Doxorubicin Research Articles

Overcoming hypoxia-induced breast cancer drug resistance: a novel strategy using hollow gold-platinum bimetallic nanoshells

Breast cancer (BC) is a significant cause of cancer-related deaths among women worldwide. Hypoxia, a common feature of solid tumor, is associated with drug resistance and a poor prognosis in BC. In this study, we present a strategy to overcome hypoxia-induced chemotherapy tolerance in BC. Specifically, we synthesized a hollow gold (Au)-platinum (Pt) bimetallic nanoshell for the first time, which acted as a drug delivery system (DDS) for doxorubicin (DOX). The photothermal effect, induced by the surface plasmon resonance (SPR) from the Au-Pt shell under near infrared-II (NIR-II) laser irradiation, not only directly causes tumor cell death through photothermal therapy (PTT), but also significantly enhances the catalase-like activity between Pt nanoparticles and endogenous H2O2. This, subsequently, results in a heightened yield of O2, which further facilitates the release of DOX. This process alleviates tumor hypoxia and down-regulating hypoxia-inducible factor-1α (HIF-1α), multidrug resistance gene 1 (MDR1), and P-glycoprotein (P-gp), which can reverse drug resistance and achieve more effective DOX chemotherapy effects. Significantly, the increased availability of oxygen further re-polarizes immunosuppressive M2 macrophages into antitumor M1 macrophages. This study presents a novel strategy to tackle tumor proliferation and enhance tumor response to chemotherapy, offering hope for reversing in drug resistance in cancerous lesions.Graphical

Multifunctional Zwitterionic N-Oxide Polymers to Overcome Cascade Physiological Barriers for Efficient Anticancer Drug Delivery.

For efficient anticancer drug delivery, cascade physiological barriers must be overcome, which requires the drug delivery vehicles to possess different or even opposite properties at different stages. Poly(tertiary amine-oxide) (PTAO) polymers with the zwitterionic feature have distinct antifouling properties in blood circulation, which can be reduced and protonated in hypoxic tumors to promote cellular internalization. Nevertheless, the effects of various PTAO structures have not been studied systemically and optimized. In this report, the side groups of PTAO are proposed to be optimized by modulating the structures. Poly(2-(N-oxide-hexamethyleneimino)ethyl methacrylate) (POC7A) with a cyclic seven-membered ring is screened as the optimized PTAO structure for in vivo applications. Moreover, the block copolymer POC7A-block-poly(ε-caprolactone) (POC7A-PCL) is prepared for the formation of micelles in aqueous solution for delivery of doxorubicin (DOX). The zwitterionic nature of POC7A shells with efficient bioreductive activity and protonation in the tumor microenvironment endows the micelles with excellent antifouling properties for long blood circulation, efficient tumor accumulation, deep penetration, and effective cellular internalization. Thus, the DOX-loaded micelles exhibit potent antitumor efficacy after intravenous administration. Zwitterionic POC7A can be used as antifouling shells of the anticancer drug delivery nanocarriers to overcome the cascade physiological barriers efficiently.

Metformin alleviates doxorubicin-induced hepatic damage by modulating oxidative stress: a molecular, biochemical, and histopathological approach in a rat model.

Doxorubicin (DOX) is one of the most commonly prescribed anti-cancer drugs. However, DOX-induced hepatotoxicity is a dose-limiting side effect. This study aimed to clarify the potential protective effects of metformin on DOX-induced hepatotoxicity in rats. The animals were divided into six groups (n = 6 each): Control Group, DOX group, metformin 200mg/kg group, DOX + metformin 50mg/kg group, DOX + metformin 100mg/kg group, and DOX + metformin 200mg/kg group. Hepatic injury was induced by a single intraperitoneal injection of DOX (20mg/kg). The activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in serum were determined. Furthermore, the hepatic histopathological changes were evaluated. To identify the markers of oxidative stress, the level of malondialdehyde (MDA) and the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in liver tissue were measured. Results showed that DOX provoked a marked elevation in ALT, AST, and ALP serum levels. In addition, oxidative stress was significantly boosted in DOX-treated rats compared to control rats. All these were abolished with the metformin administration. Histological examination also showed that metformin could substantially reduce DOX-induced alterations. The most prominent effect was observed by high-dose metformin.

