Novel Platinum Nanoclusters Activate PI3K/AKT/mTOR Signaling Pathway-Mediated Autophagy for Cisplatin-Resistant Ovarian Cancer Therapy.

Platinum (Pt)-based chemotherapy drugs such as cisplatin are the first line and core options for the treatment of ovarian cancer (OC), while cisplatin resistance has a worse prognosis and low 5 year survival rate for patients. Chemotherapeutic drugs synthesized from nanomaterials have shown great potential in biomedicine; however, research into their application for OC resistance is rarely discussed. This study is proposed to elucidate the anti-tumor effects of polyethylenimine (PEI)-caged platinum nanoclusters (Pt NCs) on cisplatin-resistant OC. The results of confocal microscopy showed that Pt NCs entered cisplatin-resistant OC cells dose-dependently and aggregated both in the cytoplasm and inside the nucleus. Subsequently, according to the results of CCK8 assay, wound healing assay, clone formation assay, Transwell assay, Ki-67 immunofluorescence assay, and flow cytometry assay, the proliferation and migration of cisplatin-resistant OC cells were inhibited by Pt NCs, as well as their apoptosis was promoted. In addition, we validated the anti-tumor effect of Pt NCs on regulating autophagy via monodansylcadaverine (MDC) staining, transmission electron microscopy observation of the autophagic ultrastructure, LC3-II-GFP and P62-GFP adenovirus single-label immunofluorescence, and western blotting; meanwhile, the role of Pt NCs in adjusting autophagy through modulation of the PI3K-AKT-mTOR signaling was verified. Based on these results, it appears that cisplatin-resistant OC cells can undergo apoptosis when Pt NCs activate autophagy by inhibiting the PI3K/AKT/mTOR pathway, exhibiting a promising potential of Pt NCs in the development of a novel chemotherapeutic agent for patients suffering from cisplatin-resistant OC.

Noble metal nanomaterials for the diagnosis and treatment of hematological malignancies.

BACKGROUND: Recently, the incidence of hematological malignancy, such as various leukemias, multiple myeloma and lymphoma, has revealed an increasing tendency, exhibiting a major impact on human health. Most of the available anti-cancer drugs, however, possess high non-targeted accumulation, dosage-associated toxicity, fast elimination, and lack specificity towards tumors, which restrict their utilization in clinical therapy. This extends also to cancer diagnosis where there is a lack of predictive biomarkers. OBJECT: Noble metal nanomaterials (NM NMs) have the potential to overcome these shortcomings due to several characteristics including ease of synthesis, ultra-small size, easy surface modification and specific physicochemical properties. At present, gold-, silver- and platinum-based nanomaterials have been employed in the tracing and treatment of hematopoietic tumors through direct individual endocytosis or in innovative drug delivery systems (DDS) by conjugation with other targeting biomolecules. PURPOSE: In this mini review, we focus on the use of localized surface plasmon resonance (LSPR)-/surface-enhanced Raman scattering (SERS)- and fluorescence-based diagnosis of NM NMs in the hematological malignancies. Furthermore, the treatment of hematological malignancies utilized the NM NMs or NM NMs-based therapy technology in the chemotherapy, targeted therapy, and photothermal therapy are depicted in depth. The construction of effective and promising NM NMs or NM NMs- dependent theranostic methodology has the potential to provide interdisciplinary knowledge in the development of clinical tracing, diagnosis and treatment of refractory hematological diseases.

The endocytic pathway of Pt nanoclusters and their induced apoptosis of A549 and A549/Cis cells through c-Myc/p53 and Bcl-2/caspase-3 signaling pathways.

