Facile synthesis of rapamycin-loaded PEG-b-PLA nanoparticles and their application in immunotherapy

Yudong Li; Jari F. Scheerstra; Yuechi Liu; Annelies C. Wauters; Jianhong Wang; Hanglong Wu; Tania Patiño; Antoni Llopis-Lorente; Jan C.M. van Hest; Loai K.E.A. Abdelmohsen

doi:10.1002/pol.20230941

Facile synthesis of rapamycin-loaded PEG-b-PLA nanoparticles and their application in immunotherapy

Yudong Li, Jari F. Scheerstra, Yuechi Liu, Annelies C. Wauters, Jianhong Wang, Hanglong Wu, Tania Patiño, Antoni Llopis-Lorente (Corresponding author), Jan C.M. van Hest (Corresponding author), Loai K.E.A. Abdelmohsen (Corresponding author)

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Abstract

Poly(ethylene glycol)-block-poly(lactide) (PEG-b-PLA) micro- and nanoparticles (NPs) have been intensively investigated for applications in biomedicine, due to their inherent biocompatibility and biodegradability, which allows them to be used as sustained release systems. Current methods for preparing PEG-b-PLA NPs typically require two different steps that include polymer synthesis and NP assembly, with the necessary intermediate polymer purification and the use of a variety of organic solvents in the process. In order to facilitate the biomedical application of PEG-b-PLA NPs, it is of great interest to develop a strategy to formulate the NPs in a simplified manner. Here, we report a straightforward method to construct PEG-b-PLA NPs through a sequential two-step process without intermediate work-up, which involves synthesizing the polymer in a water-miscible organic solvent that is, N,N-dimethylformamide (DMF), followed by addition of water to the polymer solution. In this way, large NPs (~600 nm) were prepared. We comprehensively characterized the NPs using turbidity studies, dynamic light scattering (DLS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) techniques. We further demonstrated the ability of the NPs to encapsulate drugs, exemplified in the immunotherapeutic agent rapamycin, with relatively high encapsulation efficiency. In vitro drug release tests showed that rapamycin-encapsulating NPs had comparable sustained-release profiles at different pH conditions, highlighting the broad application window of our NP platform. Moreover, in vitro T cell suppression assays revealed that rapamycin-loaded NPs exhibited similar inhibitory performance to free rapamycin on CD8⁺ cells at all rapamycin concentrations and on CD4⁺ cells at high and intermediate rapamycin concentrations, while the performance of the NPs was superior on CD4⁺ at low rapamycin concentration. Overall, this work provides a route for the scalable synthesis of biocompatible PEG-b-PLA NPs, which can be extended to other polymeric NPs, with potential in biomedical applications such as immunotherapy.

Original language	English
Pages (from-to)	2215-2230
Number of pages	16
Journal	Journal of Polymer Science
Volume	62
Issue number	10
Early online date	5 Mar 2024
DOIs	https://doi.org/10.1002/pol.20230941
Publication status	Published - 15 May 2024

Funding

This work was financially supported by the ICMS Immuno-Engineering Program (CRT), the Dutch Ministry of Education, Culture and Science (Gravitation Program 024.005.020), the Spinoza Premium, and the ERC Advanced Grant (Artisym 694120). Antoni Llopis-Lorente acknowledges the support from the MSCA Cofund Project oLife, which has received funding from the European Union's Horizon 2020 research and innovation program under the grant agreement 847675, and the Mar\u00EDa Zambrano Program from the Spanish Government funded by NextGenerationEU from the European Union. Dr. Xianwen Lou is acknowledged for his help with GC-FID measurements. Figures\u00A01 and 5 were created with BioRender.com. This work was financially supported by the ICMS Immuno\u2010Engineering Program (CRT), the Dutch Ministry of Education, Culture and Science (Gravitation Program 024.005.020), the Spinoza Premium, and the ERC Advanced Grant (Artisym 694120). Antoni Llopis\u2010Lorente acknowledges the support from the MSCA Cofund Project oLife, which has received funding from the European Union's Horizon 2020 research and innovation program under the grant agreement 847675, and the Mar\u00EDa Zambrano Program from the Spanish Government funded by NextGenerationEU from the European Union. Dr. Xianwen Lou is acknowledged for his help with GC\u2010FID measurements. Figures 1 and 5 were created with BioRender.com .

