Reactive oxygen species (ROS) play a dual role in cancer biology, contributing to both tumor progression and therapeutic responses. Many chemotherapeutic agents exert their cytotoxic effects through ROS generation, although the extent and biological relevance of this process remain influenced by cellular context, including the functional status of tumor suppressor genes such as TP53. In this study, we investigated the induction of genomic damage and oxidative stress in two isogenic human colorectal cancer cell lines-HCT116TP53+/+ and HCT116TP53-/--after exposure to four commonly used anticancer agents: oxaliplatin (OXA), irinotecan (IRI), paclitaxel (PAC), and 5-fluorouracil (5-FU). Drug concentrations were selected to ensure cell viability while inducing genotoxicity. Genome damage was assessed by micronucleus (MN) assay. ROS production was measured using the BODIPY581/591 C11 lipid peroxidation fluorescent probe. Our results showed that OXA and IRI induced both significant MN formation and robust ROS production in a dose-dependent manner, while PAC predominantly triggered genomic damage with limited ROS generation. Conversely, 5-FU exhibited marginal (or no) effect on both endpoints. Notably, with regard to the extent of ROS accumulation and MN induction, no significant differences were detected under the tested conditions between the two HCT116 cell lines. This suggests that under non-cytotoxic conditions, p53 is not a critical modulator of oxidative responses to these agents. Overall, our data reveal a drug-specific pattern of genome and oxidative damage in HCT116 colorectal cancer cells, emphasizing the importance of considering drug mechanism of action in evaluating redox responses. These insights may contribute to the development of targeted combinatorial therapies aimed at modulating oxidative stress, especially in TP53-mutated tumors.

To prepare all-trans retinoic acid (ATRA) and irinotecan (IRI) co‑loaded liposomes (ATRA-IRI@Lip) and evaluate their in vitro therapeutic effects against anaplastic thyroid carcinoma (ATC) and their ability to eliminate cancer stem cells (CSCs). ATRA-IRI@Lip was obtained through the co-encapsulation of ATRA and IRI within liposomes, using the thin-film hydration method. The particle size, Zeta potential, encapsulation efficiency, and in vitro release profiles of ATRA-IRI@Lip were characterized. Hemolysis assay was conducted to evaluate blood compatibility. Cellular uptake of FITC-labeled liposomes was assessed. The in vitro anti-ATC effects were evaluated by cell counting kit-8 (CCK‑8), Calcein‑AM/PI staining, and Transwell assays. The synergistic effect of ATRA and IRI was analyzed using the combination index, while flow cytometry was performed to detect the proportions of aldehyde dehydrogenase-positive cells and CD133-positive cells. The prepared ATRA-IRI@Lip had an average particle size of (210.3±5.2) nm, a polydispersity index of 0.254, and an average surface potential of －(13.7±2.3) mV. The encapsulation efficiencies of ATRA and IRI were (88.1±2.9)% and (86.8±1.6)%, respectively. In vitro release studies showed that ATRA-IRI@Lip significantly delayed the release of both ATRA and IRI, with 48-h cumulative release rates of (66.2±3.6)% and (77.7±4.1)%, respectively. Hemolysis assays demonstrated that all tested concentrations of ATRA-IRI@Lip exhibited hemolysis rates below 3%, indicating good hemocompatibility. CCK-8 and Calcein-AM/PI staining demonstrated that ATRA-IRI@Lip significantly inhibited the viability of ATC cells and promoted cell death, with an IC50 significantly lower than that of the free IRI group and the free ATRA+IRI group (both P<0.01). Combination index analysis demonstrated that both the free ATRA+IRI group and the ATRA-IRI@Lip group exhibited synergistic effects (combination index <1), with stronger synergism observed in the ATRA-IRI@Lip group. Flow cytometry results showed that ATRA-IRI@Lip significantly decreased the proportions of aldehyde dehydrogenase-positive cells and CD133-positive cells (both P<0.01). ATRA-IRI@Lip was successfully prepared, achieving synergistic effects of differentiation therapy and chemotherapy of ATRA and IRI, thereby effectively eliminating ATC cells and CSCs.

