Epirubicin Research Articles

Engineered VNP20009 expressing IL-15&15Rα augments anti-tumor immunity for bladder cancer treatment

Surgical resection combined with intravesical instillation of chemotherapeutics or Bacillus Calmette-Guerin (BCG) to remove residual cancer cells is the gold standard for the clinical treatment of patients with bladder cancer. In a recent clinical trial, a new super-agonist complex of IL-15 - N803, has shown promising results when used in combination with BCG to treat patients with bladder cancer who do not respond to BCG. Herein, we used temperature-controlled pBV220 plasmid encoding Interleukin-15 and its receptor alpha subunit (IL-15&15Rα) to transform VNP20009, an attenuated salmonella typhimurium strain, obtaining engineered bacteria named 15&15Rα@VNP. After induction at 42 °C, 15&15Rα@VNP can secrete functional IL-15&15Rα stably. It was found that intravesical instillation of thermally activated 15&15Rα@VNP could inhibit the growth of bladder tumors if used alone. Moreover, the sequential intravesical instillation of epirubicin (EPI), a first-line bladder cancer drug, followed by thermally activated 15&15Rα@VNP, could achieve further improved therapeutic responses, without causing significant side effects. Therefore, this study shows that 15&15Rα@VNP can be effectively used in the treatment of bladder cancer and can be used as a complementary therapy to chemotherapy agents, promising for potential clinical translation in bladder cancer treatment.

Impact of MTHFD2 Expression in Bladder/Breast Cancer and Screening of Its Potential Inhibitor.

Genes of folate-mediated 1 carbon metabolism are found to be highly upregulated in tumor cells and promote cancer cell proliferation. The current study aimed to determine the expression of the MTHFD2 gene in bladder and breast cancers. Furthermore, the determination of potential ligand-based inhibitors against MTHFD2 was performed in comparison with those of chemotherapeutic drugs and natural plant-based compounds. Semiquantitative expression analysis along with structure-based virtual ligand library screening was done to find plausible inhibitors. MTHFD2 expression was significantly increased with tumor stage progression both in low- and high-grade bladder cancer and especially in triple-negative breast cancer. Virtual ligand-based library screening against the three-dimensional MTHFD2 protein structure led to the identification of plausible inhibitors like MCULE-8109969891-0 and MCULE-9715677418-0-1 that displayed lower binding free energy as compared to that of already documented LY345899. Similar scaffold commercial drugs leucal (LEU), epirubicin (EPI), and lometrexol also displayed strong binding to the active site of MTHFD2. EPI and LEU in combinatorial therapy were also tested in vitro on MDA-MB-231 cells. The high doses of LEU in combination with EPI showed a significant reduction in cell viability at 2 and 3 μM concentrations. The interaction of breast cancer serum with high expression of MTHFD2 also showed an increase in binding of epirubicin in the presence of leucovorin. The decrease in the absorbance spectra of epirubicin at 37 and 53 °C displayed the stability induced by LEU on the interaction of EPI with the MTHFD2 binding pocket. Leucovorin tends to stabilize the interaction as the binding affinity is high even at 53 °C. Thus, MTHFD2 might be used as a cancer biomarker since its expression level changes drastically with tumor progression. Further experimental studies are required to establish the potential mode of inhibition of the novel small ligands. Future in vivo trials may validate the effectiveness of the combinatorial therapy.

US/PA/MR multimodal imaging-guided multifunctional genetically engineered bio-targeted synergistic agent for tumor therapy

Focused ultrasound ablation surgery (FUAS) is a minimally invasive treatment option that has been utilized in various tumors. However, its clinical advancement has been hindered by issues such as low safety and efficiency, single image guidance mode, and postoperative tumor residue. To address these limitations, this study aimed to develop a novel multi-functional gas-producing engineering bacteria biological targeting cooperative system. Pulse-focused ultrasound (PFUS) could adjust the ratio of thermal effect to non-thermal effect by adjusting the duty cycle, and improve the safety and effectiveness of treatment.The genetic modification of Escherichia coli (E.coli) involved the insertion of an acoustic reporter gene to encode gas vesicles (GVs), resulting in gas-producing E.coli (GVs-E.coli) capable of targeting tumor anoxia. GVs-E.coli colonized and proliferated within the tumor while the GVs facilitated ultrasound imaging and cooperative PFUS. Additionally, multifunctional cationic polyethyleneimine (PEI)-poly (lactic-co-glycolic acid) (PLGA) nanoparticles (PEI-PLGA/EPI/PFH@Fe3O4) containing superparamagnetic iron oxide (SPIO, Fe3O4), perfluorohexane (PFH), and epirubicin (EPI) were developed. These nanoparticles offered synergistic PFUS, supplementary chemotherapy, and multimodal imaging capabilities.GVs-E.coli effectively directed the PEI-PLGA/EPI/PFH@Fe3O4 to accumulate within the tumor target area by means of electrostatic adsorption, resulting in a synergistic therapeutic impact on tumor eradication.In conclusion, GVs-E.coli-mediated multi-functional nanoparticles can synergize with PFUS and chemotherapy to effectively treat tumors, overcoming the limitations of current FUAS therapy and improving safety and efficacy. This approach presents a promising new strategy for tumor therapy.Graphical

