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Journal of Colloid and Interface Science Sep 2024Hydrophilic cationic drugs such as mitoxantrone hydrochloride (MTO) pose a significant delivery challenge to the development of nanodrug systems. Herein, we report the...
HYPOTHESIS
Hydrophilic cationic drugs such as mitoxantrone hydrochloride (MTO) pose a significant delivery challenge to the development of nanodrug systems. Herein, we report the use of a hydrophobic ion-pairing strategy to enhance the nano-assembly of MTO.
EXPERIMENTS
We employed biocompatible sodium cholesteryl sulfate (SCS) as a modification module to form stable ion pairs with MTO, which balanced the intermolecular forces and facilitated nano-assembly. PEGylated MTO-SCS nanoassemblies (pMS NAs) were prepared via nanoprecipitation. We systematically evaluated the effect of the ratio of the drug module (MTO) to the modification module (SCS) on the nanoassemblies.
FINDINGS
The increased lipophilicity of MTO-SCS ion pair could significantly improve the encapsulation efficiency (∼97 %) and cellular uptake efficiency of MTO. The pMS NAs showed prolonged blood circulation, maintained the same level of tumor antiproliferative activity, and exhibited reduced toxicity compared with the free MTO solution. It is noteworthy that the stability, cellular uptake, cytotoxicity, and in vivo pharmacokinetic behavior of the pMS NAs increased in proportion to the molar ratio of SCS to MTO. This study presents a self-assembly strategy mediated by ion pairing to overcome the challenges commonly associated with the poor assembly ability of hydrophilic cationic drugs.
Topics: Mitoxantrone; Hydrophobic and Hydrophilic Interactions; Humans; Animals; Cholesterol Esters; Antineoplastic Agents; Mice; Cell Proliferation; Cations; Cell Survival; Particle Size; Nanoparticles; Surface Properties; Drug Carriers; Drug Screening Assays, Antitumor; Cell Line, Tumor; Polyethylene Glycols
PubMed: 38735255
DOI: 10.1016/j.jcis.2024.05.029 -
American Journal of Cancer Research 2024Mitoxantrone Hydrochloride Injection for Tracing (MHI), a modified new drug marketed in China, has been approved by the National Medical Products Administration for...
Safety, tolerability, and pharmacokinetics of mitoxantrone hydrochloride injection for tracing in patients with gastric cancer: a single-blind, single-center, phase I clinical trial.
Mitoxantrone Hydrochloride Injection for Tracing (MHI), a modified new drug marketed in China, has been approved by the National Medical Products Administration for lymph node tracing in thyroid cancer and sentinel lymph node biopsy in breast cancer. This single-center, single-blind, dose-escalation phase I clinical trial aimed to investigate the safety of MHI on lymph node tracing in gastric cancer. In this study, four dose groups (1.0 mL, 1.5 mL, 2.0 mL, and 3.0 mL) with 3 gastric cancer patients in each group were set. The safety, tolerability, pharmacokinetics and preliminary efficacy of different doses were investigated. Results showed that none of the patients experienced dose-limiting toxicity or developed serious adverse events or adverse drug reactions. Pharmacokinetic analyses revealed minimal absorption of the tracer, resulting in low and transient blood drug concentrations across all participants. The mean time to peak concentration was (0.561 ± 0.3728) h (with mean peak concentration (C) of 10.300 ng/mL), (0.500 ± 0.0167) h (mean C of 13.687 ng/mL), (0.494 ± 0.0096) h (mean C of 30.933 ng/mL), and (0.661 ± 0.2791) h (mean C of 21.067 ng/mL) in the 1.0 mL, 1.5 mL, 2.0 mL, and 3.0 mL dose groups, respectively. The mean lymph node staining rates were 21.0%, 24.7%, 32.5%, and 44.5%, and the mean metastatic lymph node staining rates were 20.6%, 36.1%, 42.4%, and 21.0% in each group. This study confirmed that MHI was safe, well-tolerated, and had low systemic effects when used for lymphatic tracing of gastric cancer, and the tracing effect was better in the 3 mL dose group. This trail was registered on the website of Centre for Drug Evaluation State Drug and Food Administration (http://www.chinadrugtrials.org.cn/index.html) with the name of clinical study of lymphatic tracer in lymph node tracing of gastric cancer, the code was CTR20201906.
