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Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs

Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved in recent years, with several of them in clinical trials. While most of these advances have been associated with monovalent protein degraders, bivalent PROTACs have also entered cli...

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Autores principales: Kou, Ponien, Levy, Elizabeth S., Nguyen, An D., Zhang, Donglu, Chen, Shu, Cui, Yusi, Zhang, Xing, Broccatelli, Fabio, Pizzano, Jennifer, Cantley, Jennifer, Bortolon, Elizabeth, Rousseau, Emma, Berlin, Michael, Dragovich, Peter, Sethuraman, Vijay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10458015/
https://www.ncbi.nlm.nih.gov/pubmed/37631312
http://dx.doi.org/10.3390/pharmaceutics15082098
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author Kou, Ponien
Levy, Elizabeth S.
Nguyen, An D.
Zhang, Donglu
Chen, Shu
Cui, Yusi
Zhang, Xing
Broccatelli, Fabio
Pizzano, Jennifer
Cantley, Jennifer
Bortolon, Elizabeth
Rousseau, Emma
Berlin, Michael
Dragovich, Peter
Sethuraman, Vijay
author_facet Kou, Ponien
Levy, Elizabeth S.
Nguyen, An D.
Zhang, Donglu
Chen, Shu
Cui, Yusi
Zhang, Xing
Broccatelli, Fabio
Pizzano, Jennifer
Cantley, Jennifer
Bortolon, Elizabeth
Rousseau, Emma
Berlin, Michael
Dragovich, Peter
Sethuraman, Vijay
author_sort Kou, Ponien
collection PubMed
description Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved in recent years, with several of them in clinical trials. While most of these advances have been associated with monovalent protein degraders, bivalent PROTACs have also entered clinical trials, although progression to market has been limited. One of the reasons is the complex physicochemical properties of the heterobifunctional PROTACs. A promising strategy to improve pharmacokinetics of highly lipophilic compounds, such as PROTACs, is encapsulation in liposome systems. Here we describe liposome systems for intravenous administration to enhance the PK properties of two bivalent PROTAC molecules, by reducing clearance and increasing systemic coverage. We developed and characterized a PROTAC-in-cyclodextrin liposome system where the drug was retained in the liposome core. In PK studies at 1 mg/kg for GNE-01 the PROTAC-in-cyclodextrin liposome, compared to the solution formulation, showed a 80- and a 380-fold enhancement in AUC for mouse and rat studies, respectively. We further investigated the same PROTAC-in-cyclodextrin liposome system with the second PROTAC (GNE-02), where we monitored both lipid and drug concentrations in vivo. Similarly, in a mouse PK study of GEN-02, the PROTAC-in-cyclodextrin liposome system exhibited enhancement in plasma concentration of a 23× increase over the conventional solution formulation. Importantly, the lipid CL correlated with the drug CL. Additionally, we investigated a conventional liposome approach for GNE-02, where the PROTAC resides in the lipid bilayer. Here, a 5× increase in AUC was observed, compared to the conventional solution formulation, and the drug CL was faster than the lipid CL. These results indicate that the different liposome systems can be tailored to translate across multiple PROTAC systems to modulate and improve plasma concentrations. Optimization of the liposomes could further improve tumor concentration and improve the overall therapeutic index (TI). This delivery technology may be well suited to bring novel protein targeted PROTACs into clinics.
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spelling pubmed-104580152023-08-27 Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs Kou, Ponien Levy, Elizabeth S. Nguyen, An D. Zhang, Donglu Chen, Shu Cui, Yusi Zhang, Xing Broccatelli, Fabio Pizzano, Jennifer Cantley, Jennifer Bortolon, Elizabeth Rousseau, Emma Berlin, Michael Dragovich, Peter Sethuraman, Vijay Pharmaceutics Article Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved in recent years, with several of them in clinical trials. While most of these advances have been associated with monovalent protein degraders, bivalent PROTACs have also entered clinical trials, although progression to market has been limited. One of the reasons is the complex physicochemical properties of the heterobifunctional PROTACs. A promising strategy to improve pharmacokinetics of highly lipophilic compounds, such as PROTACs, is encapsulation in liposome systems. Here we describe liposome systems for intravenous administration to enhance the PK properties of two bivalent PROTAC molecules, by reducing clearance and increasing systemic coverage. We developed and characterized a PROTAC-in-cyclodextrin liposome system where the drug was retained in the liposome core. In PK studies at 1 mg/kg for GNE-01 the PROTAC-in-cyclodextrin liposome, compared to the solution formulation, showed a 80- and a 380-fold enhancement in AUC for mouse and rat studies, respectively. We further investigated the same PROTAC-in-cyclodextrin liposome system with the second PROTAC (GNE-02), where we monitored both lipid and drug concentrations in vivo. Similarly, in a mouse PK study of GEN-02, the PROTAC-in-cyclodextrin liposome system exhibited enhancement in plasma concentration of a 23× increase over the conventional solution formulation. Importantly, the lipid CL correlated with the drug CL. Additionally, we investigated a conventional liposome approach for GNE-02, where the PROTAC resides in the lipid bilayer. Here, a 5× increase in AUC was observed, compared to the conventional solution formulation, and the drug CL was faster than the lipid CL. These results indicate that the different liposome systems can be tailored to translate across multiple PROTAC systems to modulate and improve plasma concentrations. Optimization of the liposomes could further improve tumor concentration and improve the overall therapeutic index (TI). This delivery technology may be well suited to bring novel protein targeted PROTACs into clinics. MDPI 2023-08-08 /pmc/articles/PMC10458015/ /pubmed/37631312 http://dx.doi.org/10.3390/pharmaceutics15082098 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kou, Ponien
Levy, Elizabeth S.
Nguyen, An D.
Zhang, Donglu
Chen, Shu
Cui, Yusi
Zhang, Xing
Broccatelli, Fabio
Pizzano, Jennifer
Cantley, Jennifer
Bortolon, Elizabeth
Rousseau, Emma
Berlin, Michael
Dragovich, Peter
Sethuraman, Vijay
Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs
title Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs
title_full Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs
title_fullStr Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs
title_full_unstemmed Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs
title_short Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs
title_sort development of liposome systems for enhancing the pk properties of bivalent protacs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10458015/
https://www.ncbi.nlm.nih.gov/pubmed/37631312
http://dx.doi.org/10.3390/pharmaceutics15082098
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