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International Journal of Pharmaceutics Nov 2023As the only Food and Drug Administration (FDA)-approved dual-encapsulation liposome injection for treating Acute myeloid leukemia (AML), CPX-351 outperforms the standard...
As the only Food and Drug Administration (FDA)-approved dual-encapsulation liposome injection for treating Acute myeloid leukemia (AML), CPX-351 outperforms the standard chemotherapy treatment "DA 7 + 3″ in terms of clinical effectiveness. Although research on dual-loaded liposomes has increased in recent years, little attention has been paid to their preparation, which can affect their quality, efficacy, and safety. This study explored various preparation processes to create the cytarabine/daunorubicin co-loaded liposome (the Cyt/Daun liposome) and eventually settled on two methods: the sequential loading approach, thin film hydration-extrusion-copper ion gradient, and the simultaneous encapsulation technique, copper ion gradient-concentration gradient. Different preparation methods resulted in different particle sizes and encapsulation efficiencies; the two aforementioned preparation processes generated dual-loaded liposomes with comparable physicochemical properties. The sequential encapsulation technique was selected for the subsequent research owing to its higher encapsulation efficiency prior to purification; the prepared Cyt/Daun liposomes had small and uniform particle size (108.6 ± 1.02 nm, Polydispersity index (PDI) 0.139 ± 0.01), negative charge (-(60.2 ± 1.15) mV), high drug encapsulation efficiency (Cyt 88.2 ± 0.24 %, Duan 94.2 ± 0.45 %) and good plasma stability. To improve its storage stability, the Cyt/Daun liposome was lyophilized (-40 °C for 4 h, maintained for 130 min, and dried for 1200 min) using sucrose-raffinose (mass ratio 7:3; glycolipid ratio 4:1, w/w) as a lyoprotectant. The lyophilized liposomes were purple cakes, redissolved rapidly with insignificant alterations in particle size and encapsulation efficiency, and possessed well storage stability. The pharmacokinetic and tissue distribution studies demonstrated that the Cyt/Daun liposome could achieve long circulation and maintain synergic proportions of drugs within 24 h, increasing the accumulation of drugs at tumor sites. Furthermore, the in vitro/in vivo pharmacodynamic studies confirmed its good anti-tumor activity and safety.
Topics: Humans; Liposomes; Copper; Daunorubicin; Leukemia, Myeloid, Acute; Cytarabine
PubMed: 37820944
DOI: 10.1016/j.ijpharm.2023.123500 -
International Journal of Biological... Nov 2023The combined diagnostic imaging, chemotherapy, and gene therapy based on DNA nanocarriers can reduce the toxic side effects and overcome multidrug resistance (MDR). In...
The combined diagnostic imaging, chemotherapy, and gene therapy based on DNA nanocarriers can reduce the toxic side effects and overcome multidrug resistance (MDR). In this study, we designed an antisense oligonucleotides (ASOs)-linked DNA tetrahedron (ASOs-TD). The detection limit of ASOs-TD for MDR1 mRNA was 0.05 μM. By using fluorescence spectroscopy and isothermal titration calorimetry (ITC), the interactions between doxorubicin (DOX) /daunorubicin (DAU) and ASOs-TD were investigated. The number of binding sites (n), binding constant (K), entropy change (ΔS), enthalpy change (ΔH) and Gibbs free energy change (ΔG) were obtained. The intercalation of DOX/DAU with ASOs-TD was demonstrated by differential scanning calorimetry (DSC) and quenching researches of potassium ferricyanide K[Fe(CN)]. The in vitro release rate of DOX/DAU loaded in ASOs-TD was accelerated by deoxyribonuclease I (DNase I). In vitro cytotoxicity proved the good gene therapy effect of ASOs-TD and the increased cytotoxicity of DOX/DAU to MCF-7/ADR cells. The results of confocal laser scanning microscope (CLSM) suggested that ASOs-TD could effectively identify drug-resistant cells due to its good imaging ability for MDR1 mRNA. This work offers theoretical significance for overcoming MDR using DNA nanostructures which combine diagnostic imaging, chemotherapy, and gene therapy.
Topics: Doxorubicin; Humans; Thermodynamics; DNA; Genetic Therapy; Daunorubicin; MCF-7 Cells; Drug Carriers; Oligonucleotides, Antisense
PubMed: 37562474
DOI: 10.1016/j.ijbiomac.2023.126245 -
Journal of Biomolecular Structure &... Dec 2023Daunorubicin (DNR) is a chemotherapeutic drug associated with multiple side effects, including drug resistance. As the molecular mechanism related to these side effects...
