Hydrophobic ion pairing enables co-loading of water-soluble drugs in polymeric micelles

Armin Azadkhah Shalmani; Rasika Daware; Asmaa Said Elshafei; Federica De Lorenzi; Diana Moeckel; Eva M. Buhl; Barbara Mara Klinkhammer; Peter Boor; Srinivas Banala; Alina Adams; Fabian Kiessling; Gert Storm; Josbert M. Metselaar; Alexandros Marios Sofias; Yang Shi; Twan Lammers; Quim Peña; Tarun Ojha

doi:10.1016/j.jconrel.2025.113748

Hydrophobic ion pairing enables co-loading of water-soluble drugs in polymeric micelles

Armin Azadkhah Shalmani, Rasika Daware, Asmaa Said Elshafei, Federica De Lorenzi, Diana Moeckel, Eva M. Buhl, Barbara Mara Klinkhammer, Peter Boor, Srinivas Banala, Alina Adams, Fabian Kiessling, Gert Storm, Josbert M. Metselaar, Alexandros Marios Sofias, Yang Shi, Twan Lammers^*, Quim Peña^*, Tarun Ojha^*

^*Corresponding author for this work

RWTH Aachen University

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

Abstract

Polymeric micelles are widely used for the delivery of hydrophobic drugs. However, several highly potent and ubiquitously used anticancer drugs are water-soluble, complicating their (co-)formulation in polymeric micelles without having to chemically modify them. We here explore hydrophobic ion pairing to enable the co-delivery of the water-soluble anthracycline chemotherapy drug doxorubicin and the angiotensin II receptor antagonist telmisartan (a clinically used antihypertensive drug that has shown promising (pre-) clinical outcomes in combination with anthracyclines). We show that hydrophobic ion pairing of doxorubicin and telmisartan promotes the co-encapsulation of both drugs in π electron-stabilized [PEG-b-p(HPMAm-Bz)]-based polymeric micelles. The cytotoxic activity of doxorubicin is retained, and the dual drug-loaded micelles display enhanced antitumor activity in vivo as compared to the combination of the free drugs, while also exhibiting good tolerability. Taken together, this work provides proof-of-concept for hydrophobic ion pairing as a promising formulation strategy to promote multidrug nanomedicine and drug combination therapy.

Original language	English
Article number	113748
Number of pages	12
Journal	Journal of Controlled Release
Volume	382
DOIs	https://doi.org/10.1016/j.jconrel.2025.113748
Publication status	Published - 10 Jun 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors

Keywords

Cancer
Combination therapy
Doxorubicin
Hydrophobic ion pairing
Multidrug nanomedicine
Polymeric micelle

UN SDGs

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

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Hydrophobic ion pairing enables co-loading of water-soluble drugs in polymeric micellesFinal published version, 6.3 MBLicence: CC BY-NC-ND

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Shalmani, A. A., Daware, R., Elshafei, A. S., De Lorenzi, F., Moeckel, D., Buhl, E. M., Klinkhammer, B. M., Boor, P., Banala, S., Adams, A., Kiessling, F., Storm, G., Metselaar, J. M., Sofias, A. M., Shi, Y., Lammers, T., Peña, Q., & Ojha, T. (2025). Hydrophobic ion pairing enables co-loading of water-soluble drugs in polymeric micelles. Journal of Controlled Release, 382, Article 113748. https://doi.org/10.1016/j.jconrel.2025.113748

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title = "Hydrophobic ion pairing enables co-loading of water-soluble drugs in polymeric micelles",

abstract = "Polymeric micelles are widely used for the delivery of hydrophobic drugs. However, several highly potent and ubiquitously used anticancer drugs are water-soluble, complicating their (co-)formulation in polymeric micelles without having to chemically modify them. We here explore hydrophobic ion pairing to enable the co-delivery of the water-soluble anthracycline chemotherapy drug doxorubicin and the angiotensin II receptor antagonist telmisartan (a clinically used antihypertensive drug that has shown promising (pre-) clinical outcomes in combination with anthracyclines). We show that hydrophobic ion pairing of doxorubicin and telmisartan promotes the co-encapsulation of both drugs in π electron-stabilized [PEG-b-p(HPMAm-Bz)]-based polymeric micelles. The cytotoxic activity of doxorubicin is retained, and the dual drug-loaded micelles display enhanced antitumor activity in vivo as compared to the combination of the free drugs, while also exhibiting good tolerability. Taken together, this work provides proof-of-concept for hydrophobic ion pairing as a promising formulation strategy to promote multidrug nanomedicine and drug combination therapy.",

keywords = "Cancer, Combination therapy, Doxorubicin, Hydrophobic ion pairing, Multidrug nanomedicine, Polymeric micelle",

author = "Shalmani, {Armin Azadkhah} and Rasika Daware and Elshafei, {Asmaa Said} and {De Lorenzi}, Federica and Diana Moeckel and Buhl, {Eva M.} and Klinkhammer, {Barbara Mara} and Peter Boor and Srinivas Banala and Alina Adams and Fabian Kiessling and Gert Storm and Metselaar, {Josbert M.} and Sofias, {Alexandros Marios} and Yang Shi and Twan Lammers and Quim Pe{\~n}a and Tarun Ojha",

