Encapsulation of Imatinib in Targeted KIT-5 Nanoparticles for Reducing its Cardiotoxicity and Hepatotoxicity

2020 ◽  
Vol 20 (16) ◽  
pp. 1966-1980
Author(s):  
Jaleh Varshosaz ◽  
Saeedeh Fardshouraki ◽  
Mina Mirian ◽  
Leila Safaeian ◽  
Setareh Jandaghian ◽  
...  
Keyword(s):  
Controlled Release ◽  
Side Effects ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Drug Carrier ◽  
Free Drug ◽  
Jurkat Cells ◽  
Targeted Nanoparticles ◽  
Inhibitor Drug ◽  
Histopathological Results

Background: Using imatinib, a tyrosine kinase inhibitor drug used in lymphoblastic leukemia, has always had limitations due to its cardiotoxicity and hepatotoxicity side effects. The objective of this study is to develop a target-oriented drug carrier to minimize these adverse effects by the controlled release of the drug. Methods: KIT-5 nanoparticles were functionalized with 3-aminopropyltriethoxysilane and conjugated to rituximab as the targeting agent for the CD20 positive receptors of the B-cells. Then they were loaded with imatinib and their physical properties were characterized. The cell cytotoxicity of the nanoparticles was studied by MTT assay in Ramos (CD20 positive) and Jurkat cell lines (CD20 negative) and their cellular uptake was shown by fluorescence microscope. Wistar rats received an intraperitoneal injection of 50 mg/kg of the free drug or targeted nanoparticles for 21 days. Then the level of aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Lactate Dehydrogenase (LDH) were measured in serum of animals. The cardiotoxicity and hepatotoxicity of the drug were also studied by hematoxylin and eosin staining of the tissues. Results: The targeted nanoparticles of imatinib showed to be more cytotoxic to Ramos cells rather than Jurkat cells. The results of the biochemical analysis displayed a significant reduction in AST, ALT, ALP, and LDH levels in animals treated with targeted nanoparticles, compared to the free drug group. By comparison with the free imatinib, histopathological results represented less cardiotoxicity and hepatotoxicity in the animals, which received the drug through the current designed delivery system. Conclusion: The obtained results confirmed that the rituximab targeted KIT-5 nanoparticles are promising in the controlled release of imatinib and could decrease its cardiotoxicity and hepatotoxicity side effects.

scholarly journals Recurrent Gastrointestinal Hemorrhage in Children with Philadelphia-Positive B-Cell Acute Lymphoblastic Leukemia Treated with Dasatinib: Case Reports

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Xin Liao ◽  
Yuxia Guo ◽  
Yali Shen ◽  
Jianwen Xiao
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Side Effects ◽  
B Cell ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Case Reports ◽  
Lymphoblastic Leukemia ◽  
Bleeding Disorders ◽  
Platelet Dysfunction ◽  
Cell Acute Lymphoblastic Leukemia

Dasatinib, a second-line tyrosine kinase inhibitor (TKI), has been widely used in chronic myeloid leukemia (CML) and Philadelphia-positive B-cell acute lymphoblastic leukemia (Ph + B-ALL). Although dasatinib has been well tolerated, side effects including hemorrhage are not rare. Cases of bleeding disorders ultimately result in thrombocytopenia, but platelet aggregation dysfunction induced by dasatinib has also been demonstrated in Ph + B-ALL and CML patients. We report three Chinese children with Ph + B-ALL who received a combination treatment of chemotherapy and dasatinib and developed gastrointestinal bleeding several months later. The platelet count and clotting tests were normal, and these patients presented with dasatinib-induced platelet dysfunction. These findings reveal that physicians should be aware of and carefully monitor for side effects, including bleeding disorders.

