Dual drug-loaded metal-phenolic networks for targeted magnetic resonance imaging and synergistic chemo-chemodynamic therapy of breast cancer.

The development of nanomedicines with simplified compositions and synergistic theranostic functionalities remains a great challenge. Herein, we develop a simple method to integrate both atovaquone (ATO, a mitochondrial inhibitor) and cisplatin within tannic acid (TA)-iron (Fe) networks coated with hyaluronic acid (HA) for targeted magnetic resonance (MR) imaging-guided chemo-chemodynamic synergistic therapy. The formed TFP@ATO-HA displayed good colloidal stability with a mean size of 95.5 nm, which could accumulate at tumor sites after circulation and be specifically taken up by metastatic 4T1 cells overexpressing CD44 receptors. In the tumor microenvironment, TFP@ATO-HA could release ATO/cisplatin and Fe3+ in a pH-responsive manner, deplete glutathione, and generate reactive oxygen species with endogenous H2O2 for chemodynamic therapy (CDT). Additionally, ATO could enhance chemotherapeutic efficacy by inhibiting mitochondrial respiration, relieving hypoxia, and amplifying the CDT effect by decreasing intracellular pH and elevating Fenton reaction efficiency. In vivo experiments demonstrated that TFP@ATO-HA could effectively inhibit tumor growth and suppress lung metastases without obvious systemic toxicity. Furthermore, TFP@ATO-HA exhibited a r1 relaxivity of 2.6 mM-1 s-1 and targeted MR imaging of 4T1 tumors. Dual drug-loaded metal-phenolic networks can be easily prepared and act as effective theranostic nanoplatforms for targeted MR imaging and synergistic chemo-chemodynamic therapy.

Dual encapsulation and sequential release of cisplatin and vitamin E from soy polysaccharides and ß-cyclodextrin bioadhesive hydrogel nanoparticles.

Chemically cross-linked hydrogel nanoparticles (HGNPs) offer enhanced properties over their physical counterparts, particularly in drug delivery and cell encapsulation. This study applied pH-thermal dual responsive bio-adhesive HGNPs for dual complexation and enhanced the controlled release and bioavailability of cisplatin (CDDP) and Vitamin E (VE) drugs. The CDDP was loaded into the HGNPs via chemical conjugation with the carboxyl groups in the HGNPs surface by soy polysaccharides (SSPS). At the same time, the host-guest interaction complexed the VE through the ß-cyclodextrin (ß-CD). The HGNPs showed a uniform HGNPs size distribution of 90.77 ± 14.77 nm and 81.425 ± 13.21 nm before and after complexation, respectively. The FTIR, XRD, XPS, and zeta potential confirmed the conjugation. The cumulative release percent of CDDP reached 98 % at pH 1.2, while <45 % was released at pH 7.4. Our HGNPs enhance the incorporation of CDDP by substituting its chlorides with carboxyl groups of the SSPS; the loading of CDDP and VE was 15 ± 0.33 and 11.32 ± 0.25 wt%, respectively. Moreover, the CDDP and VE also released slower from the HGNPs at 25 °C than at 37 °C and 42 °C. The (VE/CDDP)-loaded HGNPs exhibited longer circulation time in vivo than free CDDP and free VE suspension.

The therapeutic effect and MR molecular imaging of FA-PEG-FePt/DDP nanoliposomes in AMF on ovarian cancer.

