Theranostics 2022; 12(8):3747-3757. doi:10.7150/thno.72559 This issue

Research Paper

Calixarene-modified albumin for stoichiometric delivery of multiple drugs in combination-chemotherapy

Ying Wang1,2#, Zhanzhan Zhang1,2#, Xinzhi Zhao1,2, Lina Xu1,2, Yadan Zheng1,2,4, Hua-Bin Li1,3, Dong-Sheng Guo1,3, Linqi Shi1,2, Yang Liu1,2✉

1. Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin 300071, China.
2. State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
3. State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China.
4. College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Wang Y, Zhang Z, Zhao X, Xu L, Zheng Y, Li HB, Guo DS, Shi L, Liu Y. Calixarene-modified albumin for stoichiometric delivery of multiple drugs in combination-chemotherapy. Theranostics 2022; 12(8):3747-3757. doi:10.7150/thno.72559. Available from

File import instruction


Graphic abstract

Rationale: In combination chemotherapy, the molar ratio of drugs is a critical parameter that determines the synergistic effects. However, most co-delivery vectors are incapable of maintaining the optimal molar ratio of drugs throughout the delivery process. Herein, a calixarene-modified albumin (CaMA), which can co-deliver multiple drugs with precise control of the drug ratio, is presented.

Methods: CaMA was prepared by chemically conjugating multiple sulfonate azocalix[4]arenes (SAC4A) onto the surface of bovine serum albumin (BSA). The precise drug loading and synchronous drug release were measured using fluorescence spectroscopy. Mouse tumor cell 4T1 and 4T1-bearing mice were used to evaluate the combined effects of mitomycin C (MMC) and doxorubicin (DOX) in vitro and in vivo.

Results: With multiple hypoxia-responsive calixarenes conjugated onto a single albumin molecule, CaMA achieved precise drug loading and synchronous release of multiple drugs into the tumor microenvironment. This unique drug loading and release mechanism ensures that CaMA maintains the drug ratio from the initial drug loading to the release site, providing a solid foundation for multi-drug combination therapy with the goal of achieving predictable therapeutic outcomes in vivo. The delivery of the model drug combination MMC and DOX at a prescreened ratio via CaMA achieved significantly enhanced tumor suppression and reduced systemic toxicity.

Conclusions: This stoichiometric delivery feature makes CaMA a powerful tool for the development of combination chemotherapy and personalized medications for cancer treatment.

Keywords: combination chemotherapy, co-delivery, hypoxia-responsive, host-guest interaction, stoichiometric