Epirubicin/folic acid and meropenem loaded on graphene oxide-gelatin can be used as a novel candidate for anti-cancer and antibacterial drug development

Resistance to meropenem and epirubicin poses a significant global threat, particularly in developing nations with constrained health resources. To overcome this problem, nanotechnology provides several promising solutions, including drug delivery systems that can improve the effectiveness of drugs. The objectives of this work is to characterize the anticancer mechanism of Graphene Oxide (GO) coated with Gelatin (Gel) and conjugated with the anticancer drug Epirubicin (EPi), along with functionalization with Folic Acid in SK-OV3 cancer cell lines for the first time. Furthermore, meropenem was loaded onto Graphene Oxide-Gelatin (GO-Gel) to improve its efficacy. The nanocomposites were characterized using FT-IR, XRD, FESEM and EDX. The viability of the ovarian cancer cell lines (SKOV3) and normal ovarian cell lines (HUVEC) after treatment with GO-Gel, Graphene Oxide-Gelatin-Folic acid (GO-Gel-FA), free Epi and Graphene Oxide-Gelatin-Folic acid/ Epirubicin (GO-Gel–FA/Epi) nanocomposite, was studied by the MTT assay. Expression of the TNFα, Bax, Bcl-2, and NF-κB in the GO-Gel–FA/Epi nanocomposite treated cells, were investigated by qRT-PCR. Disc diffusion assay was utilized to assess the antimicrobial activity of free mer and GO-Gel-Mer nanocomposite against two gram-positive bacteria and two gram-negative bacteria. Results demonstrated that The GO-Gel–FA/Epi nanocomposite showed greater cytotoxic effects on SKOV3cells than normal HUVEC cells. The expression of the Bax was upregulated, while the expression of the Bcl-2, TNFα and NF-κB was reduced in GO-Gel–FA/Epi nanocomposite-treated cells. The Graphene Oxide-Gelatin-Meropenem (GO-Gel-Mer) nanocomposite showed a controlled release within 45 h. GO-Gel-Mer nanocomposite showed much more activity against bacteria in comparison to free Mer. GO-Gel-FA/Epi nanocomposite possesses strong anti-proliferative properties against SK-OV3 cancer cells and indicated promising inhibitory candidate for anticancer therapy. The novel synthesized GO-Gel-Mer nanocomposite can be used as an effective antimicrobial nanomaterial against a range of microbial pathogens, including gram-negative and gram-positive bacteria.

Reducing the water quenching processes using heavy water in capillary electrophoresis with fluorescence detection

Water, ubiquitous in analytical methods, is renowned for its fluorescence quenching properties, influencing techniques like fluorescence spectrophotometry or techniques with fluorescence detection. This study explores the impact of water (H₂O) substitution for heavy water (D₂O) on the fluorescence behavior of anthraquinones and anthracyclines. Anthraquinones and anthracyclines play crucial roles in pharmacy, serving as essential components in various therapeutic formulations, particularly in cancer treatment and other pharmacological interventions. Capillary electrophoresis (CE) with heavy water as the background electrolyte (BGE) solvent offers superior sensitivity to the separation and detection of these analytes. Experimental results demonstrate the improved detection limits and separation efficiency of selected anthraquinones rhein (RH), aloe-emodin (AE), and anthracyclines doxorubicin (DOX), epirubicin (EPI) and daunorubicine (DAU) in heavy water-based buffers, highlighting the potential of heavy water in advancing analytical chemistry.

Construction of a Multifunctional Upconversion Nanoplatform Based on Autophagy Inhibition and Photodynamic Therapy Combined with Chemotherapy for Antitumor Therapy.