Purpose: This study aimed to construct targeting drug-loading nanocomposites (FA-FePt/DDP nanoliposomes) to explore their potential in ovarian cancer therapy and molecular magnetic resonance imaging (MMRI). Methods: FA-FePt-NPs were prepared by coupling folate (FA) with polyethylene-glycol (PEG)-coated ferroplatinum nanoparticles and characterized. Then cisplatin (DDP) was encapsulated in FA-FePt-NPs to synthesize FA-PEG-FePt/DDP nanoliposomes by thin film-ultrasonic method and high-speed stirring, of which MMRI potential, magnetothermal effect, and the other involved performance were analyzed. The therapeutic effect of FA-FePt/DDP nanoliposomes combined with magnetic fluid hyperthermia (MFH) on ovarian cancer in vitro and in vivo was evaluated. The expression levels of Bax and epithelial-mesenchymal transition related proteins were detected. The biosafety was also preliminarily observed. Results: The average diameter of FA-FePt-NPs was about 30 nm, FA-FePt/DDP nanoliposomes were about 70 nm in hydrated particle size, with drug slow-release and good cell-specific targeted uptake. In an alternating magnetic field (AMF), FA-FePt/DDP nanoliposomes could rapidly reach the ideal tumor hyperthermia temperature (42~44 °C). MRI scan showed that FA-FePt-NPs and FA-FePt/DDP nanoliposomes both could suppress the T2 signal, indicating a good potential for MMRI. The in vitro and in vivo experiments showed that FA-FePt/DDP-NPs in AMF could effectively inhibit the growth of ovarian cancer by inhibiting cancer cell proliferation, invasion, and migration, and inducing cancer cell apoptosis, much better than that of the other individual therapies; molecularly, E-cadherin and Bax proteins in ovarian cancer cells and tissues were significantly increased, while N-cadherin, Vimentin, and Bcl-2 proteins were inhibited, effectively inhibiting the malignant progression of ovarian cancer. In addition, no significant pathological injury and dysfunction was observed in major visceras. Conclusion: We successfully synthesized FA-FePt/DDP nanoliposomes and confirmed their good thermochemotherapeutic effect in AMF and MMRI potential on ovarian cancer, with no obvious side effects, providing a favorable strategy of integrated targeting therapy and diagnosis for ovarian cancer.

Reactions of Cisplatin with Thioredoxin-1 Regulate Intracellular Redox Homeostasis.

Cisplatin is a widely used anticancer drug. In addition to inducing DNA damage, increased levels of reactive oxygen species (ROS) play a significant role in cisplatin-induced cell death. Thioredoxin-1 (Trx1), a redox regulatory protein that can scavenge ROS, has been found to eliminate cisplatin-induced ROS, while elevated Trx1 levels are associated with cisplatin resistance. However, it is unknown whether the effect of Trx1 on the cellular response to cisplatin is due to its direct reaction and how this reaction influences the activity of Trx1. In this work, we performed detailed studies of the reaction between Trx1 and cisplatin. Trx1 is highly reactive to cisplatin, and the catalytic motif of Trx1 (CGPC) is the primary binding site of cisplatin. Trx1 can bind up to 6 platinum moieties, resulting in the structural alteration and oligomerization of Trx1 depending on the degree of platination. Platination of Trx1 inhibits its interaction with ASK1, a Trx1-binding protein that regulates cell apoptosis. Furthermore, the reaction with cisplatin suppresses drug-induced ROS generation, which could be associated with drug resistance. This study provides more insight into the mechanism of action of cisplatin.

Click Chemistry-Based Force Spectroscopy Revealed Enhanced Binding Dynamics of Phosphorylated HMGB1 to Cisplatin-DNA.

Cisplatin, a cornerstone in cancer chemotherapy, is known for its DNA-binding capacity and forms lesions that lead to cancer cell death. However, the repair of these lesions compromises cisplatin's effectiveness. This study investigates how phosphorylation of HMGB1, a nuclear protein, modifies its binding to cisplatin-modified DNA (CP-DNA) and thus protects it from repair. Despite numerous methods for detecting protein-DNA interactions, quantitative approaches for understanding their molecular mechanism remain limited. Here, we applied click chemistry-based single-molecule force spectroscopy, achieving high-precision quantification of the interaction between phosphorylated HMGB1 and CP-DNA. This method utilizes a synergy of click chemistry and enzymatic ligation for precise DNA-protein immobilization and interaction in the system. Our results revealed that HMGB1 binds to CP-DNA with a significantly high rupture force of ∼130 pN, stronger than most natural DNA-protein interactions and varying across different DNA sequences. Moreover, Ser14 is identified as the key phosphorylation site, enhancing the interaction's kinetic stability by 35-fold. This increase in stability is attributed to additional hydrogen bonding suggested by molecular dynamics (MD) simulations. Our findings not only reveal the important role of phosphorylated HMGB1 in potentially improving cisplatin's therapeutic efficacy but also provide a precise method for quantifying protein-DNA interactions.

Light-Responsive Pt(IV) Prodrugs with Controlled Photoactivation and Low Dark Toxicity.