LB-100 Enhances Drugs Efficacy Through Inhibition of P-Glycoprotein Expression in Multidrug-Resistant Glioblastoma and Non-Small Cell Lung Carcinoma Cellular Models

Background/Objectives: This study explores the potential of LB-100 (a protein phosphatase 2A—PP2A inhibitor) combined with adavosertib (a WEE1 kinase inhibitor) and doxorubicin (DOX), to overcome multidrug resistance (MDR) in cancer cells and enhance treatment efficacy. Methods: We evaluated LB-100 combinations with adavosertib and DOX in patient-derived glioblastoma and non-small cell lung carcinoma cells (NSCLCs) using a real-time cell analyzer. Effectiveness was also assessed through immunofluorescence assay, and interactions were analyzed via SynergyFinder+. We also examined P-glycoprotein (P-gp) expression and drug resistance genes’ expression in MDR glioblastoma and NSCLCs after LB-100 treatment, as well as LB-100 sensitizing effect on DOX and DOX accumulation. Results: LB-100 significantly boosts the effectiveness of adavosertib and DOX after multiple applications. It also enhances these drugs’ cytotoxicity in a single application without acting synergistically. Additionally, LB-100 reduces P-gp expression in MDR glioblastoma and NSCLCs, sensitizing them to DOX and increasing its accumulation. Conclusions: LB-100 enhances the effectiveness of drugs against MDR cancer cells, presenting a promising strategy to overcome drug resistance in glioblastoma and NSCLCs through P-gp modulation.

Photobiomodulation mitigates doxorubicin resistance in MDA-MB-231 breast cancer cells: a promising avenue for overcoming chemoresistance.

One of the formidable challenges that may emerge in patients with breast cancer is drug resistance which is highly correlated with failure in cancer therapy and, as a result, poorer prognosis. Thus, developing novel approaches to overcome this undesirable event has always been a hot topic in the field of cancer. Photobiomodulation (PBM), also known as low-level laser therapy, is one such approach that has recently been introduced as a promising modality in clinical settings with interesting anti-tumor properties. Moreover, PBM has been considered a possible candidate to be employed in conjunction with conventional modalities such as chemotherapy. The present study investigated the potential effects of PBM at two wavelengths of 630nm and 980nm on chemoresistance in breast cancer MDA-MB-231 cells, which previously acquired resistance to doxorubicin (DOX) through 12 passages. Findings proposed that PBM, in conjunction with DOX, led to a reduction in the viability of resistant MDA-MB 231 cells as was evidenced by decreased IC50 values of DOX across different groups. Furthermore, gene expression studies demonstrated that PBM inhibited the overexpression of some of the important resistance-related genes, including SOX9, MDR1, NRF2, TGF-β, and ABCC1. Although both wavelengths had considerable efficiency, at 630nm, PBM performed better in overcoming DOX resistance. Overall, the present study suggests that PBM might play a promising role against breast cancer via reducing chemoresistance which, indeed, necessitates further research to better understand its mechanisms and clinical potential for translation.

A nano drug delivery system loading drugs and chlorin e6 separately to achieve photodynamic-chemo combination therapy.

To develop a new drug delivery system (DDS) that can load chemotherapy agents and photosensitizer chlorin e6 (Ce6) onto the pores and surfaces of mesoporous silica nanoparticle (MSN) separately. Doxorubicin (DOX) was loaded into the pores of MSNs. Then, polyethyleneimine (PEI) was used to coat the surface of MSN to protect DOX, and then manganese dioxide (MnO2) nanoparticles were loaded through adding potassium permanganate (KMnO4) to bind with Ce6. Finally, polydopamine (PDA) was coated and coupled with hyaluronic acid (HA). The synthesized versatile nanoparticle was pH-sensitive and exhibited positive photodynamic therapy (PDT) performance. Besides, it could be observed that the nanoparticles were efficiently taken up by tumor cells through confocal laser scanning microscopy (CLSM) and flow cytometry. Additionally, in vitro experiments suggested that the nanoparticles had pleasing toxicity to various tumor cells and equally positive therapeutic effect when curcumin replaced DOX. Our work suggests that the nanoparticles designed by our strategy have satisfactory combination therapy performance and can enable more chemotherapy drugs to be used in photodynamic-chemo combination therapy.