A Novel Dual AXL/Mertk and Aurora Kinase Inhibitor Active Against T Cell Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1519-1519
Author(s):  
Anupam Verma ◽  
J. Kimble Frazer ◽  
Alesia Trakhimets ◽  
William Heaton ◽  
Jared Bearrs ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Fluorescent Microscopy ◽  
Histone H3 ◽  
Aurora Kinase ◽  
Negative Control ◽  
Jurkat Cells ◽  
Aurora Kinase Inhibitor

Abstract Abstract 1519 INTRODUCTION: Receptor tyrosine kinases AXL and MER belong to the TYRO3 kinase family, first identified as a transforming gene in chronic myeloid leukemia and are found at high levels in various cancers, including hematopoietic malignancies like T cell acute lymphoblastic leukemia (T-ALL). Aurora kinases play important roles in chromosome alignment and cytokinesis during mitosis and are also aberrantly expressed in ALL. We describe here characterization and pre-clinical testing of Huntsman Cancer Institute-2084 (HCI-2084), a small molecule inhibitor of AXL and MER kinases that also has activity against Aurora Kinases A and B, as a novel therapeutic for T-ALL treatment, a leukemia with poor prognosis. METHODS: Quantitative RT-PCR and Western Blot confirmed elevated levels of AXL/MER expression in Jurkat, a human T-ALL, cell line. Our compound, HCI-2084, was developed using a computational structure-based approach against AXL kinase. HCI-2084 activity against AXL/MER, in cell-based assays was evaluated utilizing ATPlite. To test activity against Aurora kinase, Jurkat cells were treated with various concentrations of HCI-2084 and VX 680, a known aurora kinase inhibitor, for 24 hours. Cell lysates were evaluated for phospho-AKT (Ser473), phospho-Aurora (Thr288) and phospho-Histone H3 (Ser10) using the Meso Scale Discovery platform (MSD). Cell cycle analysis was performed on Jurkat cells incubated in the absence (negative control) or presence of 100nM HCI-2084 or VX-680 for 24 hours, stained with propidium iodide and analyzed by flow cytometry on FACS Calibur. Immunostaining was performed to evaluate the levels of phospho-Histone H3 (Ser10) and phospho-Aurora (Thr288) during mitosis in Jurkat cells incubated in the absence (negative control) or presence of 100nM HCI-2084 and VX-680 for 24 hours. In addition to the anti-phospho-Histone H3 and anti-phospho-Aurora antibodies, anti-alpha-tubulin and DAPI were used to determine the presence of mitotic chromosomes. To examine HCI-2084 as a therapeutic agent for T-ALL treatment in vivo, we tested it using transgenic Zebrafish (Danio rerio) with T-ALL driven by human MYC (hMYC). Over-expression of endogenous D. rerio axl /mertk transcripts in T-ALL from hMYC fish were verified by qRT-PCR. Fish were treated with HCI-2084, Dexamethasone (a known T-ALL therapeutic; positive control), and DMSO vehicle (HCI-2084 is reconstituted in DMSO; negative control). Trials were conducted by housing fish with fluorescently-labeled T-ALL (GFP-tagged) in water containing the agent being tested, for 14 days with monitoring of disease response by fluorescent microscopy. RESULTS: In in vitro studies, HCI-2084 showed potent activity in cell viability assays with an IC50 of 12 nM against AXL, 60 nM against MERTK and 15 nM against Aurora kinase. MSD assays demonstrated efficacy at 1 uM for reduction of phospho-AKT, phospho-Histone H3 and phospho-Aurora, as seen with VX 680. Cell cycle analyses performed on HCI-2084-treated Jurkat cells showed a significantly increased G2/M population and an accumulation of cells with ≥4N DNA, indicative of Aurora B inhibition and endo-reduplication (Figure A & B). Immunofluorescence analyzed using fluorescent microscopy demonstrated mitotic arrest with loss of phospho-Histone H3 and phospho-Aurora staining, demonstrating inhibition of Aurora kinase activity. HCI-2084 was also a potent therapeutic against Zebrafish T-ALL. Fish treated at 1uM HCI-2084 for 14 days, showed complete responses (CR), with efficacy comparable to our dexamethasone positive control (Figure C). Following treatment, fish remained disease-free for several days, and overall survival was prolonged significantly relative to untreated controls. CONCLUSION: HCI-2084 shows dual action in vitro against Jurkat cells with potent cytotoxicity via AXL/MER kinase inhibition and anti-proliferative activity via Aurora kinase inhibition. In vivo, HCI-2084 demonstrates activity against a MYC-driven vertebrate model of T-ALL, prolongs survival, and is well tolerated. We conclude that HCI-2084 is a potent dual AXL/MER kinase and Aurora kinase inhibitor which should be explored further as a potential novel therapeutic in the treatment of human T-ALL. Disclosures: Sharma: Millenium: Research Funding.