In recent years, multifunctional platinum nanoclusters (Pt-NCs) as new Pt-based anti-cancer drugs exhibit a promising therapeutic efficiency for several cancer diseases, especially for human pulmonary carcinoma. However, the endocytosis behaviors (like uptake pathway, etc.) and induced apoptosis mechanism of Pt-NCs for drug-resistant non-small cell lung cancer (NSCLC), are still inconclusive. In this research, we explored the endocytic pathway of Pt-NCs in both typical NSCLC A549 cells and cisplatin-resistant A549/Cis cells through qualitative confocal laser scanning microscope (CLSM) measurement and quantitative flow cytometry (FCM) and inductive coupled plasma-optical emission spectroscopy (ICP-OES) analysis, by the means of introducing the specific inhibitors which impede the classical ways of endocytosis. It was found that Pt-NCs dominatingly entered A549 cells via caveolin-mediated endocytosis as well as A549/Cis cells through micropinocytosis approach. Pt-NCs possessed an excellent inhibitory effect on the cell proliferation, migration and invasion, which the cell activity of A549 cells reduced to 14% and that of A549/Cis cells went down about four fifths. Moreover, Pt-NCs treatment increased caspase-3 protein levels and downregulated the expression of c-Myc and Bcl-2, proving the Pt-NCs-induced apoptosis of NSCLC cells was related to c-Myc/p53 and Bcl-2/caspase-3 signal pathways. These results demonstrate the explicit uptake pathway and apoptotic signaling pathway of Pt-NCs for NSCLC, which provides an in-depth and reasonable theoretical basis for the development of new Pt-NCs-based chemotherapeutics in future clinical practice.

Distinguishable Targeting of Non-Small Cell Lung Cancer Using Hyaluronan Functionalized Platinum Nanoclusters and Their Inhibition Behaviors of Proliferation, Invasion, Migration.

Lung cancer is the leading cause of cancer deaths worldwide and most cancer patients receiving conventional chemotherapy suffer from severe side effects due to the non-selective effects of chemotherapeutic drugs on normal cells. Targeted nanomaterials can obtain excellent accumulation at the tumor site through their active or passive targeting mechanisms, thereby reducing the toxicity of the drugs in various ways. In this study, hyaluronic acid (HA) which could specifically bind to CD44 on the surface of tumor cells, was used to modify amine-caged platinum nanoclusters (Pt NCs-NH2 ) to obtain targeting HA-Pt NCs-NH2 . Based on the differential expression of CD44 on the surface of three lung cells (non-small cell lung cancer cell H1299, small cell lung cancer cell H446, and embryonic lung fibroblast HFL1), HA-Pt NCs-NH2 can differentially enter the three cells and achieve their targeting of non-small cell lung cancer cell (NSCLC) cells. Pt NCs significantly inhibited the proliferation, migration and invasion of NSCLC cells and induced their apoptosis in comparison of classical cisplatin and carboplatin, showing a bright future in early diagnosis and treatment of NSCLC.

Versatile Pt NCs-based chemotherapeutic agents significantly induce the apoptosis of cisplatin-resistant non-small cell lung cancer.

Recently, the incidence of lung cancer is generally rising along with air pollution and smoking, and non-small cell lung cancer (NSCLC) accounts for nearly 85% among all lung cancer diagnoses. With the development of chemotherapy, the drug resistance rate of common platinum-based chemotherapeutic drugs (like cisplatin) is gradually increased, which seriously affects the chemotherapy efficiency and survival rate of patients. In this study, polyethylenimine caged platinum nanoclusters (PEI-caged Pt NCs) were proposed as a new chemotherapeutic agent to apply in the treatment of NSCLC, choosing the classical cisplatin-resistant A549/DDP cells and normal A549 cells as targets. It was found that our Pt NCs-based chemotherapeutic drugs showed its preferable therapeutic effect in cisplatin-resistant NSCLC through the results of confocal microscopic images, cell counting kit-8 test, cell apoptosis assay and western blot. Most importantly, in the cisplatin-resistance A549/DDP cells, this kind of agents could enter the nucleus obviously, and emerged a superior inhibitory and apoptotic effects than A549 via activating p53 protein and the related signaling pathways. Comparing with the traditional chemotherapy drugs, these Pt NCs-based chemotherapeutic agents exhibit great potential and advantages in the treatment and diagnosis of NSCLC regardless of the therapeutic effect or toxic side effects, especially the drug resistance.