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year = "2025",

month = jun,

day = "10",

doi = "10.1016/j.jconrel.2025.113748",

language = "English",

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Shalmani, AA, Daware, R, Elshafei, AS, De Lorenzi, F, Moeckel, D, Buhl, EM, Klinkhammer, BM, Boor, P, Banala, S, Adams, A, Kiessling, F, Storm, G, Metselaar, JM, Sofias, AM, Shi, Y, Lammers, T, Peña, Q & Ojha, T 2025, 'Hydrophobic ion pairing enables co-loading of water-soluble drugs in polymeric micelles', Journal of Controlled Release, vol. 382, 113748. https://doi.org/10.1016/j.jconrel.2025.113748

TY - JOUR

T1 - Hydrophobic ion pairing enables co-loading of water-soluble drugs in polymeric micelles

AU - Shalmani, Armin Azadkhah

AU - Daware, Rasika

AU - Elshafei, Asmaa Said

AU - De Lorenzi, Federica

AU - Moeckel, Diana

AU - Buhl, Eva M.

AU - Klinkhammer, Barbara Mara

AU - Boor, Peter

AU - Banala, Srinivas

AU - Adams, Alina

AU - Kiessling, Fabian

AU - Storm, Gert

AU - Metselaar, Josbert M.

AU - Sofias, Alexandros Marios

AU - Shi, Yang

AU - Lammers, Twan

AU - Peña, Quim

AU - Ojha, Tarun

PY - 2025/6/10

Y1 - 2025/6/10

N2 - Polymeric micelles are widely used for the delivery of hydrophobic drugs. However, several highly potent and ubiquitously used anticancer drugs are water-soluble, complicating their (co-)formulation in polymeric micelles without having to chemically modify them. We here explore hydrophobic ion pairing to enable the co-delivery of the water-soluble anthracycline chemotherapy drug doxorubicin and the angiotensin II receptor antagonist telmisartan (a clinically used antihypertensive drug that has shown promising (pre-) clinical outcomes in combination with anthracyclines). We show that hydrophobic ion pairing of doxorubicin and telmisartan promotes the co-encapsulation of both drugs in π electron-stabilized [PEG-b-p(HPMAm-Bz)]-based polymeric micelles. The cytotoxic activity of doxorubicin is retained, and the dual drug-loaded micelles display enhanced antitumor activity in vivo as compared to the combination of the free drugs, while also exhibiting good tolerability. Taken together, this work provides proof-of-concept for hydrophobic ion pairing as a promising formulation strategy to promote multidrug nanomedicine and drug combination therapy.

AB - Polymeric micelles are widely used for the delivery of hydrophobic drugs. However, several highly potent and ubiquitously used anticancer drugs are water-soluble, complicating their (co-)formulation in polymeric micelles without having to chemically modify them. We here explore hydrophobic ion pairing to enable the co-delivery of the water-soluble anthracycline chemotherapy drug doxorubicin and the angiotensin II receptor antagonist telmisartan (a clinically used antihypertensive drug that has shown promising (pre-) clinical outcomes in combination with anthracyclines). We show that hydrophobic ion pairing of doxorubicin and telmisartan promotes the co-encapsulation of both drugs in π electron-stabilized [PEG-b-p(HPMAm-Bz)]-based polymeric micelles. The cytotoxic activity of doxorubicin is retained, and the dual drug-loaded micelles display enhanced antitumor activity in vivo as compared to the combination of the free drugs, while also exhibiting good tolerability. Taken together, this work provides proof-of-concept for hydrophobic ion pairing as a promising formulation strategy to promote multidrug nanomedicine and drug combination therapy.

KW - Cancer

KW - Combination therapy

KW - Doxorubicin

KW - Hydrophobic ion pairing

KW - Multidrug nanomedicine

KW - Polymeric micelle

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U2 - 10.1016/j.jconrel.2025.113748

DO - 10.1016/j.jconrel.2025.113748

M3 - Article

C2 - 40252978

AN - SCOPUS:105003769584

SN - 0168-3659

VL - 382

JO - Journal of Controlled Release

JF - Journal of Controlled Release

M1 - 113748

ER -

Hydrophobic ion pairing enables co-loading of water-soluble drugs in polymeric micelles

Abstract

Bibliographical note

Keywords

UN SDGs

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