A Phase II Study of Methotrexate (M), Vincristine (O), Pegylated L-Asparaginase (pA), and Dexamethasone (MOpAD) in Patients with Relapsed and/or Refractory Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4308-4308
Author(s):  
Tapan M. Kadia ◽  
Jorge E. Cortes ◽  
Deborah Thomas ◽  
Farhad Ravandi ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Side Effects ◽  
Phase Ii ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Median Number ◽  
Cell Transplant ◽  
Dependent Manner ◽  
Salvage Regimen ◽  
Term Survival

Abstract Abstract 4308 Introduction Adults with relapsed or refractory (R/R) ALL have a poor prognosis, with low rates of complete remission (CR) to standard salvage therapy and long term survival of less than 5%. L-asparaginase has a unique mechanism of action and is highly active in ALL, but its use in adults has been limited by concerns for side effects. A new pegylated (peg) preparation bestows a longer half-life, less immunogenicity, and better tolerance. Additionally L-asparaginase has a significant synergy when combined with methotrexate in schedule-dependent manner. Methods Patients with previously treated, R/R ALL (including Burkitt's and Philadelphia [Ph] positive) with adequate organ function, and PS ≤ 3 were enrolled on a phase II clinical trial to determine the efficacy and safety of MOpAD. Patients were stratified in two groups: 1st salvage or3 2nd salvage. They were treated on the following schedule: methotrexate 200 mg/m2/d IV on days 1 & 15; vincristine 1.4 mg/m2/d (max 2 mg) IV on days 1,8, & 15; peg-asparaginase 2500 IU/m2/d on days 2 and 16; and dexamethasone 40 mg IV or PO daily on days 1–4 and 15–18. Patients with CD20+ ALL could receive rituximab 375 mg/m2/d IV on days 1 & 15 for the first 4 cycles (1 cycle=28 d). A later amendment allowed patients with Ph+ ALL to also receive daily imatinib, dasatinib, or nilotinib in conjunction with MOAD. Results A total of 27 patients (37% female) with R/R ALL have been enrolled thus far, with a median age of 41 (range, 24–68) and median PS of 1 (0–3). Eighteen pts (67%) had B-ALL (including 6 with Ph+ ALL), and 9 (33%) had T-ALL. The median number of prior therapies is 2 (1–6), and the breakdown by salvage is as follows: 1st salvage: 10 (37%); ≥ 2nd salvage: 17 (63%). 5 pts received rituximab, and 2 of 6 Ph+ pts received a tyrosine kinase inhibitor (TKI) (1 each of dasatinib and nilotinib). The overall response rate (ORR) was (12/27) 44%, with 8 CR (30%), 1 CRi (4%), and 3 CRp (11%). The ORR by salvage status was 25% in 1st salvage and 47% in ≥ 2nd salvage. The ORR by phenotype: Ph(−) B-ALL: 17%, Ph+ B-ALL: 67%, and T-ALL: 67%. All 6 patients (100%) with T-ALL who responded were able to go on to stem cell transplant. Response predicted for improved OS: median 9 months vs. 1 month in responders vs. non-responders. The most common grade 3/4 adverse events included low fibrinogen (44%), elevated bilirubin (37%), transaminitis (26%), elevated amylase/lipase without pancreatitis (15%), and thrombosis (11%). Side effects were manageable overall, myelosuppression was universal, and there were 3 early deaths (11%). Conclusions The non-anthracycline-based combination of MOpAD is a safe and effective salvage regimen in adult patients with relapsed ALL, particularly those with T-ALL or Ph+ disease. The chemotherapy backbone can be combined safely with rituximab and TKIs in this setting. Patients continue to be enrolled and updated results will be presented. Disclosures: Kadia: GSK: Research Funding. Borthakur:Sigma Tau: Research Funding.

scholarly journals Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia

Blood ◽  
2020 ◽  
Vol 136 (2) ◽  
pp. 210-223 ◽  
Author(s):  
Eun Ji Gang ◽  
Hye Na Kim ◽  
Yao-Te Hsieh ◽  
Yongsheng Ruan ◽  
Heather A. Ogana ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Underlying Mechanism ◽  
Conditional Knockout

Abstract Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

scholarly journals Formulation and development of metformin-loaded microspheres using Khaya senegalensis (Meliaceae) gum as co-polymer