An open-label, two-cohort, phase 1a/b study of weekly irinotecan hydrochloride liposome injection combined with vincristine and temozolomide (NALIRI-VT) in patients with advanced Ewing sarcoma.

Irinotecan (IRI), a clinically used anticancer drug, is effective against various solid tumors, including colorectal cancer, but its use is limited by side effects. Triptolide (TP), an alkaloid from Tripterygium wilfordii, has been used to treat malignancies in China, though its combined effects with IRI on colon cancer cells are not well-documented. In vitro, human colon cancer HT-29 cells were treated with IRI, TP, or both combinations. Results showed that the combination of IRI and TP significantly decreased viable cell numbers more than IRI or TP alone. IRI combined with TP also led to higher Bax and lower Bcl-2 levels, as well as increased cleaved caspase-8, -9, and -3. These findings suggest that TP enhances apoptosis in HT-29 cells and may potentiate the anticancer effects of IRI by disrupting the balance of pro- and anti-apoptotic proteins, which plays a crucial role in controlling tumor cell survival. In vivo, HT-29 cell-xenograft nude mice were treated with IRI, TP, or both combinations for 30 days. Tumor volume and body weight were measured every 2 days, and liver and kidney functions (ALT, AST, CREA, GGT) were assessed. H&E staining of tissues revealed no significant toxicity in the heart, lungs, liver, kidneys, spleen, or small intestine, suggesting that the combination therapy does not induce major organ damage. Immunohistochemical (IHC) analysis showed that IRI combined with TP resulted in higher expression of cleaved-caspase-3, -8, and -9 compared to IRI or TP alone, indicating enhanced tumor cell apoptosis. These results suggest that TP enhances IRI’s anti-cancer effects by promoting apoptosis in colon cancer cells. TP may thus serve as a potential enhancer for IRI in future colon cancer treatments, offering a novel strategy to improve therapeutic outcomes, enhance drug efficacy, and minimize side effects.

Liposomal irinotecan (nal-IRI) and conventional irinotecan (IRI) represent two formulations with distinct pharmacokinetic properties, yet their comparative safety profiles remain incompletely characterized. This study aimed to systematically evaluate their adverse event (AE) patterns through integrated pharmacovigilance and clinical analyses. We conducted a dual-approach investigation combining: (1) a single-center retrospective study of 308 pancreatic cancer patients (nal-IRI = 131; IRI = 177) treated between December 2023-September 2024, and (2) disproportionality analysis of FAERS database reports (2004-2024) using reporting odds ratios (RORs) and proportional reporting ratios (PRRs). The retrospective study demonstrated significantly higher incidence of grade 3-4 leukopenia with nal-IRI (9.16% vs. 3.39%, p < 0.05) and earlier onset of hematologic/hepatic toxicities (median time difference: 20-30days, p < 0.05). No significant differences were observed in non-hematologic toxicities between groups. FAERS analysis revealed distinct AE patterns: nal-IRI reports were predominantly associated with fatal outcomes (43.76%) and cholangitis (PRR = 996.70) in pancreatic cancer patients, while IRI showed conventional chemotherapy toxicities in colorectal cancer patients. These findings suggest that nal-IRI and IRI exhibit distinct safety profiles, which are partly attributable to differences in their liposomal pharmacokinetics, but also reflect the underlying disease characteristics and prognostic profiles of their respective patient populations. These findings emphasize the need for enhanced monitoring during initial nal-IRI treatment cycles and suggest differential safety management strategies for the two formulations. Future multicenter studies with pharmacokinetic assessments are warranted to further elucidate these differences.

