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European Journal of Medicinal Chemistry Oct 2023The chemotherapeutic drug of doxorubicin (DOX) has witnessed widespread applications for treating various cancers. DOX-treated dying cells bear cellular modifications... (Review)
Review
The chemotherapeutic drug of doxorubicin (DOX) has witnessed widespread applications for treating various cancers. DOX-treated dying cells bear cellular modifications which allow enhanced presentation of tumor antigen and neighboring dendritic cell activation. Furthermore, DOX also facilitate the immune-mediated clearance of tumor cells. However, disadvantages such as severe off-target toxicity, and prominent hydrophobicity have resulted in unsatisfactory clinical therapeutic outcomes. The effective delivery of DOX drug molecules is still challenging despite the rapid advances in nanotechnology and biomaterials. Huge progress has been witnessed in DOX nanoprodrugs owing to their brilliant benefits such as tumor stimuli-responsive drug release capacity, high drug loading efficiency and so on. This review summarized recent progresses of DOX prodrug-based nanomedicines to provide deep insights into future development and inspire researchers to explore DOX nanoprodrugs with real clinical applications.
Topics: Humans; Prodrugs; Drug Delivery Systems; Nanomedicine; Doxorubicin; Neoplasms; Nanoparticles; Cell Line, Tumor
PubMed: 37441851
DOI: 10.1016/j.ejmech.2023.115612 -
European Journal of Haematology Jun 2023Because of lacking of head-to-head comparison among recently effective novel agents' combination regimens for newly diagnosed patients with mantle-cell lymphoma (MCL)... (Meta-Analysis)
Meta-Analysis Review
Because of lacking of head-to-head comparison among recently effective novel agents' combination regimens for newly diagnosed patients with mantle-cell lymphoma (MCL) who are ineligible for intensive therapy like autologous stem-cell transplantation, the optimal option for these patients still remains undefined. We searched relevant published reports. Three randomized controlled trials with 1459 subjects were identified. In the network meta-analysis, ibrutinib plus bendamustine and rituximab (Ibru + BR) significantly improved progression-free survival (PFS) when compared to bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP; hazard ratio [HR]: 0.55, p = .03) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; HR: 0.35, p < .001) for newly diagnosed patients with MCL ineligible for intensive therapy. Among these first-line treatment regimens (Ibru + BR, VR-CAP, R-CHOP, and BR), Ibru + BR had the highest probability of 94.9% to be the best intervention in PFS analysis. No significant difference was found in adverse events analysis. Our data indicated that Ibru + BR seemed to prolong the PFS when compared to VR-CAP and R-CHOP for newly diagnosed patients with MCL ineligible for intensive therapy. Considering our limits, prospective clinical trials directly comparing these regimens are warranted.
Topics: Adult; Humans; Lymphoma, Mantle-Cell; Rituximab; Bendamustine Hydrochloride; Prednisone; Network Meta-Analysis; Prospective Studies; Vincristine; Doxorubicin; Cyclophosphamide; Antineoplastic Combined Chemotherapy Protocols; Randomized Controlled Trials as Topic
PubMed: 36919283
DOI: 10.1111/ejh.13953 -
Pharmacological Research Nov 2022Acute myeloid leukemia (AML) is featured with poor prognosis and high mortality, because chemo-resistance, nonspecific distribution and dose-limiting toxicity lead to a...
