Polymer micelle formulation for the proteasome inhibitor drug carfilzomib: Anticancer efficacy and pharmacokinetic studies in mice.
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 degrad...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5342227?pdf=render |
| _version_ | 1818143535385280512 |
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| author | Ji Eun Park Se-Eun Chun Derek Reichel Jee Sun Min Su-Chan Lee Songhee Han Gongmi Ryoo Yunseok Oh Shin-Hyung Park Heon-Min Ryu Kyung Bo Kim Ho-Young Lee Soo Kyung Bae Younsoo Bae Wooin Lee |
| author_facet | Ji Eun Park Se-Eun Chun Derek Reichel Jee Sun Min Su-Chan Lee Songhee Han Gongmi Ryoo Yunseok Oh Shin-Hyung Park Heon-Min Ryu Kyung Bo Kim Ho-Young Lee Soo Kyung Bae Younsoo Bae Wooin Lee |
| author_sort | Ji Eun Park |
| collection | DOAJ |
| description | 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 vitro performances, 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. |
| first_indexed | 2024-12-11T11:33:13Z |
| format | Article |
| id | doaj.art-84712ebbc6e04ef68bd9e82f610f0fbf |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T11:33:13Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-84712ebbc6e04ef68bd9e82f610f0fbf2022-12-22T01:08:49ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01123e017324710.1371/journal.pone.0173247Polymer micelle formulation for the proteasome inhibitor drug carfilzomib: Anticancer efficacy and pharmacokinetic studies in mice.Ji Eun ParkSe-Eun ChunDerek ReichelJee Sun MinSu-Chan LeeSonghee HanGongmi RyooYunseok OhShin-Hyung ParkHeon-Min RyuKyung Bo KimHo-Young LeeSoo Kyung BaeYounsoo BaeWooin LeeCarfilzomib (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 vitro performances, 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.http://europepmc.org/articles/PMC5342227?pdf=render |
| spellingShingle | Ji Eun Park Se-Eun Chun Derek Reichel Jee Sun Min Su-Chan Lee Songhee Han Gongmi Ryoo Yunseok Oh Shin-Hyung Park Heon-Min Ryu Kyung Bo Kim Ho-Young Lee Soo Kyung Bae Younsoo Bae Wooin Lee Polymer micelle formulation for the proteasome inhibitor drug carfilzomib: Anticancer efficacy and pharmacokinetic studies in mice. PLoS ONE |
| title | Polymer micelle formulation for the proteasome inhibitor drug carfilzomib: Anticancer efficacy and pharmacokinetic studies in mice. |
| title_full | Polymer micelle formulation for the proteasome inhibitor drug carfilzomib: Anticancer efficacy and pharmacokinetic studies in mice. |
| title_fullStr | Polymer micelle formulation for the proteasome inhibitor drug carfilzomib: Anticancer efficacy and pharmacokinetic studies in mice. |
| title_full_unstemmed | Polymer micelle formulation for the proteasome inhibitor drug carfilzomib: Anticancer efficacy and pharmacokinetic studies in mice. |
| title_short | Polymer micelle formulation for the proteasome inhibitor drug carfilzomib: Anticancer efficacy and pharmacokinetic studies in mice. |
| title_sort | polymer micelle formulation for the proteasome inhibitor drug carfilzomib anticancer efficacy and pharmacokinetic studies in mice |
| url | http://europepmc.org/articles/PMC5342227?pdf=render |
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