Overcoming drug resistance in pancreatic ductal adenocarcinoma (PDAC) remains a major challenge due to dense fibrotic stroma, DNA repair-mediated resistance, drug efflux mechanisms, and an immunosuppressive tumor microenvironment (TME). Here, we use photoactivatable multi-inhibitor liposomes (PMILs) as a clinically translatable strategy to immunomodulate and enhance PDAC treatment using FDA-approved agents: minocycline for tumor priming by downregulating Tdp1, benzoporphyrin derivative incorporated into the liposomal bilayer for photodynamic priming (PDP) of the microenvironment, and irinotecan (IRI) for cytotoxicity. PMILs enable light-triggered PDP followed by IRI release. The reduced Tdp1 combined with PDP and IRI acts synergistically to enhance antitumor activity. In an orthotopic PDAC mouse model, dual priming significantly increased intratumoral IRI accumulation while downregulating Tdp1 and ABCG2, two key mediators of IRI resistance. These effects were augmented by immune activation, including increased CD8+T-cell infiltration, reduced regulatory T cells, and M2-like macrophage population. This combination achieved sustained local tumor regression, abscopal effects in untreated distant tumors, and a significant improvement in long-term survival (63%). By integrating clinically approved agents with non-overlapping mechanisms within a light-activated delivery platform, this approach enhances IRI efficacy, reprograms the TME, and promotes antitumor immunity, offering a translatable strategy to sensitize PDAC to chemo- and immunotherapy.

The traditional chemotherapy has weaknesses on non-specific biodistribution, severe systemic toxicity, and optimum tumor accumulation. In a bid to overcome these obstacles, the present research was aimed at developing and in vitro assessing PEGylated liposomes as a core system to target cancer therapy, where Irinotecan hydrochloride, a prototype chemotherapeutic agent, was used in the study. The liposomes were prepared successfully through the thin-film hydration and sonication technique using egg phosphatidylcholine, cholesterol and methylated polyethylene glycol (MPEG). The prepared vesicles had ideal nanoscale properties with a mean particle size of 152.3 ± 4.7 nm, polydispersity index of 0.18 ± 0.02, and zeta potential of -12.5 ±1.8 mV that are favorable to passive tumor targeting through Enhanced Permeability and Retention (EPR) effect. Efficiency of drug entrapment of 85.4 ± 2.1 percent was attained. The in vitro drug release studies indicated a sustained profile of up to 48 hours and stability studies showed that storage at 4degC was essential to the maintenance of integrity of formulation during a period of one month. A comparative cellular uptake study was modeled as a demonstration of active targeting using the HER2-positive (MCF-7/HER2+) and the HER2- negative (MDA-MB-231) breed cancer cell lines. The flow cytometry and confocal microscopy were performed to observe low and non-specific uptake of the non-targeted PEGylated liposomes in both cell lines, which demonstrates the property of stealthiness of the liposomes and the need to functionalize their surface. Finally, an Irinotecan liposomal nanocarrier characterized and stable was established. These findings support the platform as an emerging basis of future conjugation with any desired targeting ligand (e.g. anti-HER2 antibodies) to undergo receptor-mediated active targeting, which is a key step to improving therapeutic efficacy and specificity in oncology.

In this study, we aimed to compare metabolomic profiles, biodistribution, and detoxification patterns of the novel SN-38 derivative NMe with irinotecan (IR), and to identify NMe-specific metabolites to evaluate its preclinical pharmacokinetic advantages. In vivo ADME studies were conducted for NMe, a 9-aminomethyl SN-38 derivative, and IR following a single intraperitoneal dose of 40 mg/kg in mice. Additionally, ADMET properties were predicted using ADMETlab and SwissADME tools for comparison. Levels of NMe and irinotecan absorbed into plasma, distributed to tissues, and metabolized were monitored in liver, lung, spleen, kidney, and stool samples at 15, 30, and 60 min post-administration. Tissue extracts were analysed using high-performance liquid chromatography (HPLC), liquid chromatography-electrospray ionization quadrupole time-of-flight-tandem mass spectrometry (LC-ESI-QTOF-MS), and nuclear magnetic resonance (NMR) techniques after lyophilization and reconstitution. We compared the metabolomic profiles of irinotecan and NMe. We identified and confirmed NMe-specific metabolites, including 9-CH2-S-cysteine conjugate, 9-CH2OH, and NMe-formyl. Notably, novel irinotecan metabolites (IR-OH and IR-ΔE) were detected in small amounts in kidney samples. In some cases, two literature-known photodegradation products of irinotecan were present. NMe was found to quickly metabolize with different distribution to tissues, significantly greater to kidney and liver. Two SN-38 glucuronides, SN-38G(α) and SN-38G(β), were detected corresponding to α- and β-anomers. Where it was possible, NMe, IR and SN-38 were quantified using external calibration curves. In IR group, controlled and prolonged release of SN-38 was confirmed in all samples, yet SN-38G was observed in minority only in plasma, kidney, or lungs. In NMe groups, great relative amounts of SN-38 and SN-38G were detected. Greater content of SN-38G in NMe group than in irinotecan is expected to contribute to modulation and alleviation of some side effects in irinotecan-involved therapies, such as gastrointestinal toxicities (GIT). NMe shows a distinct metabolic profile characterized by rapid biotransformation, higher systemic glucuronidation of SN-38, and formation of unique metabolites, suggesting a potentially wider therapeutic window and reduced toxicity compared with IR.