Targeting Methionine Addiction of Osteosarcoma with Methionine Restriction to Overcome Drug Resistance: A New Paradigm for a Recalcitrant Disease

Chemotherapy resistance in osteosarcoma results in a very poor patient prognosis, with the 5-year survival rate of approximately 20%, which not improved for over three decades; thus, the development of novel therapeutic strategies is required. Methionine addiction is a fundamental and general hallmark of cancer, termed the Hoffman effect. Cancer cells need larger amounts of exogenous methionine in order to grow compared to normal cells, despite their ability to synthesize normal or greater amounts of methionine from homocysteine, due to increased transmethylation reactions in cancer cells. Methionine restriction therapy, including recombinant methioninase (rMETase), arrests cancer cells in the late-S/G2 phase of the cell cycle by targeting methionine addiction. First-line chemotherapy for osteosarcoma, including methotrexate (MTX), doxorubicin (DOX), and cisplatinum (CDDP), targets cells in the S/G2-phase, where cancer cells are also inhibited by methionine restriction, resulting in the synergy of methionine restriction to overcome drug resistance. In the present review, we describe the synergistic efficacy of conventional chemotherapy and methionine restriction therapy, including rMETase, in overcoming the drug resistance of osteosarcoma. The clinical potential of this new paradigm to overcome the drug resistance of osteosarcoma is discussed.

In Vitro Potentiation of Doxorubicin Cytotoxicity Utilizing Clarithromycin Loaded-PEGylated Liposomes.

Doxorubicin (DOX) is a potent chemotherapeutic agent for breast cancer, but its effectiveness is often diminished by resistance mechanisms, particularly through p-glycoprotein (P-gp) mediated drug efflux. Clarithromycin (CAM), a macrolide antibiotic, inhibits multiple metabolic pathways including CYP3A and P-gp, potentially countering DOX resistance. This study aimed to evaluate the potentiation of DOX and its effectiveness against the MCF-7 breast cancer cell line by encapsulating both DOX and CAM in PEGylated liposomes. PEGylated liposomes containing DOX and CAM were prepared using the thin film hydration method. The physicochemical properties of the liposomes, including average particle size, polydispersity index (PDI), and zeta potential, were characterized. Encapsulation efficiencies for CAM and DOX were assessed, and stability of the liposomes was evaluated over 9 days at room temperature. Cell viability was measured using an IC50 assay, and P-gp expression levels were determined by ELISA. The CAM/DOX-PEGylated liposomes exhibited optimal average particle size (238 ± 26.7 nm), PDI (0.29 ± 0.107), and zeta potential (-20.9 ± 2.17 mV). These liposomes maintained good stability regarding size and charge over 9 days. Encapsulation efficiencies were 81.05% for CAM and 78.13% for DOX. The IC50 value for CAM/DOX-PEGylated liposomes was 0.13 µM, representing a significant reduction compared to the physical mixture of CAM and DOX (0.25 µM) and free DOX (0.21 µM) against MCF-7 cells. ELISA analysis showed a reduction in P-gp expression of approximately 5% with CAM/DOX-PEGylated liposomes compared to 1.61% with free DOX. The results indicate that CAM encapsulated in PEGylated liposomes enhances the effectiveness of DOX against breast cancer cells, likely through the inhibition of p-glycoprotein. This approach may offer a promising strategy to overcome DOX resistance and improve chemotherapy outcomes.

Cardioprotective Potential of Moringa Oleifera Leaf Extract Loaded Niosomes Nanoparticles - Against Doxorubicin Toxicity In Rats.

