Combined Chemoradionuclide Therapy Using Poly(ε-caprolactone-b-ethylene oxide) Micelles as the Delivery Vehicle

Huanhuan Liu; Robin A. Nadar; Retna Putri Fauzia; Adrianus C. Laan; Britt Doeswijk; Runze Wang; Astrid van de Meer; Quenteijn van Cooten; Elizabeth C.M. Carroll; Rienk Eelkema; Antonia G. Denkova

doi:10.1002/adtp.202200224

Combined Chemoradionuclide Therapy Using Poly(ε-caprolactone-b-ethylene oxide) Micelles as the Delivery Vehicle

Huanhuan Liu, Robin A. Nadar, Retna Putri Fauzia, Adrianus C. Laan, Britt Doeswijk, Runze Wang, Astrid van de Meer, Quenteijn van Cooten, Elizabeth C.M. Carroll, Rienk Eelkema^*, Antonia G. Denkova^*

^*Corresponding author for this work

Radiotherapy

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Combination of therapies is a common strategy in cancer treatment. Such combined therapies only have merit provided that there is superior therapeutic outcome with fewer side effects, compared to single therapies. Here, this work explores the possibility to combine chemotherapy with radionuclide therapy using polymeric micelles as a delivery vehicle. For this purpose, this work prepares poly(ε-caprolactone-b-ethylene oxide) (PCL-PEO) micelles and load them simultaneously with paclitaxel (PTX) and ¹⁷⁷Lu(III). This work chooses a 3D tumor spheroid composed of glioblastoma cells (U87) to evaluate the combined treatment. The diffusion of the micelles in the spheroid is investigated by confocal laser scanning microscopy (CLSM) and light-sheet fluorescence microscopy (LSFM). The results show that the micelles are able to penetrate deep into the spheroid within 24 h of incubation and mainly accumulated around or in the lysosomes once in the cell. Subsequently, this work evaluates the cell killing efficiency of the single treatments (PTX or ¹⁷⁷Lu(III)) versus combined treatment (PTX + ¹⁷⁷Lu(III)) by measuring the growth of the spheroids as well as by performing a cell-viability assay. The results indicate that the combined therapy achieves a superior therapeutic outcome with better cell growth inhibition and cell killing efficiency compared to the single treatments.

Original language	English
Article number	2200224
Journal	Advanced Therapeutics
Volume	6
Issue number	5
Early online date	25 Feb 2023
DOIs	https://doi.org/10.1002/adtp.202200224
Publication status	Published - May 2023

Bibliographical note

Funding Information:
This work is financially supported by the China Scholarship Council (Grant Number 201707040083) and the Delft Health Initiative. E.C. acknowledges support from an ENW‐XS grant (OCENW.XS.102) from the Dutch Research Council (NWO). We are grateful to Erik de Blois from Erasmus MC for the supply of Lu, we also thank Rene Nouse for the radioisotope transportation. We would also like to thank Laura Maddalena and Dr. Nicolò Ceffa for help with the light‐sheet fluorescence microscope and preliminary light‐sheet studies. 177

Funding Information:
This work is financially supported by the China Scholarship Council (Grant Number 201707040083) and the Delft Health Initiative. E.C. acknowledges support from an ENW-XS grant (OCENW.XS.102) from the Dutch Research Council (NWO). We are grateful to Erik de Blois from Erasmus MC for the supply of 177Lu, we also thank Rene Nouse for the radioisotope transportation. We would also like to thank Laura Maddalena and Dr. Nicolò Ceffa for help with the light-sheet fluorescence microscope and preliminary light-sheet studies.

Publisher Copyright:
© 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.

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title = "Combined Chemoradionuclide Therapy Using Poly(ε-caprolactone-b-ethylene oxide) Micelles as the Delivery Vehicle",

abstract = "Combination of therapies is a common strategy in cancer treatment. Such combined therapies only have merit provided that there is superior therapeutic outcome with fewer side effects, compared to single therapies. Here, this work explores the possibility to combine chemotherapy with radionuclide therapy using polymeric micelles as a delivery vehicle. For this purpose, this work prepares poly(ε-caprolactone-b-ethylene oxide) (PCL-PEO) micelles and load them simultaneously with paclitaxel (PTX) and 177Lu(III). This work chooses a 3D tumor spheroid composed of glioblastoma cells (U87) to evaluate the combined treatment. The diffusion of the micelles in the spheroid is investigated by confocal laser scanning microscopy (CLSM) and light-sheet fluorescence microscopy (LSFM). The results show that the micelles are able to penetrate deep into the spheroid within 24 h of incubation and mainly accumulated around or in the lysosomes once in the cell. Subsequently, this work evaluates the cell killing efficiency of the single treatments (PTX or 177Lu(III)) versus combined treatment (PTX + 177Lu(III)) by measuring the growth of the spheroids as well as by performing a cell-viability assay. The results indicate that the combined therapy achieves a superior therapeutic outcome with better cell growth inhibition and cell killing efficiency compared to the single treatments.",

author = "Huanhuan Liu and Nadar, {Robin A.} and Fauzia, {Retna Putri} and Laan, {Adrianus C.} and Britt Doeswijk and Runze Wang and {van de Meer}, Astrid and {van Cooten}, Quenteijn and Carroll, {Elizabeth C.M.} and Rienk Eelkema and Denkova, {Antonia G.}",

