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.
The
purpose of developing novel anticancer drug delivery systems
(DDSs) is to efficiently carry and release drugs into cancer cells
and minimize side effects. In this work, based on hollow mesoporous
silica nanoparticle (HMSN) and the charge-reversal property, a pH/GSH-dual-sensitive
DDS named DOX@HMSN–SS-PLL(cit) was reported. HMSN encapsulated
DOX with high efficacy and was then covered by the “gatekeeper”
β-cyclodextrin (β-CD) through the glutathione (GSH)-sensitive
disulfide bond. Thereafter, adamantine-blocked citraconic-anhydride-functionalized
poly-l-lysine (PLL(cit)-Ad) was decorated on the surface
of the particles via host–guest interaction. The negatively
charged carriers were stable in the neutral environment in vivo and
could be effectively transported to the tumor site. The surface charge
of the nanoparticles could be reversed in the weakly acidic environment,
which increased the cellular uptake ability of the carriers by the
cancer cells. After cellular internalization, β-CD can be removed
by breakage of the disulfide bond in the presence of a high concentration
of GSH, leading to DOX release. The preparation process of the carriers
was monitored. The charge-reversal capability and the controlled drug-release
behavior of the carriers were also investigated. In vitro and in vivo
experiments demonstrated the excellent cancer therapy effect with
low side effects of the carriers. It is expected that dual-sensitive
DOX@HMSN–SS-PLL(cit) could play an important role in cancer
therapy.
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