyl groups per polymer chain. Although tPNPs greatly improved biostability of CFZ, CFZ-loaded tPNPs (CFZ-tPNPs) still showed burst drug release and mediocre drug retention under physiological conditions. To address these issues, organic acids are tested as stabilizers in this study to improve particle stability and drug retention for tPNPs. Charge densities in the core of CFZ-tPNPs were optimized with selected organic acids such as citric acid (CA) and lactic acid (LA) at varying mixing ratios. Organic acids successfully maintained small particle size suitable for intravenous injection and drug delivery (diameters < 60 nm), improved CFZ solubility (> 1 mg/mL), allowed for lyophilization and easy reconstitution in various buffers, enhanced drug retention (> 60% post 24 h incubation), and suppressed burst drug release in the first 6 h following solubilization. These results demonstrate that organic acid stabilized tPNPs are useful as an injection formulation of CFZ, which may expand the utility of the proteasome inhibitor.
|Number of pages||6|
|Journal||Journal of Pharmaceutical Sciences|
|State||Published - Apr 2022|
Bibliographical noteFunding Information:
This work was partially supported by the National Institutes of Health grant ( R01 AG073122 ) to KK.
© 2021 American Pharmacists Association
- Drug delivery
ASJC Scopus subject areas
- Pharmaceutical Science