Light-induced release of cisplatin from Pt(IV) prodrugs represents a promising approach for precise control over the antiproliferative activity of Pt-based chemotherapeutic drugs. This method has the potential to overcome crucial drawbacks of conventional cisplatin therapy, such as high general toxicity toward healthy organs and tissues. Herein, we report two Pt(IV) prodrugs with BODIPY-based photoactive ligands Pt-1 and Pt-2, which were designed using carbamate and triazole linkers, respectively. Both prodrugs demonstrated the ability to release cisplatin under blue light irradiation without the requirement of an external reducing agent. Dicarboxylated Pt-2 prodrug turned out to be more stable in the dark and more sensitive to light than its monocarbamate Pt-1 counterpart; these observations were explained using DFT calculations. The investigation of the photoreduction mechanism of Pt-1 and Pt-2 prodrugs using DFT modeling and ΔG0 PET estimation suggests that the photoinduced electron transfer from the singlet excited state of the BODIPY axial ligand to the Pt(IV) center is the key step in the light-induced release of cisplatin from the complexes. Cytotoxicity studies demonstrated that both prodrugs were nontoxic in the dark and toxic to MCF-7 cells under low-dose irradiation with blue light, and the observed effect was solely due to the cisplatin release from the Pt(IV) prodrugs. Our research presents an elegant synthetic approach to light-activated Pt(IV) prodrugs and presents findings that may contribute to the future rational design of photoactivatable Pt(IV) prodrugs.

Binding energies and hydrogen bonds effects on DNA-cisplatin interactions: a DFT-xTB study.

CONTEXT: A systematic study of hydrogen bonds in base pairs and the interaction of cisplatin with DNA fragments was carried out. Structure, binding energies, and electron density were analyzed. xTB has proven to be an accurate method for obtaining structures and binding energies in DNA structures. Our xTB values for DNA base binding energy were in the same order and in some cases better than CAM-B3LYP values compared to experimental values. Double-stranded DNA-cisplatin structures have been calculated and the hydrogen bonds of water molecules are a decisive factor contributing to the preference for the cisplatin-Guanine interaction. Higher values of the water hydrogen bonding energies were obtained in cisplatin-Guanine structures. Furthermore, the electrostatic potential was used to investigate and improve the analysis of DNA-cisplatin structures. METHODS: We applied the xTB method and the CAM-B3LYP functional combined with def2-SVP basis set to perform and analyze of the bonding energies of the cisplatin interaction and the effects of the hydrogen bonds. Results were calculated employing the xTB and the ORCA software.

The Application of 2d Mxene Nanosheet -Based Thermosensitive Gel Delivery System Loaded with Cisplatin and Imiquimod for Lung Cancer.

Introduction: Lung cancer's high incidence and dismal prognosis with traditional treatments like surgery and radiotherapy necessitate innovative approaches. Despite advancements in nanotherapy, the limitations of single-treatment modalities and significant side effects persist. To tackle lung cancer effectively, we devised a temperature-sensitive hydrogel-based local injection system with near-infrared triggered drug release. Utilizing 2D MXene nanosheets as carriers loaded with R837 and cisplatin (DDP), encapsulated within a temperature-sensitive hydrogel-forming PEG-MXene@DDP@R837@SHDS (MDR@SHDS), we administered in situ injections of MDR@SHDS into tumor tissues combined with photothermal therapy (PTT). The immune adjuvant R837 enhances dendritic cell (DC) maturation and tumor cell phagocytosis, while PTT induces tumor cell apoptosis and necrosis by converting light energy into heat energy. Methods: Material characterization employed transmission electron microscopy, X-ray photoelectron spectroscopy, phase transition temperature, and near-infrared thermography. In vitro experiments assessed Lewis cell proliferation and apoptosis using CCK-8, Edu, and TUNEL assays. In vivo experiments on C57 mouse Lewis transplant tumors evaluated the photothermal effect via near-infrared thermography and assessed DC maturation and CD4+/CD8+ T cell ratios using flow cytometry. The in vivo anti-tumor efficacy of MDR@SHDS was confirmed by tumor growth curve recording and HE and TUNEL staining of tumor sections. Results: The hydrogel exhibited excellent temperature sensitivity, controlled release properties, and high biocompatibility. In vitro experiments revealed that MDR@SHDS combined with PTT had a greater inhibitory effect on tumor cell proliferation compared to MDR@SHD alone. Combining local immunotherapy, chemotherapy, and PTT yielded superior anti-tumor effects than individual treatments. Conclusion: MDR@SHDS, with its simplicity, biocompatibility, and enhanced anti-tumor effects in combination with PTT, presents a promising therapeutic approach for lung cancer treatment, offering potential clinical utility.