Development and in vitro cytotoxic profiles of multistage systems containing irinotecan hydrochloride and bevacizumab for the treatment of human colorectal carcinoma.

Irinotecan (IRT) is a well-established anticancer drug that primarily targets topoisomerase 1. This study reveals a direct interaction between IRT and heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), which is a protein implicated in the progression of different kinds of cancers. The Quartz Crystal Microbalance (QCM) was applied to measure a binding affinity between IRT and hnRNPA2B1, resulting in an apparent binding constant KD_QCM of (15 ± 1) × 10-3, which is comparable to the apparent binding constant KD_QCM of (17 ± 2) × 10-3 for the reference ligand camptothecin. Further computational analysis via molecular docking and molecular dynamics (MD) simulations demonstrated stable binding of IRT to the RNA recognition domain (RRM) of hnRNPA2B1, yielding a binding free energy ΔG of -10.36 kcal·mol-1. These findings suggest that IRT may exert an inhibitory effect on hnRNPA2B1, potentially contributing to its anticancer activity beyond topoisomerase 1 inhibition.

Liposomal irinotecan(Nal-IRI) plays a crucial role as a nanomedicine in cancer treatment. Although it has clinically beneficial properties, Nal-IRI is accompanied by multiple adverse events (AEs) that require close observation. This pharmacovigilance study aimed to characterize and compare the safety profiles of liposomal irinotecan (Nal-IRI) and conventional irinotecan (IRI) using the FDA Adverse Event Reporting System (FAERS), focusing on identifying hidden risks of Nal-IRI in AEs. The data were extracted from the FAERS database (from Q1 2004 to Q3 2024). AE signals of Nal-IRI and IRI were mined by calculating reporting odds ratios (ROR), proportional reporting ratios (PRR), information component (IC) and empirical bayesian geometric mean (EBGM). A total of 90 Nal-IRI-positive PTs and 437 IRI-positive PTs were identified. Both exhibited stronger signals in gastrointestinal disorders and blood and lymphatic system disorders, and Nal-IRI also demonstrated stronger signals in the hepatobiliary disorders. We identified new specific AEs of Nal-IRI, cholangitis (ROR = 56.45), enterocolitis (ROR = 41.89), hematotoxicity (ROR = 18.47) and 302 off-label use reports. Meanwhile, Nal-IRI exhibited delayed toxicity, with a prolonged median AE onset time (35 days vs. 27 days for IRI) and fewer early reactions (≤7 days: 13.88% vs. 20.51% for IRI). Furthermore, Nal-IRI exhibited stronger signals in gastrointestinal disorders (e.g. vomiting, abdominal pain) in Asian populations, while European/American populations had stronger signals in hematological/hepatic adverse reactions (e.g. neutropenia, cholangitis). Nal-IRI demonstrates distinct safety challenges, including delayed toxicity, hepatobiliary risks, and population-specific vulnerabilities. These findings have revealed the unique risks associated with nanomedicine, underscoring the necessity extending pharmacovigilance.