Inhibition of autophagy increases the sensitivity of tumor cells to radiotherapy and chemotherapy and improves the therapeutic effect on tumors. Recently, photodynamic therapy (PDT) combined with chemotherapy has been proven to further improve the efficiency of cancer treatment. As such, combining autophagy inhibition with PDT and chemotherapy may represent a potentially effective new strategy for cancer treatment. However, currently widely studied autophagy inhibitors inevitably produce various toxic side effects due to their inherent pharmacological activity. To overcome this constraint, in this study, we designed an ideal multifunctional upconversion nanoplatform, UCNP-Ce6-EPI@mPPA + NIR (MUCEN). Control, UCNP-EPI@mPPA (MUE), UCNP-EPI@mPPA + NIR (MUEN), Ce6-EPI@mPPA (MCE), Ce6-EPI@mPPA + NIR (MCEN), and UCNP-Ce6-EPI@mPPA (MUCE) groups were set up separately as controls. Based on a combination of autophagy inhibition and PDT, the average particle size of MUCEN was 197 nm, which can simultaneously achieve the double encapsulation of chlorine e6 (Ce6) and epirubicin (EPI). In vitro tests revealed that MUCE was efficiently endocytosed by 4T1 cells under near-infrared light irradiation. Further, in vivo tests revealed that MUCE dramatically inhibited tumor growth. Immunohistochemistry results indicated that MUCE efficiently increased the expression of autophagy inhibitors p62 and LC3 in tumor tissues. The synergistic effect of autophagy inhibition and PDT with MUCE exhibited superior tumor suppression, providing an innovative approach to cancer treatment.

In silico analysis of potential inhibitors for breast cancer targeting 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyses.

Breast cancer (BC) is still one of the major issues in world health, especially for women, which necessitates innovative therapeutic strategies. In this study, we investigated the efficacy of retinoic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), which plays a crucial role in the biosynthesis and metabolism of oestrogen and thereby influences the progression of BC and, the main objective of this investigation is to identify the possible drug candidate against BC through computational drug design approach including PASS prediction, molecular docking, ADMET profiling, molecular dynamics simulations (MD) and density functional theory (DFT) calculations. The result has reported that total eight derivatives with high binding affinity and promising pharmacokinetic properties among 115 derivatives. In particular, ligands 04 and 07 exhibited a higher binding affinity with values of -9.9 kcal/mol and -9.1 kcal/mol, respectively, than the standard drug epirubicin hydrochloride, which had a binding affinity of -8.2 kcal/mol. The stability of the ligand-protein complexes was further confirmed by MD simulations over a 100-ns trajectory, which included assessments of hydrogen bonds, root mean square deviation (RMSD), root mean square Fluctuation (RMSF), dynamic cross-correlation matric (DCCM) and principal component analysis. The study emphasizes the need for experimental validation to confirm the therapeutic utility of these compounds. This study enhances the computational search for new BC drugs and establishes a solid foundation for subsequent experimental and clinical research.

Epirubicin induces cardiotoxicity through disrupting ATP6V0A2-dependent lysosomal acidification and triggering ferroptosis in cardiomyocytes

Epirubicin (EPI) is effective in the treatment of malignant cancers, but its application is limited by life-threatening cardiotoxicity. Iron homeostasis disturbance has been implicated in anthracycline induced cardiotoxicity (AIC), and ferroptosis is involved in AIC which dependent upon intracellular iron. However, the role and exact mechanisms of ferroptosis in the pathogenesis of epirubicin-induced cardiotoxicity (EIC) remain elusive. In this study, we aimed to investigate mechanisms underlying ferroptosis-driven EIC. Epirubicin triggered ferroptosis both in vivo and in cultured cardiomyocytes, and pretreatment with ferroptosis inhibitor, Ferrostatin-1(Fer-1) alleviates EIC. Microarray analysis was performed to screen for potential molecules involved in EIC in neonatal primary mouse ventricular cardiomyocytes (NMVMs). We found that the transcript level of ATP6V0A2, a subunit of vacuolar ATPase (V-ATPase), was significantly downregulated when NMVMs were subjected to EPI, which was verified in vivo and in vitro as measured by real time quantitative reverse transcription PCR (qRT-PCR) and immunoblotting. Intriguingly, overexpression of ATP6V0A2 effectively decreased excessive oxidative stress and lipid-peroxidation accumulation, thereby inhibiting ferroptosis and protecting cardiomyocytes against EIC, as evidenced by functional, enzymatic, and morphological changes. Mechanistically, forced expression of ATP6V0A2 restored lysosomal acidification in EPI-treated cardiomyocytes and protected cardiomyocytes and mice hearts from ferroptosis-driven EIC. In this study, our data elucidate that ferroptosis is involved in EIC, which is ignited by ATP6V0A2-dependent lysosomal acidification dysfunction. Our study provides a new potential therapeutic target for ameliorating EIC.

