Integrin-linked kinase-frizzled 7 interaction maintains cancer stem cells to drive platinum resistance in ovarian cancer.

BACKGROUND: Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. METHODS: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. RESULTS: In response to increased fibronectin secretion and integrin ß1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and correlated with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/ß-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. CONCLUSIONS: This "outside-in" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may lead to new therapeutic approaches to eradicate OCSCs and improve patient outcomes.

Chemodynamic PtMn Nanocubes for Effective Photothermal ROS Storm a Key Anti-Tumor Therapy in-vivo.

Background: Chemodynamic therapy (CDT) is a new treatment approach that is triggered by endogenous stimuli in specific intracellular conditions for generating hydroxyl radicals. However, the efficiency of CDT is severely limited by Fenton reaction agents and harsh reaction conditions. Methods: Bimetallic PtMn nanocubes were rationally designed and simply synthesized through a one-step high-temperature pyrolysis process by controlling both the nucleation process and the subsequent crystal growth stage. The polyethylene glycol was modified to enhance biocompatibility. Results: Benefiting from the alloying of Pt nanocubes with Mn doping, the structure of the electron cloud has changed, resulting in different degrees of the shift in electron binding energy, resulting in the increasing of Fenton reaction activity. The PtMn nanocubes could catalyze endogenous hydrogen peroxide to toxic hydroxyl radicals in mild acid. Meanwhile, the intrinsic glutathione (GSH) depletion activity of PtMn nanocubes consumed GSH with the assistance of Mn3+/Mn2+. Upon 808 nm laser irradiation, mild temperature due to the surface plasmon resonance effect of Pt metal can also enhance the Fenton reaction. Conclusion: PtMn nanocubes can not only destroy the antioxidant system via efficient reactive oxygen species generation and continuous GSH consumption but also propose the photothermal effect of noble metal for enhanced Fenton reaction activity.

piR-1919609 Is an Ideal Potential Target for Reversing Platinum Resistance in Ovarian Cancer.

PURPOSE: PIWI-interacting RNAs (piRNAs) are a type of noncoding small RNA that can interact with PIWI-like RNA-mediated gene silencing (PIWIL) proteins to affect biological processes such as transposon silencing through epigenetic effects. Recent studies have found that piRNAs are widely dysregulated in tumors and associated with tumor progression and a poor prognosis. Therefore, this study aimed to investigate the effect of piR-1919609 on the proliferation, apoptosis, and drug resistance of ovarian cancer cells. METHODS: In this study, we used small RNA sequencing to screen and identify differentially expressed piRNAs in primary ovarian cancer, recurrent ovarian cancer, and normal ovaries. A large-scale verification study was performed to verify the expression of piR-1919609 in different types of ovarian tissue, including ovarian cancer tissue and normal ovaries, by RT-PCR and to analyze its association with the clinical prognosis of ovarian cancer. The expression of PIWILs in ovarian cancer was verified by RT-PCR, Western blotting and immunofluorescence. The effects of piR-1919609 on ovarian cancer cell proliferation, apoptosis and drug resistance were studied through in vitro and in vivo models. RESULTS: (1) piR-1919609 was highly expressed in platinum-resistant ovarian cancer tissues (p < 0.05), and this upregulation was significantly associated with a poor prognosis and a shorter recurrence time in ovarian cancer patients (p < 0.05). (2) PIWIL2 was strongly expressed in ovarian cancer tissues (p < 0.05). It was expressed both in the cytoplasm and nucleus of ovarian cancer cells. (3) Overexpression of piR-1919609 promoted ovarian cancer cell proliferation, inhibited apoptosis, and promoted tumor growth in nude mice. (4) Inhibition of piR-1919609 effectively reversed ovarian cancer drug resistance. CONCLUSION: In summary, we showed that piR-1919609 is involved in the regulation of drug resistance in ovarian cancer cells and might be an ideal potential target for reversing platinum resistance in ovarian cancer.

