Hypoxia, the typical and conspicuous
characteristic of most solid
tumors, worsens the tumor invasiveness and metastasis. Here, we engineered
a sequential ultrasound (US)/hypoxia-sensitive sonochemotherapeutic
nanoprodrug by initially synthesizing the hypoxia-activated azo bond-containing
camptothecin (CPT) prodrug (CPT2-Azo) and then immobilizing
it into the mesopores of sonosensitizer-integrated metal organic frameworks
(MOF NPs). Upon entering the hypoxic tumor microenvironment (TME),
the structure of CPT2-Azo immobilized MOFs (denoted as
MCA) was ruptured and the loaded nontoxic CPT2-Azo prodrug
was released from the MOF NPs. Under US actuation, this sonochemotherapeutic
nanoprodrug not only promoted sonosensitizer-mediated sonodynamic
therapy (SDT) via the conversion of oxygen into cytotoxic reactive
oxygen species (ROS) but also aggravated hypoxia in the TME by elevating
oxygen consumption. The exacerbated hypoxia in turn served as a positive
amplifier to boost the activation of CPT2-Azo, and the
controllable release of toxic chemotherapeutic drug (CPT), and compensated
the insufficient treatment efficacy of SDT. In vitro and in vivo evaluations confirmed that sequential
SDT and tumor hypoxia-activated sonochemotherapy promoted the utmost
of tumor hypoxia and thereby contributed to the augmented antitumor
efficacy, resulting in conspicuous apoptotic cell death and noteworthy
tumor suppression in vivo. Our work provides a distinctive
insight into the exploitation of the hypoxia-activated sonochemotherapeutic
nanoprodrug that utilizes the hypoxic condition in TME, a side effect
of SDT, to initiate chemotherapy, thus causing a significantly augmented
treatment outcome compared to conventional SDT.
Malignant gliomas (MGs) are among the most aggressive types of cancers in the human brain. Frequent tumor recurrence caused by a lack of effective therapeutic approaches results in a poor prognosis. Signal transducer and activator of transcription 3 (STAT3), an oncogenic protein, is constitutively activated in MGs and predicts a poor clinical outcome. STAT3 therefore is considered to be a promising target for the treatment of MGs. Cryptotanshinone (CTS), the main bioactive compound from the root of Salvia miltiorrhiza Bunge, has been reported to have various pharmacological effects. However, little is known about its function in MG cells. In this study, we evaluated the effect of CTS on the proliferation of human glioma cell lines (T98G and U87). Our results revealed that CTS significantly suppresses glioma cell proliferation. The phosphorylation of STAT3 Tyr705, but not Ser727, was inhibited by CTS, and STAT3 nuclear translocation was attenuated. Overexpression of constitutively active mutant STAT3C reversed the inhibitory effect of CTS, while knockdown STAT3 showed a similar inhibitory effect as CTS treatment. Following the downregulation of STAT3-regulated proteins cyclinD1 and survivin, cell cycle progression significantly arrested in G1/G0 phase. These results indicate that CTS may be a potential antiproliferation agent for the treatment of MGs and that its mechanism may be related to the inhibition of STAT3 signaling.
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