Journal
THERANOSTICS
Volume 7, Issue 15, Pages 3638-3652Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.20028
Keywords
cancer nanomedicine; heterodimeric prodrugs; drug combination; SN38; taxane
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Funding
- National Natural Science Foundation of China [81571799, 81572361, 81372621, 81773193, 21202147]
- Zhejiang Province Preeminence Youth Fund [LR16H160001]
- Science and Technology Research Program of Jinhua City [2017-3-020]
- Project of Public Technology and Application Research of Zhejiang Province [2017C37139]
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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 pi-pi stacking and alleviated polarity, thus enabling an exceptionally high drug loading (DL) capacity (similar to 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.
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