Co-assembly of cisplatin and dasatinib in hyaluronan nanogel to combat triple negative breast cancer with reduced side effects.

Treatment for triple negative breast cancer (TNBC) remains a huge challenge due to the lack of targeted therapeutics and tumor heterogenicity. Cisplatin (Cis) have demonstrated favorable therapeutic response in TNBC and thus is used together with various kinase inhibitors to fight the heterogenicity of TNBC. The combination of Cis with SRC inhibitor dasatinib (DAS) has shown encouraging anti-TNBC efficacy although the additive toxicity was commonly observed. To overcome the severe side effects of this Cis involved therapy, here we co-encapsulated Cis and DAS into a self-assembled hyaluronan (HA) nanogel (designated as HA/Cis/DAS (HCD) nanogel) to afford the TNBC targeted delivery by using the 4T1 mouse model. The acquired HCD nanogel was around 181 nm in aqueous solution, demonstrating the pharmacological activities of both Cis and DAS. Taking advantages of HA's targeting capability towards CD44 that is overexpressed on many TNBC cells, the HCD could well maintain the anticancer efficacy of the Cis and DAS combination, significantly increase the maximum tolerated dose and relieve the renal toxicity in vivo. The current HCD nanogel provides a potent strategy to improve the therapeutic outcome of Cis and DAS combination and thus representing a new targeted treatment option for TNBC.

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.

Nanodrugs based on co-delivery strategies to combat cisplatin resistance.

Cisplatin (CDDP), as a broad-spectrum anticancer drug, is able to bind to DNA and inhibit cell division. Despite the widespread use of cisplatin since its discovery, cisplatin resistance developed during prolonged chemotherapy, similar to other small molecule chemotherapeutic agents, severely limits its clinical application. Cisplatin resistance in cancer cells is mainly caused by three reasons: DNA repair, decreased cisplatin uptake/increased efflux, and cisplatin inactivation. In earlier combination therapies, the emergence of multidrug resistance (MDR) in cancer cells prevented the achievement of the desired therapeutic effect even with the accurate combination of two chemotherapeutic drugs. Therefore, combination therapy using nanocarriers for co-delivery of drugs is considered to be ideal for alleviating cisplatin resistance and reducing cisplatin-related toxicity in cancer cells. This article provides an overview of the design of cisplatin nano-drugs used to combat cancer cell resistance, elucidates the mechanisms of action of cisplatin and the pathways through which cancer cells develop resistance, and finally discusses the design of drugs and related carriers that can synergistically reduce cancer resistance when combined with cisplatin.

Cisplatin-loaded mesoporous polydopamine nanoparticles capped with MnO2 and coated with platelet membrane provide synergistic anti-tumor therapy.

A multifunctional nanoplatform was constructed in this work, with the goal of ameliorating the challenges faced with traditional cancer chemotherapy. Cisplatin (CP) was loaded into mesoporous polydopamine (mPDA) nanoparticles (NPs) with a drug loading of 15.8 ± 0.1 %, and MnO2 used as pore sealing agent. Finally, the NPs were wrapped with platelet membrane (PLTM). P-selectin on the PLTM can bind to CD44, which is highly expressed on the tumor cell membrane, so as to improve the targeting performance of the NPs. In addition, the CD47 on the PLTM can prevent the NPs from being phagocytosed by macrophages, which is conducive to immune escape. The final PLTM-CP@mPDA/MnO2 NPs were found to have a particle size of approximately 198 nm. MnO2 is degraded into Mn2+ in the tumor microenvironment, leading to CP release from the pores in the mPDA. CP both acts as a chemotherapy agent and can also increase the concentration of H2O2 in cells. Mn2+ can catalyze the conversion of H2O2 to OH, resulting in oxidative damage and chemodynamic therapy. In addition, Mn2+ can be used as a contrast agent in magnetic resonance imaging (MRI). In vitro and in vivo experiments were performed to explore the therapeutic effect of the NPs. When the concentration of CP is 30 µg/mL, the NPs cause approximately 50 % cell death. It was found that the PLTM-CP@mPDA/MnO2 NPs are targeted to cancerous cells, and in the tumor site cause extensive apoptosis. Tumor growth is thereby repressed. No negative off-target side effects were noted. MRI could be used to confirm the presence of the NPs in the tumor site. Overall, the nano-platform developed here provides cooperative chemotherapy and chemodynamic therapy, and can potentially be used for effective cancer treatment which could be monitored by MRI.

