Abstract
Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro. Here, we prepared the CFZ-loaded PM, PEG-PCL-deoxycholic acid (CFZ-PM) and assessed its in vivo anticancer efficacy and pharmacokinetic profiles. Despite in vitro metabolic protection of CFZ, CFZ-PM did not display in vivo anticancer efficacy in mice bearing human lung cancer xenograft (H460) superior to that of the clinically used cyclodextrin-based CFZ (CFZ-CD) formulation. The plasma pharmacokinetic profiles of CFZ-PM were also comparable to those of CFZ-CD and the residual tumors that persisted in xenograft mice receiving CFZ-PM displayed an incomplete proteasome inhibition. In summary, our results showed that despite its favorable in vitroperformances, the current CFZ-PM formulation did not improve in vivo anticancer efficacy and accessibility of active CFZ to solid cancer tissues over CFZ-CD. Careful consideration of the current results and potential confounding factors may provide valuable insights into the future efforts to validate the potential of CFZ-based therapy for solid cancer and to develop effective CFZ delivery strategies that can be used to treat solid cancers.
Document Type
Article
Publication Date
3-8-2017
Digital Object Identifier (DOI)
https://doi.org/10.1371/journal.pone.0173247
Funding Information
This work was supported in part by Basic Research Program, National Research Foundation of Korea, Ministry of Science, ICT and Future Planning (NRF-2014R1A1A3050645) and the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (No.1520250).
Repository Citation
Park, Ji Eun; Chun, Se-Eun; Reichel, Derek Alexander; Min, Jee Sun; Lee, Su-Chan; Han, Songhee; Ryoo, Gongmi; Oh, Yunseok; Park, Shin-Hyung; Ryu, Heon-Min; Kim, Kyung Bo; Lee, Ho-Young; Bae, Soo Kyung; Bae, Younsoo; and Lee, Wooin, "Polymer Micelle Formulation for the Proteasome Inhibitor Drug Carfilzomib: Anticancer Efficacy and Pharmacokinetic Studies in Mice" (2017). Pharmaceutical Sciences Faculty Publications. 88.
https://uknowledge.uky.edu/ps_facpub/88
Included in
Chemicals and Drugs Commons, Clinical Trials Commons, Pharmacy and Pharmaceutical Sciences Commons, Polymer Chemistry Commons
Notes/Citation Information
Published in PLOS ONE, v. 12, 3, e0173247, p. 1-12.
© 2017 Park et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.