Utilization of Lipid-based Nanoparticles to Improve the Therapeutic Benefits of Bortezomib

2020 ◽  
Vol 20 (6) ◽  
pp. 643-650 ◽  
Author(s):  
Mitra Korani ◽  
Shahla Korani ◽  
Elham Zendehdel ◽  
Mahmoud R. Jaafari ◽  
Thozhukat Sathyapalan ◽  
...  
Keyword(s):  
Proteasome Inhibitor ◽  
Drug Delivery Systems ◽  
Water Solubility ◽  
Cell Lymphoma ◽  
Aqueous Solubility ◽  
Therapeutic Benefits ◽  
Mantle Cell ◽  
The Us ◽  
High Incidence ◽  
And Control

Cancer is a condition where there is an uncontrolled growth of cells resulting in high mortality. It is the second most frequent cause of death worldwide. Bortezomib (BTZ) is a Proteasome Inhibitor (PI) that is used for the treatment of a variety of cancers. It is the first PI that has received the approval of the US Food and Drug Administration (FDA) to treat mantle cell lymphoma and multiple myeloma. High incidence of sideeffects, limited dose, low water solubility, fast clearance, and drug resistance are the significant limitations of BTZ. Therefore, various drug delivery systems have been tried to overcome these limitations of BTZ in cancer therapy. Nanotechnology can potentially enhance the aqueous solubility of BTZ, increase its bioavailability, and control the release of BTZ at the site of administration. The lipid-based nanocarriers, such as liposomes, solid lipid NPs, and microemulsions, are some of the developments in nanotechnology, which could potentially enhance the therapeutic benefits of BTZ.

scholarly journals Progress on the Application of Bortezomib and Bortezomib-Based Nanoformulations

Biomolecules ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 51
Author(s):  
Jianhao Liu ◽  
Ruogang Zhao ◽  
Xiaowen Jiang ◽  
Zhaohuan Li ◽  
Bo Zhang
Keyword(s):  
Proteasome Inhibitor ◽  
Drug Delivery Systems ◽  
Cell Lymphoma ◽  
Proteasome Inhibitors ◽  
Mechanisms Of Action ◽  
26S Proteasome ◽  
Amino Acid Residues ◽  
Preclinical Research ◽  
Hematological Cancers ◽  
Mantle Cell

Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in recent years, different BTZ-based drug delivery systems have been evaluated. In this review, we firstly discussed the functions of proteasome inhibitors and their mechanisms of action. Secondly, the properties of BTZ, as well as recent advances in both clinical and preclinical research, were reviewed. Finally, progress in research regarding BTZ-based nanoformulations was summarized.

A Review on Formulation and Development of Solid Self-Nano Emulsifying Drug Delivery Systems

2021 ◽  
Vol 14 (4) ◽  
pp. 5519-5228
Author(s):  
Sunitha M Reddy ◽  
Sravani Baskarla
Keyword(s):  
Drug Delivery ◽  
Dissolution Rate ◽  
Drug Delivery System ◽  
Delivery System ◽  
Drug Delivery Systems ◽  
Water Solubility ◽  
Drug Loading ◽  
Aqueous Solubility ◽  
Delivery Systems ◽  
Particle Size Reduction

This article describes current strategies to enhance aqueous solubility and dissolution rate of poor soluble drugs. Most drugs in the market are lipophilic with low or poor water solubility. There are various methods to enhance solubility: co-solvency, particle size reduction, salt formation and Self Nanoemulsifying drug delivery systems, SEDDS is a novel approach to enhance solubility, dissolution rate and bioavailability of drugs. The study involves formulation and evaluation of solid self-Nano emulsifying drug delivery system (S-SNEDDS) to enhance aqueous solubility and dissolution rate. Oral route is the most convenient route for non-invasive administration. S-SNEDDS has more advantages when compared to the liquid self-emulsifying drug delivery system. Excipients were selected depends upon the drug compatibility oils, surfactants and co surfactants were selected to formulate Liquid SNEDDS these formulated liquid self-nano emulsifying drug delivery system converted into solid by the help of porous carriers, Melted binder or with the help of drying process. Conversion process of liquid to solid involves various techniques; they are spray drying; freeze drying and fluid bed coating technique; extrusion, melting granulation technique. Liquid SNEDDS has a high ability to improve dissolution and solubility of drugs but it also has disadvantages like incompatibility, decreased drug loading, shorter shelf life, ease of manufacturing and ability to deliver peptides that are prone to enzymatic hydrolysis.  

