Chemodrug
resistance is a major reason accounting for tumor recurrence.
Given the mechanistic complexity of chemodrug resistance, molecular
inhibitors and targeting drugs often fail to eliminate drug-resistant
cancer cells, and sometimes even promote chemoresistance by activating
alternative pathways. Here, by exploiting biochemical fragility of
high-level but dynamically balanced cellular redox homeostasis in
drug-resistant cancer cells, we design a nanosized copper/catechol-based
metal–organic framework (CuHPT) that effectively disturbs this
homeostasis tilting the balance toward oxidative stress. Within drug-resistant
cells, CuHPT starts disassembly that is triggered by persistent consumption
of cellular glutathione (GSH). CuHPT disassembly simultaneously releases
two structural elements: catechol ligands and reductive copper ions
(Cu+). Both of them cooperatively function to amplify the
production of intracellular radical oxidative species (ROS) via auto-oxidation
and Fenton-like reactions through exhausting GSH. By drastically heightening
cellular oxidative stress, CuHPT exhibits selective and potent cytotoxicity
to multiple drug-resistant cancer cells. Importantly, CuHPT effectively
inhibits in vivo drug-resistant tumor growth and doubles the survival
time of tumor-bearing mice. Thus, along with CuHPT’s good biocompatibility,
our biochemical, cell biological, preclinical animal model data provide
compelling evidence supporting the notion that this copper-based MOF
is a predesigned smart therapeutic against drug-resistant cancers
through precisely deconstructing their redox homeostasis.
Cancer
chemotherapy is challenged by multidrug resistance (MDR)
mainly attributed to overexpressed transmembrane efflux pump P-glycoprotein
(P-gp) in cancer cells. Improving drug delivery efficacy while co-delivering
P-gp inhibitors to suppress drug efflux is an often-used nanostrategy
for combating MDR, which is however challenged by cascaded bio-barriers
en route to cancer cells and P-gp inhibitors’ adverse effects.
To effectively breach the cascaded bio-barriers while avoiding P-gp
inhibitors’ adverse effects, a stealthy, sequentially responsive
doxorubicin (DOX) delivery nanosystem (RCMSNs) is fabricated, composed
of an extracellular-tumor-acidity-responsive polymer shell (PEG-b-PLLDA), pH/redox dual-responsive mesoporous silica nanoparticle-based
carriers (MSNs-SS-Py), and cationic β-cyclodextrin-PEI (CD-PEI)
gatekeepers. The PEG-b-PLLDA corona makes RCMSNs
stealthy with prolonged blood circulation time. Once tumors are reached,
extracellular acidity degrades PEG-b-PLLDA, reversing
nanosystem’s surface charges to be positive, which drastically
improves RCMSNs’ tumor accumulation, penetration, and cellular
internalization. Within cancer cells, CD-PEI gatekeepers detach to
allow DOX unloading in response to intracellular acidity and glutathione
and functionally act as a P-gp inhibitor, dampening P-gp’s
efflux activity by impairing ATP production. Thus, the resultant high-efficacy
drug delivery along with reduced P-gp function cooperatively reverses
MDR in vitro. Importantly, in preclinical tumor models,
DOX@RCMSNs potently suppress MDR tumor growth without eliciting systemic
toxicity, demonstrating their potential of clinical translation.
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