Doxorubicin (DOX) is one of the most potent anticancer drugs that has ubiquitous usage in oncology; however, its marked adverse effects, such as cardiotoxicity, are still a major clinical issue. Plant extracts have shown cardioprotective effects and reduced the risk of cardiovascular diseases. The current study is intended to explore the cardioprotective effect of ethanolic Moringa oleifera extracts (MOE) leaves loaded into niosomes (MOE-NIO) against DOXinduced cardiotoxicity in rats. MOE niosomes nanoparticles (NIO-NPs) were prepared and characterized by TEM. Seventy male Wistar rats were randomly divided into seven groups: control, NIO, DOX, DOX+MOE, DOX+MOE-NIO, MOE+DOX, and MOE-NIO+DOX. DOX (4 mg/kg, IP) was injected once per week for 4 weeks with daily administration of MOE or MOENIO (250 mg/kg, PO) for 4 weeks; in the sixth and seventh groups, MOE or MOE-NIO (250 mg/kg, PO) was administered one week before DOX injection. Various parameters were assessed in serum and cardiac tissue. Pre and co-treatment with MOE-NIO have mitigated the cardiotoxicity induced by DOX as indicated by serum aspartate aminotransferase (AST), creatine kinase - MB(CK-MB) and lactate dehydrogenase (LDH), cardiac Troponin 1(cTn1) and lipid profile. MOE-NIO also alleviated lipid peroxidation (MDA), nitrosative status (NO), and inflammatory markers levels; myeloperoxidase (MPO) and tumor necrosis factor-alpha (TNF-α) obtained in DOX-treated animals. Additionally, ameliorated effects have been recorded in glutathione content and superoxide dismutase activity. MOE-NIO effectively neutralized the DOXupregulated nuclear factor kappa B (NF-kB) and p38 mitogen-activated protein kinases (p38 MAPK), and DOX-downregulated nuclear factor-erythroid 2-related factor 2 (Nrf2) expressions in the heart. It is concluded that pre and co-treatment with MOE-NIO could protect the heart against DOX-induced cardiotoxicity by suppressing numerous pathways including oxidative stress, inflammation, and apoptosis and by the elevation of tissue antioxidant status. Thus, it may be reasonable to suggest that pre and co-treatment with MOE-NIO can provide a potential cardioprotective effect when doxorubicin is used in the management of carcinoma.

Therapeutic Effects of Crocin Nanoparticles Alone or in Combination with Doxorubicin against Hepatocellular Carcinoma In vitro.

Crocin (CRO), the primary antioxidant in saffron, is known for its anticancer properties. However, its effectiveness in topical therapy is limited due to low bioavailability, poor absorption, and low physicochemical stability. This study aimed to prepare crocin nanoparticles (CRO-NPs) to enhance their pharmaceutical efficacy and evaluate the synergistic effects of Cro-NPs with doxorubicin (DOX) chemotherapy on two cell lines: human hepatocellular carcinoma cells (HepG2) and non-cancerous cells (WI38). CRO-NPs were prepared using the emulsion diffusion technique and characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), Zeta potential, and Fourier transform infrared spectroscopy (FT-IR). Cell proliferation inhibition was assessed using the MTT assay for DOX, CRO, CRO-NPs, and DOX+CRO-NPs. Apoptosis and cell cycle were evaluated by flow cytometry, and changes in the expression of apoptotic gene (P53) and autophagic genes (ATG5 & LC3) were analyzed using real-time polymerase chain reaction. TEM and SEM revealed that CRO-NPs exhibited a relatively spherical shape with an average size of 9.3 nm, and zeta potential analysis indicated better stability of CRO-NPs compared to native CRO. Significantly higher antitumor effects of CRO-NPs were observed against HepG2 cells (IC50 = 1.1 mg/ml and 0.57 mg/ml) compared to native CRO (IC50 = 6.1 mg/ml and 3.2 mg/ml) after 24 and 48 hours, respectively. Annexin-V assay on HepG2 cells indicated increased apoptotic rates across all treatments, with the highest percentage observed in CRO-NPs, accompanied by cell cycle arrest at the G2/M phase. Furthermore, gene expression analysis showed upregulation of P53, ATG5, and LC3 genes in DOX/CRO-NPs co-treatment compared to individual treatments. In contrast, WI38 cells exhibited greater sensitivity to DOX toxicity but showed no adverse response to CRONPs. Although more in vivo studies in animal models are required to corroborate these results, our findings suggest that CRO-NPs can be a potential new anticancer agent for hepatocellular carcinoma. Moreover, they have a synergistic effect with DOX against HepG2 cells and mitigate the toxicity of DOX on normal WI38 cells.