note = "Funding Information: This work is financially supported by the China Scholarship Council (Grant Number 201707040083) and the Delft Health Initiative. E.C. acknowledges support from an ENW‐XS grant (OCENW.XS.102) from the Dutch Research Council (NWO). We are grateful to Erik de Blois from Erasmus MC for the supply of Lu, we also thank Rene Nouse for the radioisotope transportation. We would also like to thank Laura Maddalena and Dr. Nicol{\`o} Ceffa for help with the light‐sheet fluorescence microscope and preliminary light‐sheet studies. 177 Funding Information: This work is financially supported by the China Scholarship Council (Grant Number 201707040083) and the Delft Health Initiative. E.C. acknowledges support from an ENW-XS grant (OCENW.XS.102) from the Dutch Research Council (NWO). We are grateful to Erik de Blois from Erasmus MC for the supply of 177Lu, we also thank Rene Nouse for the radioisotope transportation. We would also like to thank Laura Maddalena and Dr. Nicol{\`o} Ceffa for help with the light-sheet fluorescence microscope and preliminary light-sheet studies. Publisher Copyright: {\textcopyright} 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.",

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month = may,

doi = "10.1002/adtp.202200224",

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T1 - Combined Chemoradionuclide Therapy Using Poly(ε-caprolactone-b-ethylene oxide) Micelles as the Delivery Vehicle

AU - Liu, Huanhuan

AU - Nadar, Robin A.

AU - Fauzia, Retna Putri

AU - Laan, Adrianus C.

AU - Doeswijk, Britt

AU - Wang, Runze

AU - van de Meer, Astrid

AU - van Cooten, Quenteijn

AU - Carroll, Elizabeth C.M.

AU - Eelkema, Rienk

AU - Denkova, Antonia G.

N1 - Funding Information: This work is financially supported by the China Scholarship Council (Grant Number 201707040083) and the Delft Health Initiative. E.C. acknowledges support from an ENW‐XS grant (OCENW.XS.102) from the Dutch Research Council (NWO). We are grateful to Erik de Blois from Erasmus MC for the supply of Lu, we also thank Rene Nouse for the radioisotope transportation. We would also like to thank Laura Maddalena and Dr. Nicolò Ceffa for help with the light‐sheet fluorescence microscope and preliminary light‐sheet studies. 177 Funding Information: This work is financially supported by the China Scholarship Council (Grant Number 201707040083) and the Delft Health Initiative. E.C. acknowledges support from an ENW-XS grant (OCENW.XS.102) from the Dutch Research Council (NWO). We are grateful to Erik de Blois from Erasmus MC for the supply of 177Lu, we also thank Rene Nouse for the radioisotope transportation. We would also like to thank Laura Maddalena and Dr. Nicolò Ceffa for help with the light-sheet fluorescence microscope and preliminary light-sheet studies. Publisher Copyright: © 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.

PY - 2023/5

Y1 - 2023/5

N2 - Combination of therapies is a common strategy in cancer treatment. Such combined therapies only have merit provided that there is superior therapeutic outcome with fewer side effects, compared to single therapies. Here, this work explores the possibility to combine chemotherapy with radionuclide therapy using polymeric micelles as a delivery vehicle. For this purpose, this work prepares poly(ε-caprolactone-b-ethylene oxide) (PCL-PEO) micelles and load them simultaneously with paclitaxel (PTX) and 177Lu(III). This work chooses a 3D tumor spheroid composed of glioblastoma cells (U87) to evaluate the combined treatment. The diffusion of the micelles in the spheroid is investigated by confocal laser scanning microscopy (CLSM) and light-sheet fluorescence microscopy (LSFM). The results show that the micelles are able to penetrate deep into the spheroid within 24 h of incubation and mainly accumulated around or in the lysosomes once in the cell. Subsequently, this work evaluates the cell killing efficiency of the single treatments (PTX or 177Lu(III)) versus combined treatment (PTX + 177Lu(III)) by measuring the growth of the spheroids as well as by performing a cell-viability assay. The results indicate that the combined therapy achieves a superior therapeutic outcome with better cell growth inhibition and cell killing efficiency compared to the single treatments.

AB - Combination of therapies is a common strategy in cancer treatment. Such combined therapies only have merit provided that there is superior therapeutic outcome with fewer side effects, compared to single therapies. Here, this work explores the possibility to combine chemotherapy with radionuclide therapy using polymeric micelles as a delivery vehicle. For this purpose, this work prepares poly(ε-caprolactone-b-ethylene oxide) (PCL-PEO) micelles and load them simultaneously with paclitaxel (PTX) and 177Lu(III). This work chooses a 3D tumor spheroid composed of glioblastoma cells (U87) to evaluate the combined treatment. The diffusion of the micelles in the spheroid is investigated by confocal laser scanning microscopy (CLSM) and light-sheet fluorescence microscopy (LSFM). The results show that the micelles are able to penetrate deep into the spheroid within 24 h of incubation and mainly accumulated around or in the lysosomes once in the cell. Subsequently, this work evaluates the cell killing efficiency of the single treatments (PTX or 177Lu(III)) versus combined treatment (PTX + 177Lu(III)) by measuring the growth of the spheroids as well as by performing a cell-viability assay. The results indicate that the combined therapy achieves a superior therapeutic outcome with better cell growth inhibition and cell killing efficiency compared to the single treatments.

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Combined Chemoradionuclide Therapy Using Poly(ε-caprolactone-b-ethylene oxide) Micelles as the Delivery Vehicle

Abstract

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