Economic Evaluation of Ibrutinib Versus Acalabrutinib Versus Zanubrutinib for Patients with Relapsed or Refractory Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Neda Alrawashdh ◽  
Ali McBride ◽  
Marion Slack ◽  
Ivo Abraham
Keyword(s):  
Clinical Trials ◽  
Cost Effectiveness ◽  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Cost Effective ◽  
Health States ◽  
Mantle Cell ◽  
The Us ◽  
The Cost

Background . Refractory or relapsed mantle cell lymphoma (R/R MCL) is generally associated with poor outcomes; median overall survival (OS) is 4-5 years. First generation Bruton's tyrosine kinase inhibitor (BTKi) (Ibrutinib) and second generation BTKi (acalabrutinib and zanubrutinib) have led to significant improvements in efficacy and safety over conventional chemoimmunotherapy in treating R/R MCL. In the absence of direct head to head clinical trials compare between BTKi, indirect comparisons between the first and second BTKi generations show possible differences in safety and efficacy. We used existing evidence from phase I/II clinical trials for second BTKi generation to evaluate the cost-effectiveness of ibrutinib vs acalabrutinib vs zanubrutinib in treating patients with R/R MCL from the US payer perspective. Methods. A Markov model with two health states (progression-free [PF] and progression or death) was specified. Kaplan-Meier (KM) curves of PF survival (PFS) from the phase III trial by Dreyling et al. (Lancet 2016) for ibrutinib, the phase II trial by Wang et al. (Lancet 2018) for acalabrutinib, and the phase I/II trial by Tam et al. (Blood 2019) for zanubrutinib were fitted to exponential distributions to extract transition probabilities between the two health states for each drug. Wholesale acquisition costs (WAC) were obtained from RedBook and costs of adverse events management were derived from the literature. The analysis was conducted over a lifetime horizon with health utility outcomes and costs discounted at 3.5% per year after the first year. The cost and PFS life years (LYs) and PFS quality-adjusted LYs (QALYs) for each treatment, the incremental PFS LYs and PFS QALYs gained with acalabrutinib or zanubrutinib over ibrutinib, and the incremental cost-effectiveness ratio (ICER) and cost-utility ratio (ICUR) were estimated in both base and probabilistic sensitivity analyses (PSA: 100,000 simulations). Results. As detailed in the table, acalabrutinib and zanubrutinib were associated with better clinical outcomes than ibrutinib, with incremental PFS LYs gained of 1.61 and 0.98, and incremental PFS QALYs of 1.27 and 0.77, respectively. The incremental costs when comparing acalabrutinib and zanubrutinib with ibrutinib were $110,931and $64,624, respectively. In probabilistic analyses, the ICERs ($61,689/LYg for acalabrutinib; $53,438/LYg for zanubrutinib) and ICURs ($86,750/QALYg for acalabrutinib; $82,897/QALYg for zanubrutinib) were lower than the US willingness to pay (WTP) threshold of $100,000 to $150,000 per QALY for cancer treatment. At WTP of $100,000, the cost-effectiveness acceptability curves showed the probabilities of acalabrutinib, zanubrutinib, and ibrutinib being cost-effective to be 50%, 34%, and 16%, respectively. Conclusions. Acalabrutinib is more cost-effective compared with ibrutinib and zanubrutinib and improves health outcomes more in R/R MCL patients. This analysis using phase I/II trials should be validated as additional trial and real-world evidence about efficacy, safety, and associated health-related quality of life outcomes. Based on the current data, acalabrutinib offers the most cost-effective treatment option in R/R MCL. Disclosures McBride: Coherus BioSciences: Consultancy, Speakers Bureau; Merck: Speakers Bureau; Pfizer: Consultancy; Sandoz: Consultancy; MorphoSys: Consultancy; Bristol-Myers Squibb: Consultancy. Abraham:Janssen: Consultancy; Coherus BioSciences: Research Funding, Speakers Bureau; Celgene: Consultancy; Sandoz: Consultancy; MorphoSys: Consultancy; Mylan: Consultancy; Rockwell Medical: Consultancy; Terumo: Consultancy.