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.

Acidic solvent improves cisplatin action in in-vitro.

As cisplatin is one of the most broadly used chemotherapeutics, it is widely tested in vitro & in vivo assays, involving attempts to better understand its mechanism of action, develop strategies to mitigate its toxicity, or develop new drug combinations. Presently, for in vitro assays, dissolving cisplatin in dimethyl sulfoxide (DMSO) is discouraged due to its significant reduction in drug activity, Alternatively, inorganic solvents like normal saline (NS) are recommended. However, this approach is still problematic, including 1) instability of cisplatin in NS, 2) limited solubility, 3) the need to avoid long-term storage at -80 °C (or -20 °C) after dissolving, and 4) complications when combining with other DMSO-solubilized compounds. Here, we report a DMSO-HCl mixture as an alternative solvent to address these challenges. Cisplatin in DMSO-HCl not only retains comparable drug activity to cisplatin in NS but also exhibits increased stability over an extended period. Our brief report sheds light on cisplatin action, providing insights to aid in cancer research in vitro.

Glycocalyx-Mimicking Nanoparticles with Differential Organ Selectivity for Drug Delivery and Therapy.

Organ-selective drug delivery is expected to maximize the efficacy of various therapeutic modalities while minimizing their systemic toxicity. Lipid nanoparticles and polymersomes can direct the organ-selective delivery of mRNAs or gene editing machineries, but their delivery is limited to mostly liver, spleen, and lung. A platform that enables delivery to these and other target organs is urgently needed. Here, a library of glycocalyx-mimicking nanoparticles (GlyNPs) comprising five randomly combined sugar moieties is generated, and direct in vivo library screening is used to identify GlyNPs with preferential biodistribution in liver, spleen, lung, kidneys, heart, and brain. Each organ-targeting GlyNP hit show cellular tropism within the organ. Liver, kidney, and spleen-targeting GlyNP hits equipped with therapeutics effectively can alleviate the symptoms of acetaminophen-induced liver injury, cisplatin-induced kidney injury, and immune thrombocytopenia in mice, respectively. Furthermore, the differential organ targeting of GlyNP hits is influenced not by the protein corona but by the sugar moieties displayed on their surface. It is envisioned that the GlyNP-based platform may enable the organ- and cell-targeted delivery of therapeutic cargoes.

Molecular targets of cisplatin in HeLa cells explored through competitive activity-based protein profiling strategy.

Cisplatin is widely used as anticancer drugs, and DNA is considered as the main target. Considering its high affinity towards cysteines and the important role of cystine containing proteins, we applied a competitive activity-based protein profiling strategy to identify protein cysteines that bind with cisplatin in HeLa cells. Living cells were treated with cisplatin at cytotoxic concentrations, then the protein was extracted. After labeling with desthiobiotin iodoacetamide (DBIA) probe, protein was precipitated, digested and isotopically labeled, subsequently the peptides were combined, and the biotinylated cysteine-containing peptides were enriched and quantified by LC-MS/MS. A total of 3571 peptides which originated from 1871 proteins were identified using the DBIA probe. Among them, 46 proteins were screened as targets, including proteins that have been identified as binding proteins by previous study. A novel cisplatin target, calpain-1 (CAPN1), was identified and validated as binding with cisplatin in vitro.

In Situ Nanofiber Formation Blocks AXL and GAS6 Binding to Suppress Ovarian Cancer Development.