Daunorubicin (DNR) is a chemotherapeutic drug associated with multiple side effects, including drug resistance. As the molecular mechanism related to these side effects remain unclear and mostly hypothesized, this study addresses and compares the role of DNR and its metabolite Daunorubicinol (DAUNol) to induce apoptosis and drug resistance using molecular docking, Molecular Dynamics (MD) simulation, MM-PBSA and chemical pathway analysis. The results showed that DNR's interaction was stronger with Bax protein, Mcl-1:mNoxaB and Mcl-1:Bim protein complexes than DAUNol. On the other hand, contrasting results were obtained for drug resistance proteins where stronger interaction was obtained with DAUNol compared to DNR. Further, MD simulation performed for 100 ns provided the details of protein-ligand interaction. Most notable was the interaction of Bax protein with DNR, resulting in conformational changes at α-helices 5, 6 and 9, leading to Bax activation. Finally, the chemical signalling pathway analysis also revealed the regulation of different signalling pathways by DNR and DAUNol. It was observed that DNR majorly impacted the signalling associated with apoptosis while DAUNol mainly targeted pathways related to multidrug resistance and cardiotoxicity. Overall, the results highlight that DNR biotransformation reduces its capability to induce apoptosis while enhancing its ability to induce drug resistance and off-target toxicity.Communicated by Ramaswamy H. Sarma.
Topics: bcl-2-Associated X Protein; Molecular Docking Simulation; Myeloid Cell Leukemia Sequence 1 Protein; Daunorubicin; Drug Resistance, Multiple
PubMed: 36907598
DOI: 10.1080/07391102.2023.2187214 -
BMC Cancer Sep 2023Recent achievements in cancer therapy are the use of alternating electrical fields at intermediate frequencies (100-300 kHz) and low intensities (1-3 V/cm), which...
BACKGROUND
Recent achievements in cancer therapy are the use of alternating electrical fields at intermediate frequencies (100-300 kHz) and low intensities (1-3 V/cm), which specifically target cell proliferation while affecting different cellular activities depending on the frequency used.
METHODS
In this article, we examine the effect of electric fields on spherical suspended cells and propose the combination of Daunorubicin, a chemotherapy agent widely used in the treatment of acute myeloid leukemia, with electric field exposure. U937 cells were subjected to an electric field with a frequency of 200 kHz and an intensity of 0.75 V/cm, or to a combination of Daunorubicin and electric field exposure, resulting in a significant reduction in cell proliferation. Furthermore, the application of an electric field to U937 cells increased Daunorubicin uptake.
RESULTS
Apoptosis and DNA damage were induced by the electric field or in conjunction with Daunorubicin. Notably, normal cells exposed to an electric field did not show significant damage, indicating a selective effect on dividing cancer cells (U937). Moreover, the electric field affects the U937 cell line either alone or in combination with Daunorubicin. This effect may be due to increased membrane permeability.
CONCLUSIONS
Our findings suggest that the use of electric fields at intermediate frequencies and low intensities, either alone or in combination with Daunorubicin, has potential as a selective anti-cancer therapy for dividing cancer cells, particularly in the treatment of acute myeloid leukemia. Further research is needed to fully understand the underlying mechanisms and to optimize the use of this therapy.
Topics: Humans; U937 Cells; Blood Cells; Hematologic Neoplasms; Treatment Outcome; Daunorubicin
PubMed: 37700230
DOI: 10.1186/s12885-023-11339-7 -
American Journal of Hematology Nov 2020Management of AML involves choosing between purely palliative care, standard therapy and investigational therapy ("clinical trial"). Even most older patients likely... (Review)
Review
Management of AML involves choosing between purely palliative care, standard therapy and investigational therapy ("clinical trial"). Even most older patients likely benefit from treatment. Based on randomized trials CPX 351, midostaurin, gemtuzumab ozogamicin, and venetoclax, the latter three when combined with other drugs, should now be considered standard therapy. Knowledge of the likely results with these therapies is essential in deciding whether to recommend them or participate in a clinical trial, possibly including these drugs. Hence here, in the context of established prognostic algorithms, we review results with the recently- approved drugs compared with their predecessors and describe other potential options. We discuss benefit/risk ratios underlying the decision to offer allogeneic transplant and emphasize the importance of measurable residual disease. When first seeing a newly-diagnosed patient physicians must decide whether to offer conventional treatment or investigational therapy, the latter preferably in the context of a clinical trial. As noted below, such trials have led to changes in what today is considered "conventional" therapy compared to even 1-2 years ago. In older patients decision making has often included inquiring whether specific anti-AML therapy should be offered at all, rather than focusing on a purely palliative approach emphasizing transfusion and antibiotic support, with involvement of a palliative care specialist.
Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Daunorubicin; Gemtuzumab; Leukemia, Myeloid, Acute; Randomized Controlled Trials as Topic; Risk Assessment; Staurosporine; Sulfonamides; United States
PubMed: 32833263
DOI: 10.1002/ajh.25975 -
Journal of Pharmaceutical Sciences Jan 2023Acute myeloid leukemia (AML) remains a threatening disease due to severe complications, drug resistance, and high recurrence rates. Many drug combinations have...