Curcumin chemo-sensitizes intrinsic apoptosis through ROS-mediated mitochondrial hyperpolarization and DNA damage in breast cancer cells.

Curcumin (CUR), a polyphenol phyto-compound extracted from turmeric rhizome (Curcuma longa), suppresses cancer by inducing apoptosis while also limiting cell survival and proliferation. This in vitro and in silico research work focuses on the synergistic sensitization of Doxorubicin (DOXO) on regulating ROS-mediated apoptosis of the breast cancer cells (MDA-MB-231 and MCF-7) in DOXO-CUR co-treatment. We observed dose-dependent cytotoxicity, increased ROS production, and mtDNA fragmentation by reduced membrane potential. The combined molecular docking of Bcl2, Bax, and Caspase3 proteins with DOXO and CUR with lower binding energies proves the stable interactions of protein-ligand complexes in the combination doses. Cell survival was measured by MTT and flow cytometry assays. Mitochondrial ROS production, mtDNA condensation, and MMP depletion were documented using fluorescence micrographs. The enrichment analysis of the ROS pathway genes by RT-qPCR (relative fold change) indicates the activation of Caspase3-mediated intrinsic apoptosis. Autodock 4.2 and Gromac 2022.4 were performed for in silico binding interaction and stability analysis. Our study calculates the DOXO and CUR combination (0.33 + 33 μM in MDA-MB-231 and 0.14 + 14 μM in MCF-7) shows maximum growth inhibition (70-75 %) by elevated oxidative stress and reduced membrane potential, which suggests that CUR could be a potential therapeutic agent for treating breast cancers in near future. The method of apoptosis was further analyzed, where elevated cellular ROS level by CUR + DOXO combination therapy depleted mitochondrial membrane potential and enhanced the DNA condensation. The mitochondrial pro-apoptotic genes BAX, BAK, BIM, CASPASE9, and CASPASE3 and anti-apoptotic BCL2 gene expressions depicted triggering intrinsic apoptosis pathway, co-relating with the in silico molecular docking, simulation, and MM-PBSA energy calculations. The synergism between CUR and DOXO was also validated by increased binding affinity and reduced inhibitory constant against key proteins Bcl2, Bax, and Caspase3. Bcl2-DOXO showed BE: -5.03 and Bcl2-DOXO-CUR showed BE: -4.7. Whereas, Bax-DOXO binding energy was -5.49 and Bax-DOXO-CUR binding was -3.83. The most preferable synergistic binding was found with Caspase3 protein, where Caspase3-DOXO docking energy was -1.63 but Caspase3-DOXO-CUR combined docking energy was -3.51. The stability of protein-ligand complexes was accessed with MD simulations and binding free energy calculations, Bcl2-CUR-DOXO combination complex showed ∆G: -25.62, Bax-DOXO-CUR complex showed the maximum ∆G: -34.18, with Caspase-CUR-DOXO complex (∆G: -15.18), indicating the proteins most stable conformation while interacting with CUR + DOXO combination. The correlation between the in vitro and in silico analysis of apoptosis pathway components widens the further research scope for proteomics and organoid studies, which might be worthy for successful clinical trials.

Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity and the underlying mechanism

BackgroundFerroptosis is a key process in doxorubicin (DOX)-induced cardiotoxicity and is a potentially important therapeutic target. Thymoquinone (TQ) is a monoterpenoid compound isolated from black cumin extract that exhibits antitumor effects and acts as a powerful mitochondrial-targeted antioxidant. In this study, we investigated the effect of TQ on DOX-induced cardiotoxicity and the potential underlying mechanisms. Methods and resultsMice were randomly assigned to the control (CON) group, DOX (20 mg/kg) group, TQ10 (10 mg/kg/d) group, and TQ20 (20 mg/kg/d) group and intraperitoneally injected with DOX and different doses of TQ. The electrocardiogram, blood pressure, and cardiac ultrasound changes during the experiments showed that TQ exerted a protective effect against DOX-induced cardiotoxicity. The glutathione (GSH), malondialdehyde (MDA), and total antioxidant capacity (T-AOC) levels in the mouse heart tissue were significantly different from those in the CON group. Western blot analysis revealed that the expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) in the DOX group was lower than that in the control group. TQ treatment decreased these changes, indicating that TQ alleviated DOX-induced cardiotoxicity and increased the antioxidant capacity of murine cardiomyocytes. The mechanism might involve activating the Nrf2/HO-1 signaling pathway and reducing iron-mediated death. Immunohistochemical staining revealed similar effects on the expression levels of NQO1, COX-2, and NOX4. Moreover, transmission electron microscopy indicated that TQ protected murine cardiomyocytes against DOX-induced mitochondrial damage. ConclusionThe results of this study suggested that TQ can decrease oxidative stress levels and DOX-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway to alleviate ferroptosis in murine cardiomyocytes.

