Rationale: Ferroptosis is a regulated process of cell death caused by iron-dependent accumulation of lipid hydroperoxides (LPO). It is sensitive to epithelial-to-mesenchymal transition (EMT) cells, a well-known therapy-resistant state of cancer. Previous studies on nanomaterials did not investigate the immense value of ferroptosis therapy (FT) in epithelial cell carcinoma during EMT. Herein, we describe an EMT-specific nanodevice for a comprehensive FT strategy involving LPO burst.Methods: Mitochondrial membrane anchored oxidation/reduction response and Fenton-Reaction-Accelerable magnetic nanophotosensitizer complex self-assemblies loading sorafenib (CSO-SS-Cy7-Hex/SPION/Srfn) were constructed in this study for LPO produced to overcome the therapy-resistant state of cancer. Both in vitro and in vivo experiments were performed using breast cancer cells to investigate the anti-tumor efficacy of the complex self-assemblies.Results: The nano-device enriched the tumor sites by magnetic targeting of enhanced permeability and retention effects (EPR), which were disassembled by the redox response under high levels of ROS and GSH in FT cells. Superparamagnetic iron oxide nanoparticles (SPION) released Fe2+ and Fe3+ in the acidic environment of lysosomes, and the NIR photosensitizer Cy7-Hex anchored to the mitochondrial membrane, combined sorafenib (Srfn) leading to LPO burst, which was accumulated ~18-fold of treatment group in breast cancer cells. In vivo pharmacodynamic test results showed that this nanodevice with small particle size and high cytotoxicity increased Srfn circulation and shortened the period of epithelial cancer treatment.Conclusion: Ferroptosis therapy had a successful effect on EMT cells. These findings have great potential in the treatment of therapy-resistant epithelial cell carcinomas.
Photodynamic
therapy (PDT), a clinically approved cancer treatment, has faced many
drawbacks that restricted its applications. For example, the hypoxia-induced
elevated hypoxia-inducible factor-1α (HIF-1α) may desensitize
tumors to PDT, and the high concentration of glutathione (GSH) in
cancer cells can also neutralize the generated reactive oxygen species
(ROS) during PDT, resulting in insufficient therapy. Moreover, extra
probes for imaging-guided visualization therapy are always needed
to track drug release or distribution, while it may decrease the drug
loading of the drug delivery system (DDS). In the present study, we
have designed and prepared a novel multifunctional combined therapy
nanoparticle (ZnPc@Cur-S-OA NPs), in which curcumin (Cur) was not
only used as a chemotherapy drug to achieve a combination therapy
with PDT via downregulating HIF-1α and depleting GSH in B16F10
cells but also designed as a small-molecule ROS-triggered release
prodrug to deliver the photosensitizer (PS). The red fluorescence
of PS in the nanoparticles (NPs) can be used to track the NPs distribution,
while the green fluorescence of Cur showed an “OFF–ON”
activation, which enables additional imaging and real-time self-monitoring
capabilities. These results proved that the prepared combined therapy
NPs were more effective to inhibit the growth of B16F10 mouse melanoma
tumor than was monotherapy without eliciting systemic toxicity either in vitro or in vivo, which indicated the
combined therapy NPs as an effective way to improve the PDT efficacy
via downregulation of HIF-1α and depletion of GSH. Thus, the
strategy of using a multifunctional natural product as the stimuli-responsive
carrier as well as the synergist with PDT for enhancing antitumor
efficacy via multiple pathways may open an alternative avenue to fabricate
new self-delivery combination therapy nanodrugs. Besides, the fluorescence
emitted from the drug can be used for real-time self-monitoring of
drug release and distribution, which has great potential in clinic
to adjust the administration dose and irradiation time for different
tumor types and stages for individual therapy.
Ferroptosis
is an iron-dependent cell death caused by accumulation
of lipid peroxidation (LPO), which is a new strategy for cancer treatment.
Th current ferroptosis therapy nanodevices have low efficiency and
side effects generally. Hence, we developed a Black Hole Quencher
(BHQ)-based fluorescence “off–on” nanophotosensitizer
complex assembly (CSO-BHQ-IR780-Hex/MIONPs/Sor). CSO-connected BHQ-IR780-Hex
and -loaded magnetic iron oxide nanoparticles (MIONPs) and sorafenib
(Sor) formed a very concise functionalized delivery system. CSO-BHQ-IR780-Hex
disassembled by GSH attack and released IR780-Hex, MIONPs, and sorafenib.