Mild hyperthermia enhanced synergistic uric acid degradation and multiple ROS elimination for an effective acute gout therapy.

BACKGROUND: Acute gouty is caused by the excessive accumulation of Monosodium Urate (MSU) crystals within various parts of the body, which leads to a deterioration of the local microenvironment. This degradation is marked by elevated levels of uric acid (UA), increased reactive oxygen species (ROS) production, hypoxic conditions, an upsurge in pro-inflammatory mediators, and mitochondrial dysfunction. RESULTS: In this study, we developed a multifunctional nanoparticle of polydopamine-platinum (PDA@Pt) to combat acute gout by leveraging mild hyperthermia to synergistically enhance UA degradation and anti-inflammatory effect. Herein, PDA acts as a foundational template that facilitates the growth of a Pt shell on the surface of its nanospheres, leading to the formation of the PDA@Pt nanomedicine. Within this therapeutic agent, the Pt nanoparticle catalyzes the decomposition of UA and actively breaks down endogenous hydrogen peroxide (H2O2) to produce O2, which helps to alleviate hypoxic conditions. Concurrently, the PDA component possesses exceptional capacity for ROS scavenging. Most significantly, Both PDA and Pt shell exhibit absorption in the Near-Infrared-II (NIR-II) region, which not only endow PDA@Pt with superior photothermal conversion efficiency for effective photothermal therapy (PTT) but also substantially enhances the nanomedicine's capacity for UA degradation, O2 production and ROS scavenging enzymatic activities. This photothermally-enhanced approach effectively facilitates the repair of mitochondrial damage and downregulates the NF-κB signaling pathway to inhibit the expression of pro-inflammatory cytokines. CONCLUSIONS: The multifunctional nanomedicine PDA@Pt exhibits exceptional efficacy in UA reduction and anti-inflammatory effects, presenting a promising potential therapeutic strategy for the management of acute gout.

Iron promotes ovarian cancer malignancy and advances platinum resistance by enhancing DNA repair via FTH1/FTL/POLQ/RAD51 axis.

Iron is crucial for cell DNA synthesis and repair, but an excess of free iron can lead to oxidative stress and subsequent cell death. Although several studies suggest that cancer cells display characteristics of 'Iron addiction', an ongoing debate surrounds the question of whether iron can influence the malignant properties of ovarian cancer. In the current study, we initially found iron levels increase during spheroid formation. Furthermore, iron supplementation can promote cancer cell survival, cancer spheroid growth, and migration; vice versa, iron chelators inhibit this process. Notably, iron reduces the sensitivity of ovarian cancer cells to platinum as well. Mechanistically, iron downregulates DNA homologous recombination (HR) inhibitor polymerase theta (POLQ) and relieves its antagonism against the HR repair enzyme RAD51, thereby promoting DNA damage repair to resist chemotherapy-induced damage. Additionally, iron tightly regulated by ferritin (FTH1/FTL) which is indispensable for iron-triggered DNA repair. Finally, we discovered that iron chelators combined with platinum exhibit a synergistic inhibitory effect on ovarian cancer in vitro and in vivo. Our findings affirm the pro-cancer role of iron in ovarian cancer and reveal that iron advances platinum resistance by promoting DNA damage repair through FTH1/FTL/POLQ/RAD51 pathway. Our findings highlight the significance of iron depletion therapy, revealing a promising avenue for advancing ovarian cancer treatment.

A G-quadruplex-binding platinum complex induces cancer mitochondrial dysfunction through dual-targeting mitochondrial and nuclear G4 enriched genome.