Funders	Funder number
Marie Skłodowska‐Curie
European Commission
H2020 European Research Council	694120
Ministerie van Onderwijs, Cultuur en Wetenschap	024.005.020
European Union's Horizon 2020 - Research and Innovation Framework Programme	847675

Keywords

immunotherapy
nanoparticles
PEG-b-PLA
self-assembly

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title = "Facile synthesis of rapamycin-loaded PEG-b-PLA nanoparticles and their application in immunotherapy",

abstract = "Poly(ethylene glycol)-block-poly(lactide) (PEG-b-PLA) micro- and nanoparticles (NPs) have been intensively investigated for applications in biomedicine, due to their inherent biocompatibility and biodegradability, which allows them to be used as sustained release systems. Current methods for preparing PEG-b-PLA NPs typically require two different steps that include polymer synthesis and NP assembly, with the necessary intermediate polymer purification and the use of a variety of organic solvents in the process. In order to facilitate the biomedical application of PEG-b-PLA NPs, it is of great interest to develop a strategy to formulate the NPs in a simplified manner. Here, we report a straightforward method to construct PEG-b-PLA NPs through a sequential two-step process without intermediate work-up, which involves synthesizing the polymer in a water-miscible organic solvent that is, N,N-dimethylformamide (DMF), followed by addition of water to the polymer solution. In this way, large NPs (~600 nm) were prepared. We comprehensively characterized the NPs using turbidity studies, dynamic light scattering (DLS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) techniques. We further demonstrated the ability of the NPs to encapsulate drugs, exemplified in the immunotherapeutic agent rapamycin, with relatively high encapsulation efficiency. In vitro drug release tests showed that rapamycin-encapsulating NPs had comparable sustained-release profiles at different pH conditions, highlighting the broad application window of our NP platform. Moreover, in vitro T cell suppression assays revealed that rapamycin-loaded NPs exhibited similar inhibitory performance to free rapamycin on CD8+ cells at all rapamycin concentrations and on CD4+ cells at high and intermediate rapamycin concentrations, while the performance of the NPs was superior on CD4+ at low rapamycin concentration. Overall, this work provides a route for the scalable synthesis of biocompatible PEG-b-PLA NPs, which can be extended to other polymeric NPs, with potential in biomedical applications such as immunotherapy.",

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AU - Wang, Jianhong

AU - Wu, Hanglong

AU - Patiño, Tania

AU - Llopis-Lorente, Antoni

AU - van Hest, Jan C.M.

AU - Abdelmohsen, Loai K.E.A.

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AB - Poly(ethylene glycol)-block-poly(lactide) (PEG-b-PLA) micro- and nanoparticles (NPs) have been intensively investigated for applications in biomedicine, due to their inherent biocompatibility and biodegradability, which allows them to be used as sustained release systems. Current methods for preparing PEG-b-PLA NPs typically require two different steps that include polymer synthesis and NP assembly, with the necessary intermediate polymer purification and the use of a variety of organic solvents in the process. In order to facilitate the biomedical application of PEG-b-PLA NPs, it is of great interest to develop a strategy to formulate the NPs in a simplified manner. Here, we report a straightforward method to construct PEG-b-PLA NPs through a sequential two-step process without intermediate work-up, which involves synthesizing the polymer in a water-miscible organic solvent that is, N,N-dimethylformamide (DMF), followed by addition of water to the polymer solution. In this way, large NPs (~600 nm) were prepared. We comprehensively characterized the NPs using turbidity studies, dynamic light scattering (DLS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) techniques. We further demonstrated the ability of the NPs to encapsulate drugs, exemplified in the immunotherapeutic agent rapamycin, with relatively high encapsulation efficiency. In vitro drug release tests showed that rapamycin-encapsulating NPs had comparable sustained-release profiles at different pH conditions, highlighting the broad application window of our NP platform. Moreover, in vitro T cell suppression assays revealed that rapamycin-loaded NPs exhibited similar inhibitory performance to free rapamycin on CD8+ cells at all rapamycin concentrations and on CD4+ cells at high and intermediate rapamycin concentrations, while the performance of the NPs was superior on CD4+ at low rapamycin concentration. Overall, this work provides a route for the scalable synthesis of biocompatible PEG-b-PLA NPs, which can be extended to other polymeric NPs, with potential in biomedical applications such as immunotherapy.

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Facile synthesis of rapamycin-loaded PEG-b-PLA nanoparticles and their application in immunotherapy

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