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Theranostics 2017; 7(15):3638-3652. doi:10.7150/thno.20028 This issue Cite

Research Paper

Cancer Nanomedicines Stabilized by π-π Stacking between Heterodimeric Prodrugs Enable Exceptionally High Drug Loading Capacity and Safer Delivery of Drug Combinations

Hangxiang Wang^1✉, Jianmei Chen¹, Chang Xu², Linlin Shi³, Munire Tayier², Jiahui Zhou², Jun Zhang¹, Jiaping Wu¹, Zhijian Ye⁴, Tao Fang⁴, Weidong Han^3✉

1. The First Affiliated Hospital; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China;
2. School of Medicine, Zhejiang University, Hangzhou, 310027, PR China;
3. Department of Medical Oncology; Sir Run Run Shaw Hospital; School of Medicine, Zhejiang University, Hangzhou, 310003, PR China.
4. Jinhua People's Hospital, Jinhua, Zhejiang Province, 321000, PR China.

✉ Corresponding authors: Weidong Han, E-mail: hanwdedu.cn; Hangxiang Wang, E-mail: wanghxedu.cn

Abstract

Combination therapy using distinct mode-of-action drugs has sparked a rapidly growing interest because this paradigm holds promise for improving the therapeutic efficacy of anticancer therapy. However, the current drug combination therapy refers to administering individual drugs together, which is far from a perfect regimen for cancer patients. The aim of this work was to demonstrate that synergistic delivery of two chemotherapeutic drugs in a single nanoparticle reservoir could be achieved through the rational chemical ligation of the drugs followed by supramolecular nano-assembly via blending of the drugs with a minimal amount of matrix. Choosing 7-ethyl-10-hydroxycamptothecin and taxanes, which are rich in aromatic structures, as model compounds, we show that the heterodimeric conjugates of the two agents are miscible with lipids to form systemically injectable nanomedicines. The compatibility between the prodrug conjugates and lipid carriers is substantially augmented by the intermolecular π-π stacking and alleviated polarity, thus enabling an exceptionally high drug loading (DL) capacity (~92%) and a gratifyingly long drug retention time within the micellar core. We further observed superior therapeutic outcomes in a mouse tumor model without detecting accompanying systemic toxicity. This structure-based, self-assembled cancer nanomedicine increased the potency and drug tolerability in animals and thus offers a robust strategy for simultaneously formulating two or more drugs in single nanovehicles.

Keywords: cancer nanomedicine, heterodimeric prodrugs, drug combination, SN38, taxane.

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