BACKGROUND: G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored. METHODS: The mechanisms of action and therapeutic effects of a G4-binding platinum(II) complex, Pt-ttpy, on mitochondria were conducted through a comprehensive approaches with in vitro and in vivo models, including ICP-MS for platinum measurement, PCR-based genetic analysis, western blotting (WB), confocal microscope for mt morphology study, extracellular flux analyzer, JC1 and Annexin V apoptosis assay, flow cytometry and high content microscope screening with single-cell quantification of both ROS and mt specific ROS, as well as click-chemistry for IF study of mt translation. Decipher Pt-ttpy effects on nuclear-encoded mt related genes expression were undertaken via RNA-seq, Chip-seq and CUT-RUN assays. RESULTS: Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without reactive oxygen species (ROS) induction. Mechanistic study provided first evidence that most of mt ribosome genes are highly enriched in G4 structures in their promoter regions, notably, Pt-ttpy impairs most nuclear-encoded mt ribosome genes' transcription through dampening the recruiting of transcription initiation and elongation factors of NELFB and TAF1 to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy's efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin. CONCLUSION: This study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted cancer therapy.

Pt-Ru bimetallic nanoclusters with peroxidase-like activity for antibacterial therapy.

Drug-resistant bacteria arising from antibiotic abuse infections have always been a serious threat to human health. Killing bacteria with toxic reactive oxygen species (ROS) is an ideal antibacterial method for treating drug-resistant bacterial infections. Here, we prepared Pt-Ru bimetallic nanoclusters (Pt-Ru NCs) with higher peroxidase (POD)-like activity than Pt monometallic nanoclusters. Pt-Ru can easily catalyze the decomposition of H2O2 to produce ·OH, thereby catalyzing the transformation of 3,3',5,5'-tetramethylbiphenylamine (TMB) to blue oxidized TMB (oxTMB). We utilized the POD-like activity of the Pt-Ru NCs for antibacterial therapy. The results showed that at doses of 40 µg/mL and 16 µg/mL, the Pt-Ru NCs exhibited extraordinary antibacterial activity against E. coli and S. aureus, demonstrating the enormous potential of Pt-Ru NCs as antibacterial agents.

Structure-bioactivity relationship study on anticancer Pd and Pt complexes with aliphatic glycine derivative ligands.

To investigate the structure and bioactivity relationship, six Pd(II)/Pt(II) complexes with N-isobutylglycine (L1) and cyclohexylglycine (L2) as N^O amino acid bidentate ligands, 1,10'-phenanthroline (phen) and 2,2'-bipyridine (bipy) as N^N donor ligands, and [Pd(L1)(bipy)]NO3 (1), [Pd(L2)(bipy)]NO3 (2), [Pd(L1)(phen)]NO3 (3), [Pd(L2)(phen)]NO3·2H2O (4), [Pt(L1)(phen)]NO3 (5), along with [Pt(L2)(phen)]NO3 (6) were prepared and then characterized. The geometry of each compound was validated by doing a DFT calculation. Furthermore, tests were conducted on the complexes' water solubilities and lipophilicity. All bipy complexes had superior aqueous solubility and less lipophilicity in comparison with phen complexes, as well as complexes containing cyclohexyl-glycine compared to isobutyl-glycine complexes, probably because of the steric effects and polarity of cyclohexylglycine. The in-vitro anticancer activities of these compounds were examined against HCT116, A549, and MCF7 cancerous cell lines. Data revealed that all Pd/Pt complexes demonstrate higher anticancer activity than carboplatin, and complexes 3 and 4 are more cytotoxic than cisplatin against the HCT116 cell line, particularly against MCF7 cancerous cells. In addition, among all compounds, complex 4 has more anticancer ability than oxaliplatin. Due to different solubility and lipophilicity behavior, the accumulation of Pt complexes and clinical Pt drugs in each cancerous cell was investigated. The binding capabilities of these complexes to DNA, as the main target in chemotherapy, occur through minor grooves and intercalate into DNA, which was done using absorption, fluorescence, and circular dichroism spectroscopy. Finally, the docking simulation study showed the mode of DNA bindings is in good agreement with the spectral binding data.