Although the effect of thymoquinone (TQ), the biologically active component of black cumin seeds, has been investigated in many types of cancer, its effects on molecular pathways of cancer cells further need to be elucidated. This study aimed to investigate the effects of TQ on genotoxicity, oxidative stress, apoptosis, and inflammatory pathways in SW620 cells treated with irinotecan (IR), celecoxib (Clx), individually or both. DNA damage, oxidative stress/inflammatory response, cell cycle, apoptosis, and expression of carcinogenesis-related genes were determined using the Comet assay, ELISA assay, flow cytometry, and RT-PCR techniques, respectively. TQ (8 µM) combination with IR (8 µM) + Clx (4 µM) significantly increased cytotoxicity and genotoxicity of IR with/without Clx, while decreasing oxidative stress and inflammatory responses. TQ upregulated p21 and Bax, while downregulating Bcl-2 and Bcl-XL, increasing Bax/Bcl-2 ratio, which indicates an induction of apoptotic pathways. TQ also increased the percentage of cells in G2/M phase and decreased those in G0/G1 phase, thereby affecting cell cycle checkpoints in IR-treated cells with or without Clx. In conclusion, this study shows that the combination of TQ with IR, Clx, or both exerts significant effects on SW620 colon cancer cells, such that by enhancing DNA damage, TQ may induce G2/M cell cycle arrest and apoptosis, while reducing inflammatory responses, oxidative stress, and G0/G1 cell cycle arrest. These in vitro findings indicate that TQ may enhance the chemotherapeutic effects of IR and act as a potential adjuvant therapy; however, further in vivo studies are required to verify its suggested effects.

Transarterial chemoembolisation (TACE) is an important treatment method for solid tumors, such as liver cancer. Its main advantages are precise treatment and reduced trauma. However, limitations including inadequate drug loading, burst release and ectopic embolization still exist in clinical practice. In this study, we developed sodium alginate sulfate microspheres (AM) with multiple types of drug-loading groups and self-expanding behavior, achieving superior drug loading capacity and embolization stability. The framework material sodium alginate sulfate (SAS) contains various drug-loading groups, resulting in fast drug loading (30min, Doxorubicin hydrochloride), high loading capacity (68.0mg/g, Irinotecan hydrochloride), sustained release (>30days, Doxorubicin hydrochloride) and compatibility with multi-drug loading types (including gemcitabine hydrochloride and procaine hydrochloride). The fatty acid/sodium fatty acid buffer system formed at the aqueous-oil phase interface facilitated the formation of a gradient cross-linked structure, which conferred self-expansion behavior to the microspheres. In pig renal artery embolization (n=9), the AM stabilizes the embolized artery, resulting in tissue necrosis without vascular recanalization or ectopic embolization (**p=0.002 on 90days). Therefore, AM with high drug-loading capacity and self-expansion has great potential to enhance the safety and efficacy of TACE treatment.

The present study used an in-vivo inflammation-induced colorectal cancer (CRC) model to evaluate the additive effect of thapsigargin (TG) with the standard chemotherapy drug irinotecan (IRN). CRC was induced by AOM/DSS, and after 10th weeks, animals were treated with five weekly cycles of either IRN or TG or a combination of both drugs. All the animals were sacrificed after the 16th week, and the data were analysed. Coadministration of both IRN and TG substantially reduced both tumor numbers and occurrence of aberrant crypt foci (ACF) in the colon tissues as compared to only IRN/TG-treated animal groups. Further analyses revealed that IRN and TG together alleviated ultrastructural abnormalities of the colon with a recovered overall histoarchitecture, enhanced ER stress and mitochondrial dysfunction, reduction of PCNA positive cells indicating low rate of cellular proliferation, increased DNA fragmentation and apoptosis supported by higher intensity of γH2AX and cleaved caspase-3 immunohistochemistry. Gene expression analyses of key oncogenic biomarkers also suggest that the addition of TG with IRN is more effective in inhibiting carcinogenic transformation in the colon of AOM/DSS-treated mice. This study provides direct evidence of the superior therapeutic potential of a combination of both drugs compared to conventional monotherapy in the management of CRC.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-34567-2.