Acute myeloid leukemia (AML) remains a threatening disease due to severe complications, drug resistance, and high recurrence rates. Many drug combinations have demonstrated enhanced therapeutic effects in clinical practice. However, it requires complicated dosing regimens and is accompanied by increased toxicity. This study explored the combined effect of two therapeutic agents, daunorubicin (DNR) and homoharringtonine (HHT) in cell viability, apoptosis, and cell cycle in vitro and verified their synergistic effect. We encapsulated the two drugs into liposomes to construct a folic acid-modified co-delivery system (FA-DH-LP) to achieve an effective and safe therapeutic strategy. The FA-DH-LP was prepared by film hydration method. The resultant FA-DH-LP was homogeneously spherical and showed good blood compatibility with high encapsulation efficiency for DNR and HHT. The FA-DH-LP exhibited higher cellular uptake in HL60 and K562 cells and enhanced cytotoxicity than DNR/HHT co-delivery liposomes without folic acid modification (DH-LP) in vitro. In the HL60 subcutaneous xenotransplantation model, FA-DH-LP showed improved tumor targeting ability, anti-leukemia activity and safety profile superior to free combinational drugs and DH-LP after 18-day treatment. The results demonstrated that FA-DH-LP might present a promising delivery strategy to improve the efficacy of the two combinational chemotherapeutics while reducing toxicity.
Topics: Humans; Daunorubicin; Liposomes; Homoharringtonine; Folic Acid; Leukemia, Myeloid, Acute; Cell Line, Tumor
PubMed: 35469834
DOI: 10.1016/j.xphs.2022.04.014 -
International Journal of Molecular... May 2022The human gonadotropin releasing hormone (GnRH-I) and its sea lamprey analogue GnRH-III specifically bind to GnRH receptors on cancer cells and can be used as targeting...
The human gonadotropin releasing hormone (GnRH-I) and its sea lamprey analogue GnRH-III specifically bind to GnRH receptors on cancer cells and can be used as targeting moieties for targeted tumor therapy. Considering that the selective release of drugs in cancer cells is of high relevance, we were encouraged to develop cleavable, self-immolative GnRH-III-drug conjugates which consist of a -aminobenzyloxycarbonlyl (PABC) spacer between a cathepsin B-cleavable dipeptide (Val-Ala, Val-Cit) and the classical anticancer drugs daunorubicin (Dau) and paclitaxel (PTX). Alongside these compounds, non-cleavable GnRH-III-drug conjugates were also synthesized, and all compounds were analyzed for their antiproliferative activity. The cleavable GnRH-III bioconjugates revealed a growth inhibitory effect on GnRH receptor-expressing A2780 ovarian cancer cells, while their activity was reduced on Panc-1 pancreatic cancer cells exhibiting a lower GnRH receptor level. Moreover, the antiproliferative activity of the non-cleavable counterparts was strongly reduced. Additionally, the efficient cleavage of the Val-Ala linker and the subsequent release of the drugs could be verified by lysosomal degradation studies, while radioligand binding studies ensured that the GnRH-III-drug conjugates bound to the GnRH receptor with high affinity. Our results underline the high value of GnRH-III-based homing devices and the application of cathepsin B-cleavable linker systems for the development of small molecule drug conjugates (SMDCs).
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cathepsin B; Cell Line, Tumor; Daunorubicin; Female; Gonadotropin-Releasing Hormone; Humans; Molecular Targeted Therapy; Ovarian Neoplasms; Paclitaxel; Petromyzon; Pyrrolidonecarboxylic Acid; Receptors, LHRH
PubMed: 35563462
DOI: 10.3390/ijms23095071 -
Blood Advances Jan 2022Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children and adolescents and have a dismal prognosis. The mainstay therapy is...
Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children and adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT), but there has been no innovation in cytoreductive regimens. CP X-351, a fixed 5:1 molar ratio of liposomal cytarabine to daunorubicin, has shown favorable safety and efficacy in elderly individuals with secondary AML and children with relapsed de novo AML. We report the outcomes of 7 young patients (6 with newly diagnosed sMDS/AML and 1 with primary MDS/AML) uniformly treated with CP X-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-cell acute lymphoblastic leukemia; 1 had predisposing genomic instability disorder (Cornelia de Lange syndrome) and 1 had MDS-related AML and multiorgan failure. The median age at diagnosis of myeloid malignancy was 17 years (range, 13-23 years). Patients received 1 to 3 cycles of CP X-351 (cytarabine 100 mg/m2 plus daunorubicin 44 mg/m2) on days 1, 3, and 5, resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding an FLT3 inhibitor as individualized therapy in 1 patient. Six patients were alive and leukemia-free at 0.5 to 3.3 years after HCT. One patient died as a result of disease progression before HCT. To summarize, CP X-351 is an effective and well-tolerated regimen for cytoreduction in pediatric sMDS/AML that warrants prospective studies.