IR780-Hex anchored to the mitochondrial membrane, which would contribute
to amplifying the efficiency of the photosensitizer. When NIR irradiation
was given to CSO-BHQ-IR780-Hex/MIONPs/Sor-treated cells, iron supply
increased, the xCT/GSH/GPX-4 system was triggered, and a lot of LPO
burst. A malondialdehyde test showed that LPO in complex assembly-treated
cells was explosive and increased about 18-fold compared to the control.
The accumulation process of particles was monitored by an IR780-Hex
photosensitizer, which showed an excellent tumor target ability by
magnetic of nanodevice in vivo. Interestingly, the half-life of sorafenib
in a nanodevice was increased about 26-fold compared to the control
group. Importantly, the complex assembly effectively inhibits tumor
growth in the breast tumor mouse model. This work would provide ideas
in designing nanomedicines for the ferroptosis treatment of cancer.
Scheme of mPEG-HA/CSO-SS-Hex/SPION/GA self-assembly preparation and the magnetism-enhanced EPR in vivo and in vitro trafficking pathways of the polymeric self-assembly.
Intelligent systems that offer traceable cancer therapy are highly desirable for precision medicine. Although photodynamic therapy (PDT) has been approved in the clinic for decades, determining where the tumor is, when to irradiate, and how long to expose to light still confuse the clinicians. Patients are always suffering from the phototoxicity of the photosensitizer in nonmalignant tissues. Herein, an activatable theranostic agent, ZnPc@TPCB nanoparticles (NPs), is prepared by doping a photosensitizer, ZnPc, with an aggregation-induced emission probe, TPCB. The assembled or disassembled ZnPc@TPCB NPs in various phases have behaved differently in fluorescence intensity, photoacoustic (PA) signals, and PDT efficiency. The intact nanoparticles are non-emissive in aqueous media while showing strong PA signals and low PDT efficiency, which can eliminate the phototoxicity and self-monitor their distribution and image the tumors' location. Disassembling of the NPs leads to the release of ZnPc and its red fluorescence turn-on to self-report the photosensitizer's activation. Upon light irradiation, the reactive oxygen species (ROS) generated by ZnPc can induce cell apoptosis and activate the ROS sensor, TPCB, which will yield intense orange-red fluorescence and instantly predict the therapeutic effect. Moreover, enhanced PDT efficacy is achieved via the GSH-depleting adjuvant quinone methide produced by the activated TPCB. The well-designed ZnPc@TPCB NPs have shown promising potential for finely controlled PDT with good biosafety and broad application prospects in individual therapy, which may inspire the development of precision medicine.
BackgroundRunt-related transcription factor 3 (RUNX3) is a member of the runt-domain family of transcription factors. Emerging evidence indicates that RUNX3 is a tumor suppressor gene in several types of human cancers including esophageal cancer. However, the association between RUNX3 promoter methylation and esophageal cancer remains unclear. Here we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of RUNX3 promoter methylation on the incidence of esophageal cancer.MethodsA detailed literature search was made on Medline, Pubmed and Web of Science for related research publications written in English and/or Chinese. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analysis of pooled data were performed, the odds ratios (OR) were calculated and summarized respectively.ResultsFinal analysis of 558 patients from 9 eligible studies was performed. The result showed that RUNX3 methylation was significantly higher in esophageal cancer than in normal squamous mucosa from the proximal resection margin or esophageal benign lesions (OR = 2.85, CI = 2.01–4.05, P<0.00001). The prevalence of lymph node involvement, tumor size (T1–T2 vs T3–T4) and histological grade was significantly greater in RUNX3-negative cases (RUNX3 unmethylated groups) than in RUNX3-positive cases (OR = 0.25, CI = 0.14–0.43, P<0.00001). RUNX3 methylation was significantly higher in esophageal adenocarcinoma (EAC) than Barrett’s esophagus (OR = 0.35, CI = 0.20–0.59, P<0.0001). In addition, the pooled HR for overall survival (OS) showed that decreased RUNX3 expression was associated with worse survival in esophageal cancer (HR = 4.31, 95% CI = 2.57–7.37, P<0.00001).ConclusionsThe results of this meta-analysis suggest that RUNX3 methylation is associated with an increased risk, progression as well as worse survival in esophageal cancer. RUNX3 methylation, which induces the inactivation of RUNX3 gene, plays an important role in esophageal carcinogenesis.
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