Endowing Pt(IV) with Perfluorocarbon Chains and Human Serum Albumin Encapsulation for Highly Effective Antitumor Chemoimmunotherapy.

Tumor metastases and reoccurrence are considered the leading causes of cancer-associated deaths. As an emerging therapeutic method, increasing research efforts have been devoted to immunogenic cell death (ICD)-inducing compounds to solve the challenge. The clinically approved chemotherapeutic Pt complexes are not or are only poorly able to trigger ICD. Herein, the axial functionalization of the Pt(II) complex cisplatin with perfluorocarbon chains into ICD-inducing Pt(IV) prodrugs is reported. Strikingly, while the Pt(II) complex as well as the perfluorocarbon ligands did not induce ICD, the Pt(IV) prodrug demonstrated unexpectantly the induction of ICD through accumulation in the endoplasmic reticulum and generation of reactive oxygen species in this organelle. To enhance the pharmacological properties, the compound was encapsulated with human serum albumin into nanoparticles. While selectively accumulating in the tumorous tissue, the nanoparticles demonstrated a strong tumor growth inhibitory effect against osteosarcoma inside a mouse model. In vivo tumor vaccine analysis also demonstrated the ability of Pt(IV) to be an ideal ICD inducer. Overall, this study reports on axially perfluorocarbon chain-modified Pt(IV) complexes for ICD induction and chemoimmunotherapy in osteosarcoma.

Evaluation of anticancer activity of novel platinum(II) bis(thiosemicarbazone) complex against breast cancer.

The study aims to synthesize a novel bis(thiosemicarbazone) derivative based on platinum (thioPt) and evaluate its anticancer properties against MFC-7 and MDA-MB-231 breast cancer cells. A new platinum complex was synthesised by reacting K2PtCl4 with 2,2'-(1,2-diphenylethane-1,2-diylidene)bis(hydrazine-1-carbothioamide) in ethanol in the presence of K2CO3. In the obtained complex, the platinum atom is coordinated by a conjugated system = N-NC-S-The structures of the new compound were characterised using NMR spectroscopy, HR MS, IR, and X-ray structural analysis. The obtained results of the cytotoxicity assay indicate that compound thioPt had potent anticancer activity (MCF-7: 61.03 ± 3.57 µM, MDA-MB-231: 60.05 ± 5.40 µM) with less toxicity against normal MCF-10A breast epithelial cells, even compared to the reference compound (cisplatin). In addition, subsequent experiments found that thioPt induces apoptosis through both an extrinsic (↑caspase 8 activity) and intrinsic (↓ΔΨm) pathway, which ultimately leads to an increase in active caspase 3/7 levels. The induction of autophagy and levels of proteins involved in this process (LC3A/B and Beclin-1) were examined in MCF-7 and MDA-MB-231 breast cancer cells exposed to tested compounds (thio, thioPt, cisPt) at a concentration of 50 µM for 24 h. Based on these results, it can be concluded that thio and thioPt do not significantly affect the autophagy process. This demonstrates their superiority over cisplatin, which can stimulate cancer cell survival through its effect on stimulation of autophagy.

A Stem-like Patient-Derived Ovarian Cancer Model of Platinum Resistance Reveals Dissociation of Stemness and Resistance.

To understand chemoresistance in the context of cancer stem cells (CSC), a cisplatin resistance model was developed using a high-grade serous ovarian cancer patient-derived, cisplatin-sensitive sample, PDX4. As a molecular subtype-specific stem-like cell line, PDX4 was selected for its representative features, including its histopathological and BRCA2 mutation status, and exposed to cisplatin in vitro. In the cisplatin-resistant cells, transcriptomics were carried out, and cell morphology, protein expression, and functional status were characterized. Additionally, potential signaling pathways involved in cisplatin resistance were explored. Our findings reveal the presence of distinct molecular signatures and phenotypic changes in cisplatin-resistant PDX4 compared to their sensitive counterparts. Surprisingly, we observed that chemoresistance was not inherently linked with increased stemness. In fact, although resistant cells expressed a combination of EMT and stemness markers, functional assays revealed that they were less proliferative, migratory, and clonogenic-features indicative of an underlying complex mechanism for cell survival. Furthermore, DNA damage tolerance and cellular stress management pathways were enriched. This novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapies tailored to combat resistance in stem-like ovarian cancer.