An innovative electrochemical platform based on graphene for rapid screening of cancer drugs in blood plasma

This study introduces a new electrochemical platform for the rapid and sensitive detection of the potent anticancer drug epirubicin (EPB) in blood plasma. The platform utilizes a graphene/Zinc Oxide (ZnO) nanoparticle nanocomposite modified glassy carbon electrode (GCE), which was synthesized through a simple one-pot method where ZnO nanoparticles were dispersed onto graphene sheets. The graphene/ZnO/GCE nanocomposite was characterized using advanced techniques such as FE-SEM, EDS, XRD, FT-IR, and XPS in order to analyze its structural properties. The graphene/ZnO/GCE electrode exhibited minimal interference and demonstrated high selectivity and sensitivity in detecting EPB. The sensor's selectivity was validated by a recovery rate exceeding 98.40 % and a relative standard deviation below 4.65 %. The limits of detection and quantification were determined to be 6.0 nM and 9.0 nM, respectively, indicating the sensor's high sensitivity within a practical concentration range. With a sensitivity of 1.09509 µA/µM, the sensor exhibited a linear response to EPB concentrations ranging from 4.0 to 730.0 μM. Furthermore, successful detection of EPB in serum samples with a recovery rate exceeding 98.40 % underscores the practical utility of the graphene/ZnO/GCE sensor. The detailed characterization of the graphene/ZnO/GCE nanocomposite provides insights into its structural and chemical attributes, furthering its potential for biomedical applications.

A cell targeting and sorting approach based on the magnetophoretic capturing for early prognostics of metastatic cervical cancer cells

HeLa cervical cancer cells are immortal with telomerase activity and metastatic characteristics similar to circulating tumor cells (CTCs). Here, we report aptamer-modified multilayered magnetic beads (Apt@MBs) that efficiently targeted and captured HeLa cells up to a low concentration of freshly prepared cell suspension (500 cells/mL). Apt@MBs were functionalized with fluorophore-conjugated AS1411-aptamer on an outer layer made up of molybdenum disulfide (MoS2) to target nucleolin on the cell surface of captured HeLa cells. Moreover, this outer MoS2 layer of MBs was nanoporous and could load anticancer drugs inside its porous cavities with the possibility of killing the captured and metastatic CTCs in vivo. An internal core layer of Apt@MBs consisting of Ag–Fe3O4 magnetic particles (MPs) was designed for magnetic manifestations and cell sorting with the possibility of screening CTCs (in the patient's blood samples) for early diagnosis of metastatic cancers. The Apt@MBs after cell capture gave rise to the heavier HeLa-MBs composites to get settled down under gravitational/inertial forces to the bottom of the tube quicker than the free cells (within 10 min). The gravitational settling of HeLa-MBs was further coupled with exposing a magnetic field to effectively capture and enrich the cells at the bottom of the tube (from 91 to 98 % cells). While the fluid containing dead, non-cancerous, or uncaptured cells in the supernatant layers were easily removed by pipetting. The HeLa-MBs after sorting out were resuspended into a fresh culture medium for further incubation or cellular analysis. Moreover, both cisplatin (CP) and epirubicin (EP) loaded Apt@MBs showed the killing of about 50 % of the captured cells. Therefore, we are confident that Apt@MBs can contribute to enumerating patients' blood samples for screening CTCs to timely and efficiently detect metastatic cancers along with the ability to effectively perform prognosis, and treatment of metastatic cancers.

Design and Optimization of Sesamol Nanosuspensions to Potentiate the Anti-Tumor Activity of Epirubicin against Ehrlich Solid Carcinoma-Bearing Mice.

There is a growing interest in discovering natural sources of anti-cancer drugs. Sesamol (SES) is a phenolic compound with antitumor effects. The present study aimed to investigate the anticancer properties of SES and its nano-suspensions (SES-NS) combined with Epirubicin (EPI) in breast cancer (BC) using mice bearing a solid Ehrlich tumor. The study involved 35 female albino mice and investigated the effects of SES and EPI on tumor growth, proliferation, apoptosis, autophagy, angiogenesis, and oxidative stress. Methods including ELISA, qRT-PCR, and immunohistochemistry were utilized. The findings revealed reductions in tumor growth and proliferation using SES either alone or combined and evidenced by decreased AKT (AKT Serine/Threonine kinase1) levels, angiogenesis indicated by lower levels of VEGFR (vascular endothelial growth factor), and apoptosis demonstrated by elevated caspase3 and BAX levels. Furthermore, autophagy increased and was indicated by increased levels of beclin1 and lc3, along with decreased oxidative stress as evidenced by elevated TAC (total antioxidant capacity) and reduced MDA (malondialdehyde) levels. Interestingly, SES-NS demonstrated more significant effects at lower doses. In summary, this study underscores the potential of SES as a promising agent for BC treatment. Moreover, SES-NS potentiated the beneficial effects of EPI while mitigating its adverse effects.

Epirubicin and Non-Muscle Invasive Bladder Cancer Treatment: A Systematic Review.