Anexelekto (AXL) is an attractive molecular target for ovarian cancer therapy because of its important role in ovarian cancer initiation and progression. To date, several AXL inhibitors have entered clinical trials for the treatment of ovarian cancer. However, the disadvantages of low AXL affinity and severe off-target toxicity of these inhibitors limit their further clinical applications. Herein, by rational design of a nonapeptide derivative Nap-Phe-Phe-Glu-Ile-Arg-Leu-Arg-Phe-Lys (Nap-IR), a strategy of in situ nanofiber formation is proposed to suppress ovarian cancer growth. After administration, Nap-IR specifically targets overexpressed AXL on ovarian cancer cell membranes and undergoes a receptor-instructed nanoparticle-to-nanofiber transition. In vivo and in vitro experiments demonstrate that in situ formed Nap-IR nanofibers efficiently induce apoptosis of ovarian cancer cells by blocking AXL activation and disrupting subsequent downstream signaling events. Remarkably, Nap-IR can synergistically enhance the anticancer effect of cisplatin against HO8910 ovarian tumors. It is anticipated that the Nap-IR can be applied in clinical ovarian cancer therapy in the near future.

A Transparent and Injectable Biomaterial Prepared by Mixing Collagen and Anti-Cancer Platinum Derivatives.

This study presents the synthesis of a cross-linked collagen material, named platinum-containing collagen gel (PCG), which is achieved by simply mixing collagen and derivatives of an anti-cancer platinum complex. The cross-linking reagents are derivatives of cisplatin or transplatin, generated through a ligand exchange with dimethyl sulfoxide. PCG exhibits superior physical strength and transparency compared with the native collagen gel formed through spontaneous fibril formation. The versatility of PCG as a cell culture scaffold, applicable to both 2D and 3D models, with low cytotoxicity is demonstrated. Furthermore, PCG exhibits pH-responsive gel-forming properties. This enables the removal of free cross-linker by dialysis in an acidic solution and subsequent gel formation upon neutralization. This material holds promise for application in cell culture scaffolds and medical injections.

Platinum(0)-η2-1,2-(E)ditosylethene Complexes Bearing Phosphine, Isocyanide and N-Heterocyclic Carbene Ligands: Synthesis and Cytotoxicity towards Ovarian and Breast Cancer Cells.

A wide range of platinum(0)-η2-(E)-1,2-ditosylethene complexes bearing isocyanide, phosphine and N-heterocyclic carbene ancillary ligands have been prepared with high yields and selectivity. All the novel products underwent thorough characterization using spectroscopic techniques, including NMR and FT-IR analyses. Additionally, for some compounds, the solid-state structures were elucidated through X-ray diffractometry. The synthesized complexes were successively evaluated for their potential as anticancer agents against two ovarian cancer cell lines (A2780 and A2780cis) and one breast cancer cell line (MDA-MB-231). The majority of the compounds displayed promising cytotoxicity within the micromolar range against A2780 and MDA-MB-231 cells, with IC50 values comparable to or even surpassing those of cisplatin. However, only a subset of compounds was cytotoxic against cisplatin-resistant cancer cells (A2780cis). Furthermore, the assessment of antiproliferative activity on MRC-5 normal cells revealed certain compounds to exhibit in vitro selectivity. Notably, complexes 3d, 6a and 6b showed low cytotoxicity towards normal cells (IC50 > 100 µM) while concurrently displaying potent cytotoxicity against cancer cells.

Elucidating shape-mediated drug carrier mechanics of hematite nanomaterials for breast cancer therapeutics.

Metallic nanomaterials have gained significant attention in cancer therapy as potential nanocarriers due to their unique properties at the nanoscale. However, nanomaterials face several drawbacks, including biocompatibility, stability, and cellular uptake. Hematite (α-Fe2O3) nanoparticles are emerging as promising nano-carriers to reduce adverse outcomes of conventional chemotherapeutics. However, the shape-mediated drug carrier mechanics of hematite nanomaterials are not raveled. In this study, we tailored hematite nanoparticles in ellipsoidal (EHNP) and spherical (SHNP) shapes with excellent biocompatibility and efficient drug encapsulation and release. We elucidate that EHNP exhibits higher cellular uptake than SHNP. With effective cellular internalization, the cisplatin-loaded EHNP showed excellent cytotoxicity with an IC50 value of 200 nM compared to the cisplatin-loaded SHNP. The flow cytometry cell sorting (FACS) analysis showed a four-fold increase in cell death by arresting the cells at the G0/G1 and G1 phases for cis-EHNP compared to cis-SHNP. The results show that ellipsoidal-shaped hematite nanoparticles can act as attractive nanocarriers with improved therapeutic efficacy in cancer therapy.