Radiopaque hydrogel-in-liposomes towards theranostic applications for malignant tumors.

A radiopaque hydrogel-in-liposome (RHL) system was developed for micro-computed tomography (μCT) imaging of tumor tissue and simultaneous delivery of a cytotoxic agent. Iopamidol (IPD) and doxorubicin (DOX) were incorporated as the CT contrast and anti-cancer agents, respectively. The presence of a polyethylene glycol hydrogel core in the liposomes was confirmed via attenuated total reflectance Fourier transform infrared, proton nuclear magnetic resonance, and selective solvent extraction. Nano-sized (∼160 nm) spherical DOX/IPD-loaded RHLs with a narrow size distribution and negative zeta potential were successfully fabricated. The RHLs demonstrated enhanced cellular uptake of DOX in SCCVII cells compared to conventional radiopaque liposomes, likely due to clathrin-mediated endocytosis. Additionally, pH-dependent DOX release and reduced IPD leakage were observed. In vivo studies using SCCVII tumor-xenografted mice showed that RHLs exhibited improved CT contrast efficiency and anti-tumor efficacy, along with systemic biocompatibility, attributed to enhanced tumor-targeting properties. These findings suggest that the RHL system could serve as a promising nano-platform for tumor theranostics.

Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids

Human cardiac organoids closely replicate the architecture and function of the human heart, offering a potential accurate platform for studying cellular and molecular features of aging cardiomyopathy. Senolytics have shown potential in addressing age-related pathologies but their potential to reverse aging-related human cardiomyopathy remains largely unexplored. We employed human iPSC-derived cardiac organoids (hCOs/hCardioids) to model doxorubicin(DOXO)-induced cardiomyopathy in an aged context. hCardioids were treated with DOXO and subsequently with a combination of two senolytics: dasatinib (D) and quercetin (Q). DOXO-treated hCardioids exhibited significantly increased oxidative stress, DNA damage (pH2AX), cellular senescence (p16INK4A) and decreased cell proliferation associated with a senescence-associated secretory phenotype (SASP). DOXO-treated hCardioids were considerably deprived of cardiac progenitors and displayed reduced cardiomyocyte proliferation as well as contractility. These distinctive aging-associated characteristics were confirmed by global RNA-sequencing analysis. Treatment with D+Q reversed these effects, reducing oxidative stress and senescence markers, alleviating SASP, and restoring hCardioids viability and function. Additionally, senolytics replenished cardiac progenitors and reversed the cardiomyocyte proliferation deficit. Doxorubicin triggers an age-associated phenotype in hCardioids reliably modelling the main cellular and molecular features of aging cardiomyopathy. Senescence is a key mechanism of the aged-hCOs phenotype as senolytics rejuvenated aged-hCardioids restoring their structure and function while reverting the age-associated regenerative deficit.

Managing Doxorubicin Cardiotoxicity: Insights Into Molecular Mechanisms and Protective Strategies.