(1) Background: Intravesical chemotherapy is the standard of care in intermediate-risk non-muscleinvasive bladder cancer (NMIBC). Different agents are used across the world based on availability, cost, and practice patterns. Epirubicin (EPI), one of these agents, has been used by many centers over many decades. However, its true differential efficacy compared to other agents and its tolerability are still poorly reported. We aimed to assess the differential efficacy and safety of intravesical EPI in NMIBC patients. (2) Methods: This study aimed to systematically review the efficacy and safety profile of Epirubicin (EPI) in the management of non-muscle invasive bladder cancer (NMIBC) compared to other adjuvant therapies. A systematic search of the PUBMED, Web of Science, clinicaltrials.gov, and Google Scholar databases was conducted on 31 December 2023, using relevant terms related to EPI, bladder cancer, and NMIBC. The inclusion criteria targeted studies that evaluated patients treated with EPI following the transurethral resection of bladder tumors (TURBT) for NMIBC and compared oncological outcomes such as recurrence and progression with other adjuvant therapies, including Mitomycin C (MMC), Gemcitabine (GEM), and Bacillus Calmette-Guérin (BCG). Additionally, studies investigating the safety profile of EPI administered intravesically at room temperature and under hyperthermia, as well as oncological outcomes associated with hyperthermic intravesical EPI administration, were included. (3) Results: Eleven studies reported adverse events after adjuvant intravesical instillations with EPI; the most frequently reported adverse events included cystitis (34%), dysuria, pollakiuria, hematuria, bladder irritation/spasms, fever, nausea and vomiting, and generalized skin rash (2.3%). Nine studies compared EPI to BCG in terms of recurrence and progression rates; BCG instillations showed a lower recurrence rate compared to EPI, with limited or non-significant differences in progression rates. Two studies found no significant differences between EPI and MMC regarding progression and recurrence rates. One study showed statistically significant lower recurrence and progression rates with GEM in high-risk NMIBC patients. Another study found no significant differences between EPI and GEM regarding recurrence and progression. (4) Conclusions: EPI exhibits similar oncological performances to Gemcitabine and Mitomycin C currently used for adjuvant therapy in NMIBC. Novel delivery mechanisms such as hyperthermia are interesting newcomers.

A prospective, open-label, single-arm phase II clinical study of inetetamab in combination with pyrotinib and albumin-bound paclitaxel for the neoadjuvant treatment of patients with HER2+ early and locally advanced breast cancer.

e12635 Background: Chemotherapy combined with dual anti-HER2 target therapy has become the standard neoadjuvant therapy regimen for HER2+ breast cancer. Patients achieving pCR have a relatively better prognosis. Inetetamab (Septin) is an innovative HER2 monoclonal antibody drug developed in China. It has been proven to delay the progression of HER2+ metastatic breast cancer patients and bring survival benefits. The purpose of this study was to explore the efficacy and safety of Inetetamab, Pyrotinib and Albumin-bound Paclitaxel in the neoadjuvant treatment of HER2+ breast cancer. Methods: This phase II trial included patients with HER2+ early or locally advanced breast cancer whose tumor size was>20mm or confirmed axillary lymph node metastasis. Patients receive Inetetamab initial dose of 8 mg/kg over 90 minutes IV infusion, followed 6 mg/kg over 30 to 90 minutes IV infusion q3w, Pyrotinib 400 mg orally every day and Albumin-bound Paclitaxel 125mg/m2, IV, D1/8/15, q3w. Patients receive above treatment every 3 weeks for a total of 4 cycles, followed by surgery. After surgery, EC (90mg/m2 of Epirubicin Hydrochloride, 600mg/m2 of Cyclophosphamide, q21 days, 4 cycles) was administered, followed by maintenance treatment with trastuzumab combined with pertuzumab for 1 year. And provide radiotherapy and endocrine therapy to the patient according to the specific situation. The primary endpoint was pathological complete response (pCR). Results: Until February 4, 2024, 18 patients were enrolled, of which 15 had completed surgical treatment. The median age of enrolled patients was 49 years (35-60 years). 66.7% (10 cases) of patients achieved RCB grade 0 (pCR), 26.7% (4 cases) achieved RCB grade I, 6.7% (1 case) achieved RCB grade II. Of the 15 patients, 73.3% (11 cases) were HR+/HER2+, with 72.7% (8 cases) achieved pCR. Among the 4 HR-/HER2+ patients, 50% (2 case) achieved pCR. HR+/HER2+ patients were more likely to achieve pCR than HR-/HER2+ patients. No severe (grade 3/4) toxicity was observed in any patients. Conclusions: Our current data show that the pCR rate in HER2+ breast cancer patients reaches 66.7%, and even 72.7% in HR+ patients. In the previous Neosphere and PEONY studies of the H+P dual target regimen, the pCR of HR+/HER2+patients increased by only 6% and 8.3%, while in the NeoALTTO and PHEDRA studies of the H+L or H+Py regimen, the pCR increased by 18.9% and 17.7%, indicating that the combination of large and small molecules with dual target neoadjuvant therapy for HR+/HER2+ breast cancer was significantly better than that of the monoclonal antibody dual target therapy. Therefore, Inetetamab, Pyrotinib and albumin-bound paclitaxel is a potential effective new adjuvant treatment for HER2+ breast cancer, especially for HR+ patients. Clinical trial information: NCT054444998 .