Subsequent management and outcomes after first-line PARP inhibitors progression in ovarian cancer patients.

OBJECTIVES: This retrospective study aims to evaluating the subsequent management and outcomes after first-line PARPi progression in Chinese ovarian cancer population. METHODS: Clinical and pathologic variables, treatment modalities, and outcomes were assessed. We investigated the subsequent management and outcomes after first-line PARPi progression. The objective response rate (ORR) and disease control rate (DCR) parameters were evaluated to determine the response to subsequent chemotherapy. For the survival analyses, progression-free survival 1 (PFS1), PFS2, overall survival (OS) and PFS2 - PFS1 were analysed. RESULTS: A total of 124 patients received PARPi maintenance treatment after first-line chemotherapy during the study period in our center. 44 of them (35.5%) experienced a recurrence. The median duration of PARPi in these patients was 11.1 months (range: 1.2-75.1 months). A total of 40 patients (40/44, 90.9%) received subsequent chemotherapy with 35 (35/44, 79.5%) and 5 (5/44, 11.4%) patients received platinum-based and non-platinum-based chemotherapy in our center. 2 patients (4.5%) received target therapy and other 2 patients (4.5%) received best supportive care. 27.3% (12/44) patients received secondary cytoreduction surgery (SCS). After subsequent chemotherapy, 14 patients received PARPi retreatment as maintenance therapy. In patients who received platinum-based regimens (n = 35), 23 of 35 patients (65.7%) had complete/partial response (CR/PR), 8 of 35 (22.9%) had stable disease (SD), and 4 of 35 (12.1%) had progressive disease (PD). The ORR and DCR of patients who received subsequent chemotherapy was 65.7% and 88.6%, respectively. 15 patients (57.7%, 15/26) were reported to be platinum resistant with a platinum-free interval (PFI) of < 6 months in patients whose platinum sensitivity of the second line platinum-based regimens was evaluable. Patients who received SCS after PARPi resistant associated with a borderline better PFS2 (median PFS2: 41.9 vs. 29.2 months, P = 0.051) and a non-significantly increased PFS2-PFS1 (median PFS2-PFS1: 12.2 vs. 9.8 months, P = 0.551). Patients with a PFI ≥ 12 months had a significantly better PFS2 (median PFS2: 37.0 vs. 25.3 months, P < 0.001) and a tendency towards a better PFS2-PFS1 than those with a PFI < 12 months (median PFS2-PFS1: 11.2 vs. 8.5 months, P = 0.334). A better PFS2 was observed in patients who received second PARPi maintenance therapy (median PFS2 of 35.4 vs. 28.8 months); however, the difference was not statistically significant (P = 0.200). A better PFS2-PFS1 was observed in patients who received second PARPi maintenance therapy (median PFS2-PFS1: 13.6 vs. 8.9 months, P = 0.002) than those without. CONCLUSIONS: In summary, some degree of resistance to standard subsequent platinum and non-platinum chemotherapy is noted in the entire cohort. A trend towards higher benefit from subsequent chemotherapy after first-line PARP inhibitors progression was observed in the PFI ≥ 12 months subgroup than those with PFI < 12 months. PARPi retreatment as maintenance therapy and SCS can be offered to some patients with PARPi resistance.

Bio synthesis, comprehensive characterization, and multifaceted therapeutic applications of BSA-Resveratrol coated platinum nanoparticles.