The cost-effectiveness of liposome irinotecan (II) (HR070803) in combination with 5-fluorouracil and leucovorin as a treatment for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma offering a potential new standard of care has not been established. Considering the high cost of liposome irinotecan (II), the aim of this study was to evaluate the economic value of liposome irinotecan (II) combined with 5-fluorouracil and leucovorin（5-FU/LV） versus placebo combined with 5-FU/LV for this indication from the perspective of the Chinese healthcare system. We developed a three-state Markov model based on the trial: NCT05074589 to estimate lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effect ratios (ICERs) in terms of cost per QALY gained. The utility of health status and the disutility of adverse events were obtained from the published literature. Costs were obtained from local hospitals and published literature. Costs and outcomes were discounted at a discount rate of 5% per year. To assess the robustness of the model, univariate and probabilistic sensitivity analysis was performed. In the base-case analysis, liposome irinotecan (II) regimen provided an additional 0.08 QALYs compared to the placebo regimen with an ICER of $310,418.81/ QALY gained, which indicates that the liposome irinotecan (II) regimen is not cost-effective at the $39,221.95/ QALY threshold. One-way sensitivity analyses showed that the model was most sensitive to the utility of PFS, the cost of liposome irinotecan (II), and the utility of PD. Probabilistic sensitivity analyses showed that the liposome irinotecan (II) regimen had a probability of 0 for having a cost effect at $39,221.95/ QALY. Price simulations show that the liposome irinotecan (II) option is cost-effective at a willingness-to-pay (WTP) of $39,221.95/QALY if the price of liposome irinotecan (II) is reduced to $2.93/mg (88.6% reduction). From the perspective of the Chinese healthcare system, liposome irinotecan (II) in combination with 5-FU/LV was less cost-effective than placebo in combination with 5-FU/LV for locally advanced or metastatic pancreatic ductal adenocarcinoma.

To overcome therapy resistance driven by breast cancer stem cells (BCSCs) and the systemic toxicity of conventional chemotherapy, we engineered a multi-stimuli-responsive nanoprodrug (DT/PAC@AI NPs) implementing a "chemo-differentiation-cancer stem cell inhibition" strategy. This system co-delivers irinotecan (IRI), all-trans retinoic acid (ATRA), and CPUL119 via (1) a hypoxia-responsive prodrug (PAC: PEG2k-Azo-CPUL119) and (2) a pH/esterase-responsive conjugate (AI: ATRA-IRI). The targeted NPs (90-130 nm), modified with DSPE-PEG2k-Try for LAT1-mediated uptake, demonstrated tumor microenvironment-triggered drug release: rapid PAC release under hypoxia and enhanced AI release at pH 5.0/esterase. In vitro, DT/PAC@AI NPs showed 20% higher cellular uptake and potent cytotoxicity against MDA-MB-231 cells (IC50 = 4.77 ± 0.32 µM vs. free drugs: IRI, 23.17 µM; CPUL119, 9.27 µM; ATRA > 50 µM), inducing 3.7-fold more apoptosis (32.6% vs. 8.7%). Critically, they reduced CD44+/CD24- BCSCs by 13.7% and inhibited tumor sphere formation by 87.6%. In vivo, they achieved optimal tumor suppression and BCSC elimination in xenografts with negligible systemic toxicity. This nanoprodrug platform offers straightforward synthesis, high drug-loading capacity, and potent dual-action efficacy against bulk tumor cells and BCSCs, presenting a promising advanced breast cancer therapy.

Study on anti-breast cancer effect of paclitaxel palmitate and irinotecan hydrochloride co-encapsulated liposomes

Poor tumor targeting, strong toxic side effects, and high drug resistance remain clinical challenges for conventional chemotherapy. Here, it is reported that drug‐cocktail core@shell nanocarriers are developed for the codelivery of lipophilic irinotecan (ITC) and the hydrophilic 5‐fluorouracil (5‐FU) metabolite (FdUMP), a commonly used combination in chemotherapy regimens for colorectal cancer. With a drug loading of 57% by mass, these nanocarriers achieve one of the highest reported drug payloads for a chemotherapeutic drug cocktail. Crucially, using a probe‐based imaging strategy with mechanistically responsive fluorescent reporters, we found that after slow uptake predominantly via macropinocytosis, the nanocarriers rapidly traffic to endolysosomal compartments, where the acidic environment triggers sustained drug release. In alignment with the slow uptake and trafficking behavior, these nanocarriers induce a delayed yet prolonged cytotoxic effect in colorectal cancer cells. These findings provide the first direct evidence linking slow uptake, intracellular trafficking, and progressive nuclear delivery of nanocarrier cargo to the delayed yet sustained cytotoxic response. Together, this work highlights both the therapeutic potential of these nanocarriers and the broad applicability of the probe‐based imaging approach to elucidate the mechanistic intracellular trafficking and nuclear delivery of different types of nanoparticles delivering cargoes beyond cancer chemotherapy in various cellular models.