Efficient delivery of anticancer drugs using functionalized-Ag-decorated Fe3O4@SiO2 nanocarrier with folic acid and β-cyclodextrin

Nanocarrier surface functionalization has been widely regarded as a promising approach for achieving precise and targeted drug delivery systems. In this work, the fabrication of functionalized-Ag-decorated Fe3O4@SiO2 (Fe3O4@SiO2-Ag) nanocarriers with folic acid (FA) and β-cyclodextrin (BCD) exhibit a remarkable capacity for delivering two types of anticancer drugs, i.e., doxorubicin (DOX) and epirubicin (EPI), into cancer cells. The effective functionalization of Fe3O4@SiO2-Ag nanoparticles has been achieved through the use of cysteine (Cys) as an anchor for attaching FA and BCD via EDC-NHS coupling and Steglich esterification methods, respectively. The findings indicate that surface functionalization had no significant impact on the physicochemical characteristics of the nanoparticles. However, it notably affected DOX and EPI loading and release efficiency. The electrostatic conjugation of DOX/EPI onto the surface of Fe3O4@SiO2-Ag/Cys/FA and Fe3O4@SiO2-Ag/Cys/BCD exhibited maximum loading efficiency of 50–60% at concentration ratio of DOX/EPI to nanoparticles of 1:14. These nanocarriers also achieved an 40–47% DOX/EPI release over 36 days. Furthermore, the drug-loaded functionalized-nanocarrier showed cytotoxic effects on SK-MEL-2 cells, as demonstrated by an in vitro MTT assay. This suggests that the as-prepared functionalized-nanoparticles have promise as a carrier for the efficient anticancer drugs.

Plasmonic photothermal therapy based synergistic drug release application through gold nanoparticles coated and embedded PLGA nanoparticles

Drug carrier structures based on the biocompatible polymer Poly(D-lactic-co-glycolic acid) (PLGA) are considered traditional delivery systems. To increase the potential of PLGA nanoparticle (NP)-based carriers for use in near infrared radiation (NIR)-based photothermal drug release applications, two important approaches are the combined use of gold nanoparticles with PLGA NPs structures. In this study, AuNPs were prepared both decorated on PLGA NPs and embedded in PLGA NPs structures. The particles were prepared and characterized for their structural and thermal properties using Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), and Differential Scanning Calorimetry (DSC) methods. Morphological features and size distributions were also determined using Scanning Electron Microscope (SEM), Transmission Electron Microscopy (TEM), and Dynamic Light Scattering (DLS). Thermal changes caused by plasmonic particles under 808 nm NIR laser were examined using a thermal camera for spherical gold nanoparticle (AuNP) and star-shaped gold nanoparticle (AuNS). The most suitable increase in temperature has been obtained in the AuNS structures. Epirubicin (EPI) release studies were conducted using PLGA NPs embedded with AuNS, employing NIR and an ON/OFF based approach. Basic toxicological evaluations of these particles were performed on mouse fibroblast (L929) cells to assess biocompability properties. The study also investigated the impact of prepared EPI-loaded particles and laser-controlled drug release on cytotoxicity, ROS production, and genotoxicity, in human neuroblastoma (SH-SY5Y) cells. The results indicated that the activity of EPI-loaded AuNP@PDOP@PLGA NPs increases synergistically with the ON/OFF-based approach, as shown by the calculated combination index (CI) value. The developed combination approach shows promise for further evaluation before clinical use.

A Redox-Triggered Autophagy-Induced Nanoplatform with PD-L1 Inhibition for Enhancing Combined Chemo-Immunotherapy.