This study examines the manufacturing, characterization, and biological evaluation of platinum nanoparticles, which were synthesized by Enterobacter cloacae and coated with Bovine Serum Albumin (BSA) and Resveratrol (RSV). The formation of PtNPs was confirmed with the change of color from dark yellow to black, which was due to the bioreduction of platinum chloride by E. cloacae. BSA and RSV functionalization enhanced these nanoparticles' biocompatibility and therapeutic potential. TGA, SEM, XRD, and FTIR were employed for characterization, where PtNPs and drug conjugation-related functional groups were studied by FTIR. XRD confirmed the crystalline nature of PtNPs and Pt-BSA-RSV NPs, while TGA and SEM showed thermal stability and post-drug coating morphological changes. Designed composite was also found to be biocompatible in nature in hemolytic testing, indicating their potential in Biomedical applications. After confirmation of PtNPs based nanocaompsite synthesis, they were examined for anti-bacterial, anti-oxidant, anti-inflammatory, and anti-cancer properties. Pt-BSA-RSV NPs showed higher concentration-dependent DPPH scavenging activity, which measured antioxidant capability. Enzyme inhibition tests demonstrated considerable anti-inflammatory activity against COX-2 and 15-LOX enzymes. In in vitro anticancer studies, Pt-BSA-RSV NPs effectively killed human ovarian cancer cells. This phenomenon was demonstrated to be facilitated by the acidic environment of cancer, as the drug release assay confirmed the release of RSV from the NP formulation in the acidic environment. Finally, Molecular docking also demonstrated that RSV has strong potential as an anti-oxidant, antibacterial, anti-inflammatory, and anticancer agent. Overall, in silico and in vitro investigations in the current study showed good medicinal applications for designed nanocomposites, however, further in-vivo experiments must be conducted to validate our findings.

The influence of thioether-substituted ligands in dicopper(II) complexes: Enhancing oxidation and biological activities.

This paper describes the synthesis, structural analysis, as well as the magnetic and spectroscopic characterizations of three new dicopper(II) complexes with dinucleating phenol-based ligands containing different thioether donor substituents: aromatic (1), aliphatic (2) or thiophene (3). Temperature-dependent magnetometry reveals the presence of antiferromagnetic coupling for 1 and 3 (J = -2.27 cm-1 and -5.01 cm-1, respectively, H = -2JS1S2) and ferromagnetic coupling for 2 (J = 5.72 cm-1). Broken symmetry DFT calculations attribute this behavior to a major contribution from the dz2 orbitals for 1 and 3, and from the dx2-y2 orbitals for 2, along with the p orbitals of the oxygens. The bioinspired catalytic activities of these complexes related to catechol oxidase were studied using 3,5-di-tert-butylcatechol as substrate. The order of catalytic rates for the substrate oxidation follows the trend 1 > 2 > 3 with kcat of (90.79 ± 2.90) × 10-3 for 1, (64.21 ± 0.99) × 10-3 for 2 and (14.20 ± 0.32) × 10-3 s-1 for 3. The complexes also cleave DNA through an oxidative mechanism with minor-groove preference, as indicated by experimental and molecular docking assays. Antimicrobial potential of these highly active complexes has shown that 3 inhibits both Staphylococcus aureus bacterium and Epidermophyton floccosum fungus. Notably, the complexes were found to be nontoxic to normal cells but exhibited cytotoxicity against epidermoid carcinoma cells, surpassing the activity of the metallodrug cisplatin. This research shows the multifaceted properties of these complexes, making them promising candidates for various applications in catalysis, nucleic acids research, and antimicrobial activities.

Hyaluronic acid functionalized iron-platinum nanoparticles for photothermal therapy and photoacoustic imaging.