Topics: Adolescent; Aged; Child; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Neoplasms, Second Primary; Prospective Studies
PubMed: 34710216
DOI: 10.1182/bloodadvances.2021006139 -
Pediatric Blood & Cancer Sep 2020Approximately 40% children with acute myeloid leukemia (AML) invariably relapse, after attaining the first complete remission (CR), with dismal long-term outcome. There...
Outpatient ADE (cytarabine, daunorubicin, and etoposide) is feasible and effective for the first relapse of pediatric acute myeloid leukemia: A prospective, phase II study.
BACKGROUND
Approximately 40% children with acute myeloid leukemia (AML) invariably relapse, after attaining the first complete remission (CR), with dismal long-term outcome. There is little consensus regarding choice of optimal induction chemotherapy regimen for relapsed pediatric AML.
PROCEDURE
A prospective single arm phase II study (CTRI/2017/02/007757) was carried out at our center to evaluate the safety and efficacy of outpatient cytarabine, daunorubicin, and etoposide (ADE) regimen in pediatric AML (≤18 years) at the first relapse. Response evaluation was done by bone marrow aspiration morphology along with minimal residual disease (MRD) assessment. All adverse events including need and duration of hospitalization, transfusion support, and antimicrobial use were recorded.
RESULTS
Total 45 patients were included with median age of 12 years. The CR rate of the cohort was 66% and 54% of patients were MRD negative. The estimated 2-year event-free survival (EFS) and overall survival (OS) were 29% (±7%) and 34% (±7%), respectively. The presence of fever at relapse was associated with inferior CR rate (P = .001), positive MRD (P = .01), and inferior EFS (P = .02), while not achieving nadir absolute neutrophil count of zero during induction was associated with inferior CR rate (P = .03) and inferior OS (P = .04). Approximately all patients developed ≥Grade 3 cytopenia and febrile neutropenia. Twenty-six (59%) patients required hospitalization for management of toxicity and there were four (9%) deaths attributed to infection.
CONCLUSION
ADE is an effective induction regimen for pediatric AML patients at the first relapse with reasonable toxicity profile. Outpatient administration of the regimen is feasible in the presence of proper support structure and rigorous follow up.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Prospective Studies; Recurrence; Survival Rate
PubMed: 32672904
DOI: 10.1002/pbc.28404 -
Drug Delivery Dec 2020Proliferative vitreoretinopathy (PVR) is a significant threat for vision recovery from retinal detachment or ocular trauma. Currently, no approved pharmacological...
Proliferative vitreoretinopathy (PVR) is a significant threat for vision recovery from retinal detachment or ocular trauma. Currently, no approved pharmacological intervention to prevent PVR. Daunorubicin (DNR) and dexamethasone (DEX) were sequentially loaded into oxidized porous silicon (pSiO) particles by covalent conjugation. The DNR + DEX-loaded particles, and control particles loaded with DNR only and DEX only were incubated with RPE-populated collagen for daily gel surface quantitation. Toxicity was monitored by ophthalmic examinations and histological evaluation 21 days after injection. At 3rd week following intravitreal injection, a localized retinal detachment (RD) was created by subretinal injection of Healon in all pretreated eyes in addition to 3 non-interventional control eyes. 10 µg of bromodeoxyuridine (BrdU) was injected into the vitreous 4 h before sacrifice on day 3 after RD induction. Retinal sections were stained for glial fibrillary green protein (GFAP) and BrdU to identify activated glial cells and retinal cell proliferation. The studies demonstrated that all three pSiO particle types were well tolerated in vivo. DNR alone and DNR + DEX combination formulations demonstrated equally strong suppression on gel contraction (least square mean area of the gel: control = 1.71 vs. 30DNR = 1.85 or 30/40Dual = 1.83, < .05). Eyes pretreated with pSiO-DNR + DEX exhibited the least GFAP activation (least square mean intensity mm: Dual = 4.03, DNR = 7.76, Dex = 16.23, control = 29.11, < .05) and BrdU expression (Mean number of BrdU positive cells per mm of retina: Dual = 2.77, DNR = 4.58, Dex = 4.01, control = 6.16, < .05). The synergistic effect of a sustained release pSiO-DNR/DEX showed promise for the prevention of PVR development while reducing the necessary therapeutic concentration of each drug.
Topics: Animals; Daunorubicin; Delayed-Action Preparations; Dexamethasone; Drug Delivery Systems; Intravitreal Injections; Porosity; Rabbits; Retina; Retinal Detachment; Silicon; Vitreoretinopathy, Proliferative; Vitreous Body
PubMed: 33100053
DOI: 10.1080/10717544.2020.1833382