PubMed: 38726280
DOI: 10.62347/LSDV5580 -
Transplantation and Cellular Therapy May 2024Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplantation (HCT) the sole therapy...
Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplantation (HCT) the sole therapy likely to result in cure. We conducted the present study to determine the feasibility of early HCT-within 60 days of beginning reinduction chemotherapy-to see whether getting patients to HCT in an expeditious manner would expand the number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults age 18 to 75 years with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis who were eligible for a reduced-intensity HCT. Subjects received reinduction chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/ melphalan). We enrolled 30 subjects, all of whom received CLAG-M reinduction, although only 9 underwent HCT within 60 days (<15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range, 42 to 60 days). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplantation of 83 days (range, 53 to 367 days). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit the real-world uptake of such early-to-transplantation protocols.
PubMed: 38710302
DOI: 10.1016/j.jtct.2024.05.002 -
ACS Sensors May 2024drug monitoring is crucial for evaluating the effectiveness and safety of drug treatment. Blood sampling and analysis is the current gold standard but needs...
drug monitoring is crucial for evaluating the effectiveness and safety of drug treatment. Blood sampling and analysis is the current gold standard but needs professional skills and cannot meet the requirements of point-of-care testing. Dermal interstitial fluid (ISF) showed great potential to replace blood for drug monitoring; however, the detection was challenging, and the drug distribution behavior in ISF was still unclear until now. In this study, we proposed surface-enhanced Raman spectroscopy (SERS) microneedles (MNs) for the painless and real-time analysis of drugs in ISF after intravenous injection. Using methylene blue (MB) and mitoxantrone (MTO) as model drugs, the innovative core-satellite structured Au@Ag SERS substrate, hydrogel coating over the MNs, rendered sensitive and quantitative drug detection in ISF of mice within 10 min. Based on this technique, the pharmacokinetics of the two drugs in ISF was investigated and compared with those in blood, where the drugs were analyzed via liquid chromatography-mass spectrometry. It was found that the MB concentration in ISF and blood was comparable, whereas the concentration of MTO in ISF was 2-3 orders of magnitude lower than in blood. This work proposed an efficient tool for ISF drug monitoring. More importantly, it experimentally proved that the penetration ratio of blood to ISF was drug-dependent, providing insightful information into the potential of ISF as a blood alternative for drug detection.
Topics: Animals; Spectrum Analysis, Raman; Extracellular Fluid; Needles; Methylene Blue; Mice; Hydrogels; Drug Monitoring; Silver; Mitoxantrone; Gold; Skin
PubMed: 38696667
DOI: 10.1021/acssensors.4c00276 -
Animals : An Open Access Journal From... Apr 2024Mammary cancer is a frequent disease in female dogs, where a high proportion of cases correspond to malignant tumors that may exhibit drug resistance. Within the mammary...
