Multidrug micelles and sonopermeation for chemotherapy co-delivery to brain tumors

Anshuman Dasgupta; Jan Niklas May; Geir Klinkenberg; Helena C. Besse; Eva Miriam Buhl; Diana Moeckel; Rahaf Mihyar; Quim Peña; Armin Azadkhah Shalmani; Christopher Hark; Anne Rix; Susanne Koletnik; Josbert Metselaar; Yang Shi; Wim E. Hennink; Gert Storm; Dannis van Vuurden; Chrit Moonen; Mario Ries; Ruth Schmid; Fabian Kiessling; Twan Lammers

doi:10.1016/j.jconrel.2025.02.018

Multidrug micelles and sonopermeation for chemotherapy co-delivery to brain tumors

Anshuman Dasgupta, Jan Niklas May, Geir Klinkenberg, Helena C. Besse, Eva Miriam Buhl, Diana Moeckel, Rahaf Mihyar, Quim Peña, Armin Azadkhah Shalmani, Christopher Hark, Anne Rix, Susanne Koletnik, Josbert Metselaar, Yang Shi, Wim E. Hennink, Gert Storm, Dannis van Vuurden, Chrit Moonen, Mario Ries, Ruth SchmidFabian Kiessling, Twan Lammers^*

^*Corresponding author for this work

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

Abstract

Brain tumors are difficult to target and treat. The blood-brain barrier (BBB) limits drug delivery to pathological sites, and standard mono-chemotherapy typically results in suboptimal efficacy and development of drug resistance. We here set out to load a synergistic drug combination in polymeric micelles, and combined them with ultrasound- and microbubble-mediated BBB opening in glioma models in mice. Via high-throughput screening of various chemotherapy combinations in different glioma cell lines, valrubicin and panobinostat were identified as a synergic drug combination and co-loaded in mPEG-b-p(HPMAm-Bz)-based polymeric micelles. Intravenous administration of double-drug micelles showed good tolerability and resulted in significant tumor growth inhibition in mice with subcutaneous GL261 gliomas. In orthotopically inoculated patient-derived HSJD-DIPG-007 diffuse intrinsic pontine gliomas, notoriously known to have an intact BBB and poor drug responsiveness, we provide initial experimental evidence showing that multidrug micelles plus sonopermeation can help to improve treatment efficacy. Our work exemplifies that synergistic drug combinations can be efficiently co-loaded in polymeric micelles, and that advanced nanosonochemotherapy combination regimens hold promise for the treatment of hard-to-treat brain tumors.

Original language	English
Pages (from-to)	818-828
Number of pages	11
Journal	Journal of Controlled Release
Volume	380
DOIs	https://doi.org/10.1016/j.jconrel.2025.02.018
Publication status	Published - 10 Apr 2025

Bibliographical note

Publisher Copyright:
© 2024

Funding

The authors gratefully acknowledge support by the European Commission (EuroNanoMed-III: NSC4DIPG ), the European Research Council ( ERC-CoG 864121 : Meta-Targeting), the German Federal Ministry of Research and Education (BMBF: Gezielter Wirkstofftransport, PP-TNBC, 16GW0319K ), and the German Research Foundation (DFG: GRK/RTG2375 (grant #331065168 ), SFB1066, FOR5011, and LA2937/4-1). BioRender software ( https://biorender.com ) was employed for creating schematics.

Funders	Funder number
Deutsche Forschungsgemeinschaft	GRK/RTG2375, LA2937/4-1, FOR5011, 331065168, SFB1066
European Commission	NSC4DIPG
European Research Council	ERC-CoG 864121
Bundesministerium für Bildung und Forschung	16GW0319K

Keywords

Brain cancer
Combination therapy
DIPG
Nanomedicine
Tumor targeting

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jconrel.2025.02.018Licence: CC BY-NC

1-s2.0-S0168365925001312-mainFinal published version, 7.69 MBLicence: CC BY-NC

Cite this

Dasgupta, A., May, J. N., Klinkenberg, G., Besse, H. C., Buhl, E. M., Moeckel, D., Mihyar, R., Peña, Q., Shalmani, A. A., Hark, C., Rix, A., Koletnik, S., Metselaar, J., Shi, Y., Hennink, W. E., Storm, G., van Vuurden, D., Moonen, C., Ries, M., ... Lammers, T. (2025). Multidrug micelles and sonopermeation for chemotherapy co-delivery to brain tumors. Journal of Controlled Release, 380, 818-828. https://doi.org/10.1016/j.jconrel.2025.02.018

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abstract = "Brain tumors are difficult to target and treat. The blood-brain barrier (BBB) limits drug delivery to pathological sites, and standard mono-chemotherapy typically results in suboptimal efficacy and development of drug resistance. We here set out to load a synergistic drug combination in polymeric micelles, and combined them with ultrasound- and microbubble-mediated BBB opening in glioma models in mice. Via high-throughput screening of various chemotherapy combinations in different glioma cell lines, valrubicin and panobinostat were identified as a synergic drug combination and co-loaded in mPEG-b-p(HPMAm-Bz)-based polymeric micelles. Intravenous administration of double-drug micelles showed good tolerability and resulted in significant tumor growth inhibition in mice with subcutaneous GL261 gliomas. In orthotopically inoculated patient-derived HSJD-DIPG-007 diffuse intrinsic pontine gliomas, notoriously known to have an intact BBB and poor drug responsiveness, we provide initial experimental evidence showing that multidrug micelles plus sonopermeation can help to improve treatment efficacy. Our work exemplifies that synergistic drug combinations can be efficiently co-loaded in polymeric micelles, and that advanced nanosonochemotherapy combination regimens hold promise for the treatment of hard-to-treat brain tumors.",

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day = "10",

doi = "10.1016/j.jconrel.2025.02.018",

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Dasgupta, A, May, JN, Klinkenberg, G, Besse, HC, Buhl, EM, Moeckel, D, Mihyar, R, Peña, Q, Shalmani, AA, Hark, C, Rix, A, Koletnik, S, Metselaar, J, Shi, Y, Hennink, WE , Storm, G, van Vuurden, D, Moonen, C, Ries, M, Schmid, R, Kiessling, F & Lammers, T 2025, 'Multidrug micelles and sonopermeation for chemotherapy co-delivery to brain tumors', Journal of Controlled Release, vol. 380, pp. 818-828. https://doi.org/10.1016/j.jconrel.2025.02.018

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AU - Dasgupta, Anshuman

AU - May, Jan Niklas

AU - Klinkenberg, Geir

AU - Besse, Helena C.

AU - Buhl, Eva Miriam

AU - Moeckel, Diana

AU - Mihyar, Rahaf

AU - Peña, Quim

AU - Shalmani, Armin Azadkhah

AU - Hark, Christopher

AU - Rix, Anne

AU - Koletnik, Susanne

AU - Metselaar, Josbert

AU - Shi, Yang

AU - Hennink, Wim E.

AU - Storm, Gert

AU - van Vuurden, Dannis

AU - Moonen, Chrit

AU - Ries, Mario

AU - Schmid, Ruth

AU - Kiessling, Fabian

AU - Lammers, Twan

PY - 2025/4/10

Y1 - 2025/4/10

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KW - Combination therapy

KW - DIPG

KW - Nanomedicine

KW - Tumor targeting

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ER -

Multidrug micelles and sonopermeation for chemotherapy co-delivery to brain tumors

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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