Treatment with Histone Deacetylase 6-Specific Inhibitor WT-161 Disrupts hsp90 Function, Abrogates Aggresome Formation and Sensitizes Human Mantle Cell Lymphoma Cells to Lethal ER Stress Induced by Proteasome Inhibitor Carfilzomib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2856-2856 ◽  
Author(s):  
Rekha Rao ◽  
Warren Fiskus ◽  
Ramesh Balusu ◽  
Hongwei Ma ◽  
James Bradner ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Histone Deacetylase ◽  
Proteasome Inhibitor ◽  
Cell Lymphoma ◽  
Specific Inhibitor ◽  
Er Stress Response ◽  
Mantle Cell ◽  
Aggresome Formation ◽  
Induced Apoptosis

Abstract Abstract 2856 The proteasome inhibitor bortezpmib has been shown to markedly increase the intracellular levels of misfolded proteins, induce aggresome formation and cause endoplasmic reticulum (ER) stress, resulting in apoptosis of human Mantle Cell Lymphoma (MCL) cells. Consistent with this, Bortezomib displays clinical efficacy in patients with relapsed and refractory MCL. We have recently reported that the pan-histone deacetylase (HDAC) inhibitor panobinostat, by also inhibiting HDAC6, abrogates aggresome formation and induces Endoplasmic Stress (ER) stress, as well as potentiates bortezomib-induced apoptosis of MCL cells. Here, we determined the anti-MCL cell activity of an HDAC6-specific inhibitor, WT-161 alone and in combination with the novel, orally bio-available, proteasome inhibitor carfilzomib (Proteolix Inc.) against human, cultured and primary, patient-derived MCL cells. Treatment with WT-161 (0.1 to 1.0 uM) resulted in a dose-dependent increase in the acetylation of alpha-tubulin and heat shock protein (hsp) 90, without any appreciable increase in the levels of acetylated histone (H) 3. Consistent with WT-161 mediated hyperacetylation and inhibition of hsp90 chaperone function, treatment with WT-161 increased the intracellular levels of polyubiuitylated proteins in the cultured MCL JeKo-1 and Z138 cells. WT-161 was also noted to dose-dependently deplete the levels of cyclin D1 in the cultured MCL cells. Treatment with WT-161 also induced ER stress response in the MCL cells, demonstrated by increase in the protein levels of Glucose regulated protein (GRP) 78, phosphorylated eIF2 (eukaryotic initation factor 2) α, and induction of the pro-apoptotic transcription factor CHOP (CAAT/Enhancer Binding Protein Homologous Protein). We next determined the effects of co-treatment with WT-161 on carfilzomib-induced aggresome formation, ER stress response and apoptosis of the cultured and primary MCL cells. Co-treatment with WT-161 (0.25 uM) abrogated carfilzomib-induced aggresome formation in MCL cells, as evidenced by confocal immunofluorescent staining of aggresomes with anti-HDAC6 and anti-ubiquitin antibodies. Compared to each agent alone, co-treatment with WT-161 and carfilzomib induced more intracellular polyubiquitylated proteins and induced higher levels of CHOP in the cultured MCL cells. Co-treatment with WT-161 and carfilzomib also synergistically induced apoptosis of the cultured MCL cells (combination indices < 1.0). Notably, co-treatment with WT-161 and carfilzomib also synergistically induced apoptosis of primary MCL cells (combination indices < 1.0). These findings strongly support the in vivo testing of the combination of an HDAC6-specific inhibitor such as WT-161 with the proteasome inhibitor carfilzomib against human MCL cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Safety Results from the United States Cohort of the Ibrutinib Early Access Treatment Protocol (EAP: MCL4001) in Patients with Relapsed or Refractory Mantle Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4461-4461
Author(s):  
Peter Martin ◽  
Andre Goy ◽  
Radhakrishnan Ramchandren ◽  
Lucille Ferrante ◽  
Vijay Reddy ◽  
...  
Keyword(s):  
Adverse Events ◽  
Mantle Cell Lymphoma ◽  
Progressive Disease ◽  
Cell Lymphoma ◽  
Serious Adverse Events ◽  
Major Hemorrhage ◽  
Once Daily ◽  
Mantle Cell ◽  
The Us ◽  
Grade 3