Mammary cancer is a frequent disease in female dogs, where a high proportion of cases correspond to malignant tumors that may exhibit drug resistance. Within the mammary tumor microenvironment, there is a cell subpopulation called cancer stem cells (CSCs), which are capable of forming spheres in vitro and resisting anti-tumor treatments, partly explaining the recurrence of some tumors. Previously, it has been described that spheres derived from canine mammary carcinoma cells CF41.Mg and REM 134 exhibit stemness characteristics. Melatonin has shown anti-tumor effects on mammary tumor cells; however, its effects have been poorly evaluated in canine mammary CSCs. This study aimed to analyze the effect of melatonin on the chemoresistance exhibited by stem-like neoplastic cells derived from canine mammary carcinoma to cytotoxic drugs such as doxorubicin and mitoxantrone. CF41.Mg and REM 134 cells were cultured in high-glucose DMEM supplemented with fetal bovine serum and L-glutamine. The spheres were cultured in ultra-low attachment plates in DMEM/F12 medium without fetal bovine serum and with different growth factors. The CD44/CD24 phenotype was analyzed by flow cytometry. The viability of sphere-derived cells (MTS reduction) was studied in the presence of melatonin (0.1 or 1 mM), doxorubicin, mitoxantrone, and luzindole. In addition, the gene (RT-qPCR) of the multidrug resistance bombs and were analyzed in the presence of melatonin. Both cell types expressed the gene, which encodes the melatonin receptor MT1. Melatonin 1 mM does not modify the CD44/CD24 phenotype; however, the hormone reduced viability ( < 0.0001) only in CF41.Mg spheres, without inducing an additive effect when co-incubated with cytotoxic drugs. These effects were independent of the binding of the hormone to its receptor MT1, since, by pharmacologically inhibiting them, the effect of melatonin was not blocked. In CF41.Mg spheres, the relative gene expression of and was decreased in response to the hormone ( < 0.001). These results indicate that melatonin negatively modulates the cell survival of spheres derived from CF41.Mg cells, in a way that is independent of its MT1 receptor. These effects did not counteract the resistance to doxorubicin and mitoxantrone, even though the hormone negatively regulates the gene expression of and .
PubMed: 38672378
DOI: 10.3390/ani14081229 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Apr 2024To investigate the safety and efficacy of mitoxantrone liposome in the treatment of children with high-risk acute myeloid leukemia (AML).
OBJECTIVE
To investigate the safety and efficacy of mitoxantrone liposome in the treatment of children with high-risk acute myeloid leukemia (AML).
METHODS
The children with high-risk AML who received the mitoxantrone liposome regimen at Wuhan Children's Hospital from January 2022 to February 2023 were collected as the observation group, and the children with high-risk AML who received idarubicin regimen were enrolled as controls, and their clinical data were analyzed. Time to bone marrow recovery, the complete remission rate of bone marrow cytology, the clearance rate of minimal residual disease, and treatment-related adverse reactions were compared between the two groups.
RESULTS
The patients treated with mitoxantrone liposome showed shorter time to recovery of leukocytes(17 21 day), granulocytes(18 24 day), platelets(17 24 day), and hemoglobin(20 26 day) compared with those treated with idarubicin, there were statistical differences ( <0.05). The effective rate and MRD turning negative rate in the observation group were 90.9% and 72.7%, respectively, while those in the control group were 94.1% and 76.4%, with no statistical difference ( >0.05). The overall response rate of the two groups of patients was similar.
CONCLUSION
The efficacy of mitoxantrone liposome is not inferior to that of idarubicin in children with high-risk AML, but mitoxantrone liposome allows a significantly shorter duration of bone marrow suppression and the safety is better.
Topics: Humans; Mitoxantrone; Leukemia, Myeloid, Acute; Liposomes; Child; Idarubicin; Male; Female; Adolescent
PubMed: 38660837
DOI: 10.19746/j.cnki.issn.1009-2137.2024.02.006 -
Journal of Feline Medicine and Surgery Apr 2024The aim of this study was to determine response rates, median progression-free intervals (PFIs) and median survival times (MSTs) for cats with intermediate-large cell...
Evaluation of a multiagent chemotherapy protocol combining vincristine, cyclophosphamide, mitoxantrone and prednisolone (CMOP) for treatment of feline intermediate-large cell lymphoma.
OBJECTIVES
The aim of this study was to determine response rates, median progression-free intervals (PFIs) and median survival times (MSTs) for cats with intermediate-large cell lymphoma treated with a vincristine, cyclophosphamide, mitoxantrone and prednisolone (CMOP) protocol. A secondary objective was to determine the tolerability of mitoxantrone used within this multiagent protocol.
