Ternary Polypeptide Nanoparticles with Improved Encapsulation, Sustained Release, and Enhanced In Vitro Efficacy of Carf
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RESEARCH PAPER
Ternary Polypeptide Nanoparticles with Improved Encapsulation, Sustained Release, and Enhanced In Vitro Efficacy of Carfilzomib Preye Agbana 1 & Min Jae Lee 1 & Piotr Rychahou 2 & Kyung-Bo Kim 1 & Younsoo Bae 1
Received: 24 April 2020 / Accepted: 1 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose To develop a new nanoparticle formulation for a proteasome inhibitor Carfilzomib (CFZ) to improve its stability and efficacy for future in vivo applications. Methods CFZ-loaded ternary polypeptide nanoparticles (CFZ/tPNPs) were prepared by using heptakis(6-amino-6deoxy)-β-cyclodextrin(hepta-hydrochloride) (HaβCD) and azido-poly(ethylene glycol)-block-poly(L-glutamic acid sodium salt) (N3-PEG-PLE). The process involved ternary (hydrophobic/ionic/supramolecular) interactions in three steps: 1) CFZ was entrapped in the cavity of HaβCD by hydrophobic interaction, 2) the drug-cyclodextrin inclusion complexes were mixed with N3-PEG-PLE to form polyion complex nanoparticles, and 3) the nanoparticles were modified with fluorescent dyes (AFDye 647) for imaging and/or epithelial cell adhesion molecule (EpCAM) antibodies for cancer cell targeting. CFZ/ tPNPs were characterized for particle size, surface charge, drug release, stability, intracellular uptake, proteasome inhibition, and in vitro cytotoxicity. Results tPNPs maintained an average particle size of 50 nm after CFZ entrapment, EpCAM conjugation, and freeze drying. tPNPs achieved high aqueous solubility of CFZ (>1 mg/ mL), sustained drug release (t1/2 = 6.46 h), and EpCAMmediated cell targeting, which resulted in increased intracellular drug accumulation, prolonged proteasome inhibition, and enhanced cytotoxicity of CFZ in drug-resistant DLD-1 colorectal cancer cells.
* Younsoo Bae [email protected] 1
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, Kentucky 40536-0596, USA
2
Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA
Conclusions tPNPs improved stability and efficacy of CFZ in vitro, and these results potentiate effective cancer treatment using CFZ/tPNPs in future vivo studies.
KEY WORDS cell targeting . colorectal cancer . drug delivery . drug resistance . polypeptide nanoparticles . proteasome inhibitors
ABBREVIATIONS CFZ CFZ/EpCAM-tPNPs CFZ/tPNPs EpCAM FL-CFZ/tPNPs FL-tPNPs HaβCD N3-PEG-PLE tPNPs
Carfilzomib EpCAM-conjugated CFZ/tPNPs tPNPs entrapping CFZ Epithelial cell adhesion molecule Fluorescent CFZ/tPNPs tPNPs modified with fluorescent dye AFDye 647 Heptakis(6-amino-6-deoxy)-β -cyclodextrin(hepta-hydrochloride) Azido-poly(ethylene glycol)-block -poly(L-glutamic acid sodium salt) Ternary polypeptide nanoparticles
INTRODUCTION Carfilzomib (CFZ) is a second-generation proteasome inhibitor approved by the FDA for the treatment of multiple myeloma (1). It has shown great efficacy in treating patients with relapsed/refractory multiple myeloma that is often resistant to the first-generation prot
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