Epirubicin (EPI) alone can trigger mildly protective autophagy in residual tumor cells, resulting in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and leads to antiprogrammed death ligand 1 (anti-PD-1)/PD-L1 therapy resistance, posing a significant clinical challenge in tumor immunotherapy. The combination of checkpoint inhibitors targeting the PD-1/PD-L1 pathway and amplifying autophagy presents an innovative approach to tumor treatment, which can prevent tumor immune escape and enhance therapeutic recognition. Herein, we aimed to synthesize a redox-triggered autophagy-induced nanoplatform with SA&EA-induced PD-L1 inhibition. The hyaluronic acid (HA) skeleton and arginine segment promoted active nanoplatform targeting, cell uptake, and penetration. The PLGLAG peptide was cleaved by overexpressing matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment, and the PD-L1 inhibitor D-PPA was released to inhibit tumor immune escape. The intense autophagy inducers, STF-62247 and EPI, were released owing to the cleavage of disulfide bonds influenced by the high glutathione (GSH) concentration in tumor cells. The combination of EPI and STF induced apoptosis and autophagic cell death, effectively eliminating a majority of tumor cells. This indicated that the SA&EA nanoplatform has better therapeutic efficacy than the single STF@AHMPP and EPI@AHMPTP groups. This research provided a way to set up a redox-triggered autophagy-induced nanoplatform with PD-L1 inhibition to enhance chemo-immunotherapy.

Efficacy and Safety of Resveratrol in the Treatment of Bladder Cancer Derived Organoids

AbstractIntravesical instillation is a prevalent approach in bladder cancer (BC) management, yet it often causes adverse reactions and drug resistance. Safer and more effective alternative is therefore in urgent need, and resveratrol (RES) emerges as a promising candidate. However, the effectiveness of RES against BC remains unexplored. In this study, BC‐derived organoids (BCOs) are established to evaluate the efficacy of RES in comparison to conventional anti‐BC drugs (epirubicin (EPI), cisplatin (CDDP), gemcitabine (GEM), and vinorelbine (VNR)). After a 96‐h treatment, RES demonstrates superior anti‐BCOs efficacy (64.00%; 16/25) compared to the other chemotherapeutics (15.38% to 53.85%). Eighteen BCOs are treated with RES, EPI, or a combination of RES and EPI (RES/EPI) in short‐term (3 h per day for four times) to mimic intravesical instillation. RES exhibits the stronger efficacy (44.44%; 8/18) than EPI against BCOs, and the RES/EPI enhances sensitivity of a single drug (50.00%; 9/18). RES inhibits the activation of β‐catenin/CD44 axis in RES‐sensitive BCOs. The organoid‐forming potential of mouse bladder is preserved after intravesical instillation of RES, and 200 × 10−6 m RES demonstrates no adverse effects on patient‐derived bladder urothelial organoids. The findings highlight the potential of RES, particularly in combination with EPI, to improve intravesical instillation outcomes in BC management.

Electrochemical Nanosensor for the Simultaneous Determination of Anticancer Drugs Epirubicin and Topotecan Using UiO-66-NH2/GO Nanocomposite Modified Electrode.

In this work, UiO-66-NH2/GO nanocomposite was prepared using a simple solvothermal technique, and its structure and morphology were characterized using field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDS), and X-ray diffraction (XRD). An enhanced electrochemical sensor for the detection of epirubicin (EP) was proposed, which utilized a UiO-66-NH2/GO nanocomposite-modified screen-printed graphite electrode (UiO-66-NH2/GO/SPGE). The prepared UiO-66-NH2/GO nanocomposite improved the electrochemical performance of the SPGE towards the redox reaction of EP. Under optimized experimental conditions, this sensor demonstrates a remarkable limit of detection (LOD) of 0.003 µM and a linear dynamic range from 0.008 to 200.0 µM, providing a highly capable platform for sensing EP. Furthermore, the simultaneous electro-catalytic oxidation of EP and topotecan (TP) was investigated at the UiO-66-NH2/GO/SPGE surface utilizing differential pulse voltammetry (DPV). DPV measurements revealed the presence of two distinct oxidation peaks of EP and TP, with a peak potential separation of 200 mV. Finally, the UiO-66-NH2/GO/SPGE sensor was successfully utilized for the quantitative analysis of EP and TP in pharmaceutical injection, yielding highly satisfactory results.

Cobalt-catalysed bicarbonate-activated peroxide as a promising system for the advanced oxidation of epirubicin in wastewaters

Epirubicin (EPI) is a common cytostatic drug often found as a pollutant in hospital wastewater. While many studies have focused on the degradation kinetics of its epimer, doxorubicin (DOX), none have reported the kinetics of EPI degradation. Herein, we report a new cost-efficient, environmentally friendly system for the advanced degradation of EPI consisting of cobalt-catalysed bicarbonate-activated peroxide. We propose a new kinetic model for EPI degradation that shows the hydroperoxyl radical is the most important reactive oxygen species (ROS) involved in the degradation process. Seven degradation products are identified using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS). The effect of surfactants, commonly found in wastewaters, is also investigated and the presence of the cationic surfactant hexadecylpyridinium chloride (CPC) in the reaction medium leads to a 6.1-fold increase in the degradation rate. Modelling the reaction kinetics using the Piszkiewicz model unveils the rate constant for the micellar degradation of EPI to be 4.66×10‐3s‐1. The ecotoxicity study of the degradation products shows a dramatic decrease in both acute and chronic toxicity. Although the level of mineralisation of the products is less than 10%, this method is still suitable as a pre-treatment of wastewaters. The same system is successfully used for the degradation of DOX, mitoxantrone, and quinizarin. In the case of DOX, a rate constant of 3.74×10‐2s‐1 is obtained, the highest reported so far.