METHODS
The medical records of 31 cats treated at a single institution between 2009 and 2022 were reviewed to identify suitable cases. Cats were included in the study if they had a confirmed diagnosis of intermediate-large cell lymphoma, had received a CMOP protocol as first-line treatment and had completed at least one 4-week cycle of this protocol. Modifications allowed in the protocol included the use of l-asparaginase, vinblastine substitution for vincristine, chlorambucil substitution for cyclophosphamide and dexamethasone or methylprednisolone substitution for prednisolone.
RESULTS
The overall response rate was 74% (n = 23), with 45% (n = 14) achieving complete remission (CR), 29% (n = 9) achieving partial remission (PR) and 26% (n = 8) achieving stable disease (SD). The Kaplan-Meier median PFI and MST were 139 days and 206 days, respectively. Responders (CR or PR) had a significantly longer ( <0.001) median PFI and MST compared with non-responders (SD) (176 days vs 62 days, and 251 days vs 61 days, respectively). Cats that achieved CR had a significantly longer median PFI and MST ( <0.001) at 178 days and 1176 days, respectively. The 6-month and 1- and 2-year survival rates in cats with CR were 64%, 57% and 35%, respectively. Treatment with mitoxantrone was generally well tolerated, with no cats experiencing Veterinary Cooperative Oncology Group adverse effects above grade 2.
CONCLUSIONS AND RELEVANCE
The CMOP protocol is an alternative and well-tolerated treatment for cats with intermediate-large cell lymphoma. As demonstrated with previous chemotherapy protocols, cats that respond to treatment, particularly those that achieve CR, are likely to have more durable responses.
Topics: Animals; Cats; Mitoxantrone; Cat Diseases; Vincristine; Cyclophosphamide; Antineoplastic Combined Chemotherapy Protocols; Prednisolone; Male; Female; Retrospective Studies; Treatment Outcome
PubMed: 38647264
DOI: 10.1177/1098612X241234614 -
Biochemical Pharmacology Apr 2024The pivotal roles of ATP-binding cassette (ABC) transporters in drug resistance have been widely appreciated. Here we report that marein, a natural product from...
The pivotal roles of ATP-binding cassette (ABC) transporters in drug resistance have been widely appreciated. Here we report that marein, a natural product from Coreopsis tinctoria Nutt, is a potent chemo-sensitizer in drug resistant cancer cells overexpressing ABCG2 transporter. We demonstrate that marein can competitively inhibit efflux activity of ABCG2 protein and increase the intracellular accumulation of the chemotherapeutic drugs that belong to substrate of this transporter. We further show that marein can bind to the conserved amino acid residue F439 of ABCG2, a critical site for drug-substrate interaction. Moreover, marein can significantly sensitize the ABCG2-expressing tumor cells to chemotherapeutic drugs such as topotecan, mitoxantrone, and olaparib. This study reveals a novel role and mechanism of marein in modulating drug resistance, and may have important implications in treatment of cancers that are resistant to chemotherapeutic drugs that belong to the substrates of ABCG2 transporters.
PubMed: 38643907
DOI: 10.1016/j.bcp.2024.116219 -
Advanced Materials (Deerfield Beach,... Apr 2024Therapy-induced immunogenic cell death (ICD) can initiate both innate and adaptive immune responses for amplified anti-tumor efficacy. However, dying cell-released ICD...
Therapy-induced immunogenic cell death (ICD) can initiate both innate and adaptive immune responses for amplified anti-tumor efficacy. However, dying cell-released ICD signals are prone to being sequestered by the TIM-3 receptors on dendritic cell (DC) surfaces, preventing immune surveillance. Herein, dismantlable coronated nanoparticles (NPs) are fabricated as a type of spatiotemporally controlled nanocarriers for coupling tumor cell-mediated ICD induction to DC-mediated immune sensing. These NPs are loaded with an ICD inducer, mitoxantrone (MTO), and wrapped by a redox-labile anti-TIM-3 (αTIM-3) antibody corona, forming a separable core-shell structure. The antibody corona disintegrates under high levels of extracellular reactive oxygen species in the tumor microenvironment, exposing the MTO-loaded NP core for ICD induction and releasing functional αTIM-3 molecules for DC sensitization. Systemic administration of the coronated NPs augments DC maturation, promotes cytotoxic T cell recruitment, enhances tumor susceptibility to immune checkpoint blockade, and prevents the side effects of MTO. This study develops a promising nanoplatform to unleash the potential of host immunity in cancer therapy.
