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Cancer Nanomedicines Stabilized by ?-? Stacking between Heterodimeric Prodrugs
Enable Exceptionally High Drug Loading Capacity and Safer Delivery of Drug
Combinations
#MMPMID29109766
Wang H
; Chen J
; Xu C
; Shi L
; Tayier M
; Zhou J
; Zhang J
; Wu J
; Ye Z
; Fang T
; Han W
Theranostics
2017[]; 7
(15
): 3638-3652
PMID29109766
show ga
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 ?-? 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.
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