Cancer ranks as the second leading cause of death in the United States and poses a significant health challenge globally. Numerous therapeutic options exist for treating cancer, with chemotherapy being one of the most prominent. Chemotherapy involves the use of antineoplastic drugs, either alone or in combination with other medications, to target and kill cancer cells. However, these drugs can also adversely affect healthy cells, leading to various side effects. Among the most commonly used chemotherapy agents are anthracyclines, which include doxorubicin, daunorubicin, and epirubicin. Doxorubicin is particularly notable for its effectiveness but is also associated with significant cardiotoxicity, a common concern for patients undergoing chemotherapy. Unfortunately, there is currently no definitive treatment to prevent or reverse this cardiotoxicity. The cardiac effects of doxorubicin can manifest in several ways, including changes in electrocardiograms, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, heart failure, and congestive heart failure. These complications may arise during treatment, shortly after it concludes, or even weeks later. Various mechanisms have been proposed to explain doxorubicin-induced cardiotoxicity. Key factors include the inhibition of topoisomerase IIβ, mitochondrial damage, reactive oxygen species (ROS) production due to iron metabolism, increased oxidative stress, heightened inflammatory responses, and elevated rates of apoptosis and necrosis within cardiac tissue. This review article will provide a comprehensive overview of the current state of knowledge regarding doxorubicin-induced cardiomyopathy. We will explore the underlying molecular mechanisms contributing to this condition and discuss emerging therapeutic strategies aimed at mitigating its impact on cancer survivors.

A human skin-on-a-chip platform for microneedling-driven skin cancer treatment.

Skin-on-a-chip models provide physiologically relevant platforms for studying diseases and drug evaluation, replicating the native skin structures and functions more accurately than traditional 2D or simple 3D cultures. However, challenges remain in creating models suitable for microneedling applications and monitoring, as well as developing skin cancer models for analysis and targeted therapy. Here, we developed a human skin/skin cancer-on-a-chip platform within a microfluidic device using bioprinting/bioengineering techniques. The fabricated skin models include vascular, dermal, and epidermal layers, demonstrating increased functionalities and maturation of dermal (Collagen I & Fibronectin for 7 days) as well as epidermal (Filaggrin & Keratin 10, 14, and 19at the air-liquid interface (ALI) for 21 days) layers. Histological analysis confirmed the formation of a differentiated epidermis and ridges at the dermal-epidermal junction in our model, closely resembling native skin tissue. Melanoma cells were embedded approximately 400μm beneath the epidermis to simulate tumor invasion into the dermis. The platform was further used to test doxorubicin (DOX)-loaded gelatin methacryloyl (GelMA) microneedles (MNs) for localized transdermal drug delivery targeting melanoma. The DOX-loaded MNs penetrated uniformly to a depth of approximately 600μm, effectively reaching the melanoma cells. Drug delivery via MNs demonstrated significantly higher efficiency than diffusion through media flow, confirming the practicality and robustness of the proposed model for future therapeutic applications.

Chitosan-based thermosensitive injectable hydrogel with hemostatic and antibacterial activity for preventing breast cancer postoperative recurrence and metastasis via chemo-photothermal therapy.

Primary resection surgery is a conventional approach in breast cancer treatment, which plays a pivotal role in the prevention of recurrence and metastasis. In this study, an injectable hydrogel comprising chitosan (CS), β-glycerophosphate (β-GP), and dopamine (DA) with near-infrared (NIR) photothermal attributes was developed. The composite hydrogels integrate doxorubicin (DOX), termed DCGD, and can be used for chemotherapy, synergistic photothermal therapy, anti-bacterial and hemostasis. Local administration of injectable DCGD hydrogels into breast cancer resection cavities could prevent the postoperative breast cancer recurrence and metastasis via chemo-photothermal therapy. Additionally, the remarkable hemostatic and anti-bacterial properties of DCGD facilitated postoperative wound healing. Notably, the DCGD hydrogel had a dual pH- and photothermal-responsive DOX release profile, ensuring sustained drug release to residual tumor tissues triggered by NIR laser irradiation and the acidic tumor microenvironment. Histological analyses including H&E, TUNEL, and Ki67 immunohistochemistry confirmed the potent anti-recurrent and anti-metastatic efficacy of DCGD hydrogels. Therefore, the DCDG hydrogels developed in our study had the favorable hemostatic, anti-bacterial, photothermal and drug-loading effects, which provided a new strategy for postoperative breast cancer recurrence and metastasis treatment.

Multifunctional drug delivery nanoparticles for combined chemotherapy/chemodynamic/photothermal therapy against colorectal cancer through synergistic cuproptosis/ferroptosis/apoptosis.