Abstract PO2-03-11: A novel peripheral CD4+ T cell immune network associated with response to PD-1 inhibitor in early-stage triple negative breast cancer

Abstract A novel peripheral CD4+ T cell immune network associated with response to PD-1 inhibitor in early-stage triple negative breast cancer Background: Immunotherapy has showed benefits in early-stage triple-negative breast cancer (eTNBC). However, there is an urgent need to identify novel biomarkers that can guide stratification for immunotherapy in eTNBC. Anti-tumor immunity is a systemic response that encompasses the mobilization of dendritic cells, lymphocytes, and myeloid cells involving the tumor, blood, and lymph nodes. The activation of anti-tumor immune responses via immunotherapy is expected to reflect in the subset change of circulation. Combined with advantage of dynamic monitoring by liquid biopsy, we detected peripheral blood in the eTNBC patients under immunotherapy to explore potential immune therapeutic predictive subsets. Methods: Single-cell (sc) RNA sequencing was utilized to determine the transcriptomics of immune cells in the peripheral blood. Meanwhile scTCR sequencing was used to trace the dynamic changes of clonetypes under multi-therapy. Nanostring analysis of primary tumor and in vivo models were used to validate the mechanism of immune crosstalk. Prediction index was built based on the proportion of immune subsets at each time point and change of tumor size in each patient. Results: 12 eTNBC patients who participated in neoadjuvant chemotherapy in combination with PD-1 inhibitor (Toripalimab) clinical trial were included in this study. The clinical trial consists of two stages. All eligible patients received four cycles of EC (cyclophosphamide plus epirubicin) regimen and followed four cycles of nab-paclitaxel plus PD-1 inhibitor. Among the 12 patients, 5 patients achieved pCR, while the remaining 7 patients were non-pCR. Peripheral blood samples were collected at baseline, after chemotherapy induction, and on PD-1 inhibitor treatment for scRNA- and scTCR-sequencing. Through prediction index, a novel predictive pattern based on ratio of memory T cells (central memory T and resident memory T) to effective T cells in the peripheral was vividly defined, by which the patients could be classified into C-type (memory T cells dominated) and E-type (effective T cells dominated). The C-type indicated better efficacy of immunotherapy combination therapy, while the E-type suggested better efficacy of chemotherapy alone. Meanwhile, a novel peripheral CD4+Trm (resident-memory-like) subset that possessed both strong differentiation potential and memory function was higher in pCR group at baseline. TCR-tracing analysis revealed that the new clones induced by chemotherapy mainly belong to the CD4+ Trm and CD8+ CD161+ Tcm (central memory) subsets, and the upregulation of CD8+ CD161+ Tcm during therapy was a dynamic predictor for immunotherapy benefits. Besides, most of CD4+Trm transitioned into CD4+Th1-like cells as an activated status, which considered CD4+Trm as a group of reservoirs with polyclonality and differentiation potential for tumor-killing. Meanwhile, the increase in CD5+ cDC2 (type 2 conventional dendritic cell) after chemotherapy was associated with enhanced antigen-presenting function and cell communication and co-stimulation with CD4+ Trm cells which helped the activated transition from CD4+Trm into CD4+Th1-like cells in lymph nodes. Moreover, CD4+Th1-like cells increased secretion of Th1 cytokines thus leading to promote CD8+CD161+ Tcm upregulation and tumor-infiltration after immunotherapy. Conclusions: A novel peripheral pattern based on subsets of T cells as C-type and E-type was established as potential predictors for immunotherapy stratification in eTNBC patients. Meanwhile, a novel peripheral CD4+Trm immune network was identified, in which CD5+cDC2 activated the transition of CD4+Trm into CD4+Th1-like subset leading to activation and tumor-infiltration of CD8+CD161+Tcm. All the above provided potential therapeutic targets for enhancing immunotherapy. Citation Format: Zehao Wang, Zhibo Shao, Bingqiu Xiu, Jiong Wu. A novel peripheral CD4+ T cell immune network associated with response to PD-1 inhibitor in early-stage triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-03-11.