This study represents an innovative approach to construct multi-functional nanoplatforms for cancer diagnosis and therapy by combining hyaluronic acid (HA) with iron-platinum nanoparticles (FePt NPs). These HA-coated FePt NPs, referred to as FePt@HA NPs, demonstrated remarkable biocompatibility, high absorption, and excellent light-to-heat conversion properties in the near-infrared (NIR) region, making them ideal candidates for photothermal therapy (PTT). In vitro studies revealed their effective cancer cell eradication under NIR laser irradiation, while in vivo experiments on mice showcased their superior heating capabilities. Moreover, FePt@HA NPs exhibited a distinct and strong photoacoustic (PA) signal, facilitating enhanced and precise intra-tumoral PA imaging. Our results highlight the potential of FePt@HA NPs as promising photothermal agents for future PTT applications. They offer high selectivity, precision, and minimal side effects in cancer treatment, along with their valuable PA imaging application for tumor localization and characterization.

Are DNA Repair Gene Alterations Associated With the Response to Platinum-Based Regimen and Immune Checkpoint Inhibitors in Patients With Solid Tumors?

We analyzed the antitumor activity of platinum-based chemotherapies and then immune checkpoint inhibitors (ICI) in all-comers patients with solid tumors having a somatic DNA damage repair gene alteration (DDR-GA) identified through a prospective precision medicine study (NCT02534649). Each DDR-GA was classified as pathogenic (Pa), probably pathogenic (PPa), and unknown pathogenicity (UPa) according to OncoKB and ClinVAR databases. Between January 2018 and May 2020, 662 patients were screened. One hundred ninety-nine tumors with DDR-GA were found in 121 (18.3%) patients. Ninety-six patients received platinum-based chemotherapy in the advanced setting. No difference in objective response rate (ORR) under platinum regimen was observed between the 3 DDR-GA groups. The only predictor of worse progression-free survival (PFS) in Cox regression was the existence of a Pa alteration compared to the UPa group: HR = 2.11 (95% CI = 1.2-3.7), P = .009. Forty-eight patients received ICI alone or in combination. We observed a significant trend in better ORR to ICI according to the DDR-GA status: 1/11 (9%) patients in UPa, 5/17 (29.4%) patients in PPa, and 9/20 (45%) patients in Pa (P = .003, Cochran-Armitage trend test), and an increased 6-month PFS probability of 11%, 44%, and 50% in the UPa, PPa, and Pa groups, respectively (P = .37, log-rank test). Overall, somatic pathogenic DDR-GAs were not associated with ORR or PFS to platinum-based chemotherapy in patients with unselected advanced solid tumors. However, DDR-GA seemed to impact ORR and PFS to ICI, paving the way for a therapeutic combination with ICI and molecules targeting the DDR mechanisms, which are currently evaluated in ongoing clinical trials.

Platinum-induced upregulation of ITGA6 promotes chemoresistance and spreading in ovarian cancer.

Platinum (PT)-resistant Epithelial Ovarian Cancer (EOC) grows as a metastatic disease, disseminating in the abdomen and pelvis. Very few options are available for PT-resistant EOC patients, and little is known about how the acquisition of PT-resistance mediates the increased spreading capabilities of EOC. Here, using isogenic PT-resistant cells, genetic and pharmacological approaches, and patient-derived models, we report that Integrin α6 (ITGA6) is overexpressed by PT-resistant cells and is necessary to sustain EOC metastatic ability and adhesion-dependent PT-resistance. Using in vitro approaches, we showed that PT induces a positive loop that, by stimulating ITGA6 transcription and secretion, contributes to the formation of a pre-metastatic niche enabling EOC cells to disseminate. At molecular level, ITGA6 engagement regulates the production and availability of insulin-like growth factors (IGFs), over-stimulating the IGF1R pathway and upregulating Snail expression. In vitro data were recapitulated using in vivo models in which the targeting of ITGA6 prevents PT-resistant EOC dissemination and improves PT-activity, supporting ITGA6 as a promising druggable target for EOC patients.

Disrupting glycolysis and DNA repair in anaplastic thyroid cancer with nucleus-targeting platinum nanoclusters.