This study aims to evaluate the cost-effectiveness of irinotecan hydrochloride liposome in combination with 5-fluorouracil and leucovorin (5-FU/LV) as a second-line treatment in locally advanced or metastatic pancreatic ductal adenocarcinoma, from the perspective of the healthcare system in China. A partitioned survival model was developed based on data from PAN-HEROIC-1 clinical trial (NCT05074589) and relevant literature. The simulation horizon was set at 5 years, with a cycle length of 2 weeks. Costs and utility values were discounted at an annual rate of 5%. Quality-adjusted life years (QALYs) served as the primary outcome measure, and the incremental cost-effectiveness ratio was calculated to compare irinotecan hydrochloride liposome plus chemotherapy regimen (experimental group) with the 5-FU/LV regimen (control group). One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the results. The results revealed that the ICER for the experimental group compared to the control group was ¥1,271,796.38/QALY, exceeding the willingness-to-pay (WTP) threshold of three times China's per capita gross domestic product (GDP) in 2023. One-way sensitivity analysis indicated that parameters such as utility value during progression-free survival, body surface area, the cost of irinotecan hydrochloride liposome and the utility value during disease progression significantly influenced the model outcomes. Probabilistic sensitivity analysis demonstrated that the probability of the irinotecan hydrochloride liposome being cost-effective was 0. When using three times per capita GDP of China in 2023 as the WTP threshold, the irinotecan hydrochloride liposome plus chemotherapy regimen is not considered cost-effective compared to the standard 5-FU/LV regimen.

Pediatric acute-myeloid-leukemia (pAML) is an aggressive malignancy and the second most common blood cancer in children. In spite of significant advances in the frontline therapeutic approaches, approximately 50% of pAML patients show poor prognosis and relapse. Though drugs show positive response against the cancer cells initially, however, it becomes resistant in the long run of treatment, requiring the use of alternative drugs. Therefore, this study aimed to discover pAML-causing druggable molecular signatures highlighting their pathogenetic processes and alternative therapeutic agents. To address these issues, at first, we performed an integrated single-cell RNA sequencing (scRNA-seq) profile analysis of two datasets with accession IDs GSE154109 and GSE235923, which revealed 6 pAML-related key cell types (Erythroid cells, GdT-cells, Naive B-cells, Naive CD4 T-cells, Non-Classical Monocytes, and T-regs) and 198 common differentially expressed genes (cDEGs) between pAML and healthy groups. The protein-protein interaction (PPI) analysis yielded top-ranked eight cDEGs (JUN, MDM2, FOS, SOD2, FBXW7, CHD3, MCL1, and MAP2K1) as common key genes (cKGs) across the key cell types. Disease-cKGs enrichment analysis further confirmed the relevance of these genes to pAML and other leukemic diseases. Regulatory network analysis identified top four transcription factors (FOXC1, GATA2, RELA, and TP53) and three microRNAs (hsa-let-7a-5p, hsa-let-7e-5p, hsa-miR-15a-5p) that regulate these cKGs. Gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results reflected their potential roles in pAML pathogenesis. Pathway perturbation analysis through gene-set enrichment analysis (GSEA) tool identified significantly perturbed pathways, highlighting how they are altered in pAML environment and how the cKGs are linked in the process. Subsequently, three potential therapeutic candidates (IRINOTECAN HYDROCHLORIDE, IMATINIB and IBRUTINIB) were disclosed through an integrative strategy combining molecular docking, drug-likeness, ADME/T, and DFT analyses. Molecular dynamics (MD) simulation studies for the top three drug-target complexes indicated the stability of complexes. Thus, the findings potentially offer valuable insights for pAML pathogenesis and effective therapeutic candidates for pAML patients.