Abstract Background: Bruton’s tyrosine kinase (BTK) is a critical signaling molecule in the B-cell receptor pathway. Ibrutinib is a first-in-class, once daily, oral covalent inhibitor of BTK that was approved in the US (November 2013) based on an international multi-center Phase 2 study in patients with relapsed or refractory mantle cell lymphoma (MCL), with an ORR of 68% (CR 21% and PR 47%) and median progression free survival of 13.9 months (Wang et al. NEJM 2013). This EAP was conducted in a similar patient population to provide access to ibrutinib prior to market authorization and to collect additional safety data. The results of the US cohort are reported here. Methods: This was an open-label EAP in patients with relapsed or refractory MCL, who resided in areas where ibrutinib was not available and were ineligible for ongoing ibrutinib trials. Key entry criteria were as follows: age ≥ 18 years, relapsed or refractory MCL, and no prior ibrutinib therapy. Patients received ibrutinib 560mg orally once daily in 28 day cycles until progressive disease, unacceptable toxicity, no further benefit or end of study (US approval). Adverse events (Grade ≥ 3), serious adverse events, and adverse events of interest (major hemorrhage, intracranial hemorrhage) were collected. Results: In total,149 patients participated in the EAP at 46 US sites from May 2013 to April 2014. Median age was 68 years (range: 39-90 years) and 89% were white. Median treatment exposure was 3.65 months (range: 0.0-7.7 months), with approximately 26% of patients receiving treatment for more than 6 months. Of the 149 patients, 58.5% had refractory disease and 66.7% had received ≥3 prior lines of therapy. Adverse events grade ≥3 were reported in 59 patients (39.6%), the most common of which were neutropenia (6.7%), dyspnea (4%), anemia (3.4%) and thrombocytopenia (3.4%). Serious adverse events were reported in 46 patients (30.9%). Adverse events of interest were reported in two patients (1.3%): 1 major hemorrhage (0.7%) and 1 intracranial hemorrhage (0.7%). Ten patients (6.7%) discontinued treatment due to adverse events. The primary reason for discontinuation was progressive disease in 20 patients (13.4%) and death in 12 patients (8.1%). The majority of patients (66%) continued on therapy until the end of study (US approval). Conclusions: The safety profile observed in this US cohort of the EAP was consistent with that observed during the registration trial for MCL. No new safety signals were observed in this predominantly refractory population of patients. Moreover, this EAP provided an important mechanism for patients to receive ibrutinib prior to US approval. Disclosures Martin: Janssen: Honoraria. Ferrante:Janssen Scientific Affairs, LLC: Employment. Reddy:Janssen Scientific Affairs, LLC: Employment. Londhe:Janssen Scientific Affairs, LLC: Employment. Wildgust:Janssen Global Services: Employment. McGowan:Janssen Scientific Affairs, LLC: Employment.

CNS involvement in mantle-cell lymphoma.

1996 ◽  
Vol 14 (3) ◽  
pp. 941-944 ◽  
Author(s):  
E Montserrat ◽  
F Bosch ◽  
A López-Guillermo ◽  
F Graus ◽  
M J Terol ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Lymphoid Cells ◽  
University Hospital ◽  
Cns Involvement ◽  
Resistant Disease ◽  
Mantle Cell ◽  
High Incidence ◽  
Hodgkin's Lymphomas ◽  
Lymphoma Type

PURPOSE In non-Hodgkin's lymphomas, CNS involvement is highly dependent on the histology of the lymphoma. Mantle-cell lymphoma (MCL) is a lymphoma type with distinctive histologic, biologic, and clinical features in which CNS involvement has only been rarely described. The purpose of this report is to describe the incidence, clinical characteristics, and outcome of CNS infiltration in patients with MCL seen at a single institution. PATIENTS AND METHODS Twenty-two patients with MCL, who account for 6% of all patients with nodal lymphomas diagnosed and monitored at a university hospital from 1987 to 1994, were studied. Analysis of the incidence of CNS involvement by the disease was performed. RESULTS Five of 22 patients (22%; exact 95% confidence interval [CI], 7.8% to 45.4%) with MCL developed CNS involvement at a median of 18 months (range, 6 to 59) from diagnosis. All of these patients presented with poor MCL histologic subtypes and advanced disease. When the CNS infiltration became apparent, all of the patients displayed neurologic signs and had lymphoid cells consistent with the diagnosis of MCL in the CSF. In most of the cases, CNS infiltration was part of resistant disease or generalized relapse and had an ominous significance. CONCLUSION The incidence of CNS involvement in MCL might be higher than previously recognized. The frequency of CNS infiltration in MCL deserves to be investigated in other series and, if a high incidence is confirmed, the risk factors, mechanisms, and clinical implications of such a complication should be further studied.

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