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Chukwuebuka H. Ozoude ◽  
Chukwuemeka P. Azubuike ◽  
Modupe O. Ologunagba ◽  
Sejoro S. Tonuewa ◽  
Cecilia I. Igwilo
Keyword(s):  
Controlled Release ◽  
Sodium Alginate ◽  
Release Kinetics ◽  
Drug Carrier ◽  
In Vitro Release ◽  
Entrapment Efficiency ◽  
Metformin Hydrochloride ◽  
Scanning Calorimetry ◽  
Khaya Senegalensis

Abstract Background Khaya gum is a bark exudate from Khaya senegalensis (Maliaecae) that has drug carrier potential. This study aimed to formulate and comparatively evaluate metformin-loaded microspheres using blends of khaya gum and sodium alginate. Khaya gum was extracted and subjected to preformulation studies using established protocols while three formulations (FA; FB and FC) of metformin (1% w/v)-loaded microspheres were prepared by the ionic gelation method using 5% zinc chloride solution as the cross-linker. The formulations contained 2% w/v blends of khaya gum and sodium alginate in the ratios of 2:3, 9:11, and 1:1, respectively. The microspheres were evaluated by scanning electron microscopy, Fourier transform-infrared spectroscopy, differential scanning calorimetry, entrapment efficiency, swelling index, and in vitro release studies. Results Yield of 28.48%, pH of 4.00 ± 0.05, moisture content (14.59% ± 0.50), and fair flow properties (Carr’s index 23.68 ± 1.91 and Hausner’s ratio 1.31 ± 0.03) of the khaya gum were obtained. FTIR analyses showed no significant interaction between pure metformin hydrochloride with excipients. Discrete spherical microspheres with sizes ranging from 1200 to 1420 μm were obtained. Drug entrapment efficiency of the microspheres ranged from 65.6 to 81.5%. The release of the drug from microspheres was sustained for the 9 h of the study as the cumulative release was 62% (FA), 73% (FB), and 80% (FC). The release kinetics followed Korsmeyer-Peppas model with super case-II transport mechanism. Conclusion Blends of Khaya senegalensis gum and sodium alginate are promising polymer combination for the preparation of controlled-release formulations. The blend of the khaya gum and sodium alginate produced microspheres with controlled release properties. However, the formulation containing 2:3 ratio of khaya gum and sodium alginate respectively produced microspheres with comparable controlled release profiles to the commercial brand metformin tablet.

scholarly journals Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 365
Author(s):  
Carina Colturato-Kido ◽  
Rayssa M. Lopes ◽  
Hyllana C. D. Medeiros ◽  
Claudia A. Costa ◽  
Laura F. L. Prado-Souza ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clinical Problem ◽  
Jurkat Cells ◽  
Leukemia Cells ◽  
Peripheral Mononuclear Blood ◽  
Induced Apoptosis ◽  
Cure Rates

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve the disease outcome. Antipsychotic phenothiazines have emerged as potential candidates to be repositioned as antitumor drugs. It was previously shown that the anti-histaminic phenothiazine derivative promethazine induced autophagy-associated cell death in chronic myeloid leukemia cells, although autophagy can act as a “double-edged sword” contributing to cell survival or cell death. Here we evaluated the role of autophagy in thioridazine (TR)-induced cell death in the human ALL model. TR induced apoptosis in ALL Jurkat cells and it was not cytotoxic to normal peripheral mononuclear blood cells. TR promoted the activation of caspase-8 and -3, which was associated with increased NOXA/MCL-1 ratio and autophagy triggering. AMPK/PI3K/AKT/mTOR and MAPK/ERK pathways are involved in TR-induced cell death. The inhibition of the autophagic process enhanced the cytotoxicity of TR in Jurkat cells, highlighting autophagy as a targetable process for drug development purposes in ALL.

scholarly journals A Novel Hollow Hydroxyapatite Microspheres/Chitosan Composite Drug Carrier for Controlled Release

2016 ◽  
Vol 31 (4) ◽  
pp. 434 ◽  
Author(s):  
ZHU Kai-Ping ◽  
SUN Jing ◽  
YE Song ◽  
ZHOU Jie ◽  
WANG Hui ◽  
...  
Keyword(s):  
Controlled Release ◽  
Drug Carrier ◽  
Chitosan Composite
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