The use of combination therapies that employ a variety of cell death mechanisms has emerged as a promising avenue of research in the treatment of cancer. However, the optimization of therapeutic synergies when integrating different modes remains a significant challenge. To this end, we developed a multifunctional intelligent drug-carrying nanoparticle (DFMTCH NPs) based on the metal-organic framework MIL-100, loaded with doxorubicin (DOX) and disulfiram (DSF), coated with a Cu-tannic acid (Cu-TA) network and hyaluronic acid (HA), for the purpose of combined chemotherapy/chemodynamic/photothermal anti-cancer therapy. On the one hand, the DFMTCH NPs exhibited a range of therapeutic capabilities, including chemotherapy, photothermal therapy (PTT), and chemodynamic therapy (CDT), which collectively enhanced the anti-tumor efficacy of chemotherapeutic agents. In addition, DFMTCH NPs proved sensitive photoacoustic imaging (PAI) in image-guided therapy. On the other hand, DFMTCH NPs could produce reactive oxygen species (ROS) and consume glutathione (GSH) by amplifying cellular oxidative stress, while causing intracellular mitochondrial dysfunction, inducing effective cuproptosis/ferroptosis/apoptosis to inhibit tumor growth. Collectively, this work provided an innovative strategy for designing multifunctional nanoparticles for effective combination therapies to combat colorectal cancer (CRC).

Explorations of novel MDR-related hub genes and the potential roles TRIM9 played in drug-resistant hepatocellular carcinoma.

Current chemotherapeutic efficacy is limited by the rapid development of multidrug resistance (MDR) in hepatocellular carcinoma (HCC). In this study, 66 MDR-related hub genes in drug-resistant HCC were identified through combined analysis of differential expressed genes (DEGs), gene functional enrichment, Cox proportional regression, weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network construction. A prognostic risk model was established through the LASSO-Cox regression analysis. Based on the comparison of gene mutation frequency, tumor mutation burden (TMB) and immune infiltration in high- and low-risk groups, we explored the relationships between the MDR-related hub genes and immune regulation. The competitive endogenous RNA (ceRNA) network and associated non-coding RNAs (ncRNAs) were predicted to investigate the potential mechanisms. Five MDR-related hub genes in drug-resistant HCC were finally confirmed, namely ABCB6, FLNC, MCC, NAV3 and TRIM9. TRIM9 was identified as the most significant gene enhancing MDR. Inhibiting TRIM9 caused a decrease in the IC50 of doxorubicin (DOX), and significant increases in the intracellular uptake, retention and absorption of DOX in HepG2/ADR cells. These findings may provide new insights into the mechanism of MDR development. The MDR-related hub genes, especially TRIM9 may be targeted therapeutically to enhance the prognosis of patients with drug-resistant HCC.

Hyaluronic acid-functionalized nanoparticles enable enhanced chemo/chemodynamic therapy for the targeted treatment of colon cancer.

Colon cancer (CC) is the third most common cancer globally and one of the leading causes of death. Therefore, there is an urgent need to develop an efficient and low-toxicity CC treatment regimen. The combination of chemotherapy (CT) and chemodynamic therapy (CDT) has great potential in cancer treatment. In this work, an amphiphilic molecule, HA-Fc-PEG-SS-CPT, containing ferrocene and camptothecin (CPT) was designed and synthesized. HA-Fc-PEG-SS-CPT was self-assembled and loaded with doxorubicin (DOX) to prepare a nanoparticle (HCF@DOX) with active targeting, GSH consumption, controlled drug release, and induction of reactive oxygen species (ROS) burst to achieve CT/CDT anti-CC. The results of in vitro and in vivo studies demonstrated that the particle size and morphology of HCF@DOX are suitable for passive targeting effects. HCF@DOX was found to have excellent stability, antitumor activity and biosafety. In addition, HCF@DOX achieved CT/CDT anti-CC by inhibiting tumour cell proliferation through ferroptosis and apoptosis. In summary, this study provides an interesting strategy for nanoparticles based on CT/CDT to enhance anti-CC efficacy. This research may pave the way for the development of innovative and transformative treatments for CC.