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

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 Wang1✉, Jianmei Chen1, Chang Xu2, Linlin Shi3, Munire Tayier2, Jiahui Zhou2, Jun Zhang1, Jiaping Wu1, Zhijian Ye4, Tao Fang4, Weidong Han3✉

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.

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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How to cite this article:
Wang H, Chen J, Xu C, Shi L, Tayier M, Zhou J, Zhang J, Wu J, Ye Z, Fang T, Han W. Cancer Nanomedicines Stabilized by π-π Stacking between Heterodimeric Prodrugs Enable Exceptionally High Drug Loading Capacity and Safer Delivery of Drug Combinations. Theranostics 2017; 7(15):3638-3652. doi:10.7150/thno.20028. Available from http://www.thno.org/v07p3638.htm