Cancer cells rely on aerobic glycolysis and DNA repair signals to drive tumor growth and develop drug resistance. Yet, fine-tuning aerobic glycolysis with the assist of nanotechnology, for example, dampening lactate dehydrogenase (LDH) for cancer cell metabolic reprograming remains to be investigated. Here we focus on anaplastic thyroid cancer (ATC) as an extremely malignant cancer with the high expression of LDH, and develop a pH-responsive and nucleus-targeting platinum nanocluster (Pt@TAT/sPEG) to simultaneously targets LDH and exacerbates DNA damage. Pt@TAT/sPEG effectively disrupts LDH activity, reducing lactate production and ATP levels, and meanwhile induces ROS production, DNA damage, and apoptosis in ATC tumor cells. We found Pt@TAT/sPEG also blocks nucleotide excision repair pathway and achieves effective tumor cell killing. In an orthotopic ATC xenograft model, Pt@TAT/sPEG demonstrates superior tumor growth suppression compared to Pt@sPEG and cisplatin. This nanostrategy offers a feasible approach to simultaneously inhibit glycolysis and DNA repair for metabolic reprogramming and enhanced tumor chemotherapy.

Defect-rich sonosensitizers based on CeO2 with Schottky heterojunctions for boosting sonodynamic/chemodynamic synergistic therapy.

Sonodynamic therapy (SDT) has been recognized as a promising treatment for cancer due to its advantages of superior specificity, non-invasiveness, and deep tissue penetration. However, the antitumor effect of SDT remains restricted by the limited generation of reactive oxygen species (ROS) due to the lack of highly efficient sonosensitizers. In this work, we developed the novel sonosensitizer Pt/CeO2-xSx by constructing oxygen defects through S doping and Pt loading in situ. Large amounts of oxygen defects have been obtained by S doping, endowing Pt/CeO2-xSx with the ability to suppress electron-hole recombination, further promoting ROS production. Moreover, the introduction of Pt nanoparticles can not only produce oxygen in situ for relieving hypoxia but also form a Schottky heterojunction with CeO2-xSx for further inhibiting electron-hole recombination. In addition, Pt/CeO2-xSx could effectively deplete overexpressed glutathione (GSH) via redox reactions, amplifying oxidative stress in the tumor microenvironment (TME). Combined with the excellent POD-mimetic activity, Pt/CeO2-xSx can achieve highly efficient synergistic therapy of SDT and chemodynamic therapy (CDT). All these findings demonstrated that Pt/CeO2-xSx has great potential for cancer therapy, and this work provides a promising direction for designing and constructing efficient sonosensitizers.

Structure-Guided Design of Ferritin-Platinum Prodrugs for Targeted Therapy of Esophageal Squamous Cell Carcinoma.

Due to its intrinsic tumor-targeting attribute, limited immunogenicity, and cage architecture, ferritin emerges as a highly promising nanocarrier for targeted drug delivery. In the effort to develop ferritin cage-encapsulated cisplatin (CDDP) as a therapeutic agent, we found unexpectedly that the encapsulation led to inactivation of the drug. Guided by the structural information, we deciphered the interactions between ferritin cages and CDDP, and we proposed a potential mechanism responsible for attenuating the antitumor efficacy of CDDP encapsulated within the cage. Six platinum prodrugs were then designed to avoid the inactivation. The antitumor activities of these ferritin-platinum prodrug complexes were then evaluated in cells of esophageal squamous cell carcinoma (ESCC). Compared with free CDDP, the complexes were more effective in delivering and retaining platinum in the cells, leading to increased DNA damage and enhanced cytotoxic action. They also exhibited improved pharmacokinetics and stronger antitumor activities in mice bearing ESCC cell-derived xenografts as well as patient-derived xenografts. The successful encapsulation also illustrates the critical significance of comprehending the interactions between small molecular drugs and ferritin cages for the development of precision-engineered nanocarriers.