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

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.