PubMed: 38643386
DOI: 10.1002/adma.202313097 -
Journal of Clinical Oncology : Official... Jun 2024Measurable residual disease (MRD) by using flow cytometry after induction therapy is strongly prognostic in pediatric AML, and hematopoietic stem-cell transplant (hSCT)... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
PURPOSE
Measurable residual disease (MRD) by using flow cytometry after induction therapy is strongly prognostic in pediatric AML, and hematopoietic stem-cell transplant (hSCT) may counteract a poor response. We designed a phase III study with intensified response-guided induction and MRD-based risk stratification and treated poor induction response with hSCT. The efficacy of liposomal daunorubicin (DNX) in induction was compared with mitoxantrone.
METHODS
The study planned to randomly assign 300 patients, but the production of DNX ceased in 2017. One hundred ninety-four patients were randomly assigned to mitoxantrone or experimental DNX in induction 1. Ninety-three non-randomly assigned patients served as an observation cohort. Primary end point was fraction of patients with MRD <0.1% on day 22 after induction 1. Patients with MRD ≥15% after induction 1 or ≥0.1% after induction 2 or -ITD with wildtype were stratified to high-risk therapy, including hSCT.
RESULTS
Outcome for all 287 children was good with 5-year event-free survival (EFS) 66.7% (CI, 61.4 to 72.4) and 5-year overall survival (OS) 79.6% (CI, 75.0 to 84.4). Overall, 75% were stratified to standard-risk and 19% to high-risk. There was no difference in the proportion of patients with MRD <0.1% on day 22 after induction 1 (34% mitoxantrone, etoposide, araC [MEC], 30% DNX, = .65), but the proportion increased to 61% for MEC versus 47% for DNX ( = .061) at the last evaluation before induction 2. EFS was significantly lower, 56.6% (CI, 46.7 to 66.5) versus 71.9% (CI, 63.0 to 80.9), and cumulative incidence of relapse (CIR) was higher, 35.1% (CI, 25.7 to 44.7) versus 18.8% (CI, 11.6 to 27.2) for DNX. The inferior outcome for DNX was only in standard-risk patients with EFS 55.3% (CI, 45.1 to 67.7) versus 79.9% (CI, 71.1 to 89.9), CIR 39.5% (CI, 28.4 to 50.3) versus 18.7% (CI, 10.5 to 28.7), and OS 76.2% (CI, 67.2 to 86.4) versus 88.6% (CI, 81.4 to 96.3). As-treated analyses, including the observation cohort, supported these results. For all high-risk patients, 85% received hSCT, and EFS was 77.7 (CI, 67.3 to 89.7) and OS was 83.0 (CI, 73.5 to 93.8).
CONCLUSION
The intensification of induction therapy with risk stratification on the basis of response to induction and hSCT for high-risk patients led to improved outcomes. Mitoxantrone had a superior anti-leukemic effect than liposomal daunorubicin.
Topics: Humans; Mitoxantrone; Daunorubicin; Neoplasm, Residual; Child; Leukemia, Myeloid, Acute; Male; Child, Preschool; Female; Infant; Adolescent; Liposomes; Flow Cytometry; Nucleophosmin; Risk Assessment; Hematopoietic Stem Cell Transplantation; Induction Chemotherapy; Antibiotics, Antineoplastic
PubMed: 38603646
DOI: 10.1200/JCO.23.01841