Acute myeloid leukemia (AML) is featured with poor prognosis and high mortality, because chemo-resistance, nonspecific distribution and dose-limiting toxicity lead to a high rate of relapse and a very low 5-year survival percentage of less than 25%. CXCR4 is a highly expressed chemokine receptor in multiple types of AML cells and closely associated with the drug resistance and relapse. In this work, we integrate a chemically synthesized CXCR4 antagonistic peptide and doxorubicin using DSPE-mPEG2000 micelles (referred to as M-E5-Dox) that is applied to a very challenging refractory AML mouse model as well as human AML cell lines. Results showed that M-E5-Dox can effectively bind to the CXCR4-expressing AML cells, downregulating the signaling proteins mediated by CXCR4/CXCL12 axis and increasing the cellular uptake of Dox. Importantly, M-E5-Dox remarkably decreases the leukemic cells in the peripheral blood and bone marrow, as well as their infiltration in the spleen and liver of the AML mice, which in turn prolongs the survival significantly. Meanwhile, M-E5-Dox did not increase the cardiotoxicity of Dox. In conclusion, M-E5-Dox harnesses the functions of CXCR4 specific binding and CXCR4 antagonism of the peptide and the tumor cell killing capacity of Dox, which displays significant therapeutic effects and promising translational potentials for the treatment of refractory AML.
Topics: Humans; Mice; Animals; Leukemia, Myeloid, Acute; Doxorubicin; Signal Transduction; Peptides; Recurrence; Receptors, CXCR4
PubMed: 36241000
DOI: 10.1016/j.phrs.2022.106503 -
Cellular Oncology (Dordrecht) Dec 2023Tissue-specific drug uptake has not been well studied, compared to the deeper understanding of drug resistance mediated by the cellular efflux system such as MDR1...
PURPOSE
Tissue-specific drug uptake has not been well studied, compared to the deeper understanding of drug resistance mediated by the cellular efflux system such as MDR1 proteins. It has been suggested that many drugs need active or defined transporters to pass the cell membrane. In contrast to efflux components induced after anti-cancer drugs reach the intracellular compartment, drug importers are required for initial drug responses. Furthermore, tissue-specific uptake of anti-cancer drugs may directly impact the side effects of many drugs when they accumulate in healthy tissues. Therefore, linking anti-cancer drugs to their respective drug import transporters would directly help to predict drug responses, whilst minimizing side effects.
METHODS
To identify drug transporters of the commonly used anti-cancer drug doxorubicin, we performed focused CRISPR activation and knockout genetic screens targeting all potential membrane-associated transporters and proteins. We monitored the direct uptake of doxorubicin by fluorescence-activated cell sorting (FACS) as the screening readout for identifying transporters/proteins directly involved in doxorubicin uptake.
RESULTS
Integrating the data from these comprehensive CRISPR screenings, we confirmed previously indicated doxorubicin exporters such as ABCB1 and ABCG2 genes, and identified novel doxorubicin importer gene SLC2A3 (GLUT3). Upregulation of SLC2A3 led to higher doxorubicin uptake and better cell killing, indicating SLC2A3 could be a new marker to predict doxorubicin drug response and minimize side effects for the personalized application of this conventional chemotherapeutic drug.
CONCLUSIONS
Our study provides a comprehensive way for identifying drug transporters, as exemplified by the commonly used anti-cancer drug doxorubicin. The newly identified importers may have direct clinical implications for the personalized application of doxorubicin in treating distinct tumors. Our results also highlight the necessity of combining both CRISPR knockout and CRISPR activation genetic screens to identify drug transporters.
Topics: Humans; Clustered Regularly Interspaced Short Palindromic Repeats; Drug Resistance, Neoplasm; Doxorubicin; Antineoplastic Agents; Neoplasms; Cell Line, Tumor
PubMed: 37523060
DOI: 10.1007/s13402-023-00847-0 -
Journal of Cellular and Molecular... Nov 2020Oncolytic adenovirus (OA) has attracted increasing attention due to their specific proliferation in tumour cells and resulting in lysis of tumour cells. To further...
Oncolytic adenovirus (OA) has attracted increasing attention due to their specific proliferation in tumour cells and resulting in lysis of tumour cells. To further improve the antitumour effect of OA, in this study, we combined CD55-TRAIL-IETD-MnSOD (CD55-TMn), a CEA-controlled OA constructed previously, and chemotherapy to investigate their synergistic effect and possible mechanisms. MTT assay was performed to detect antitumour effects. Hoechst 33 342 and flow cytometric analysis were used to examine cell apoptosis. Western blotting was performed to examine cell pyroptosis and apoptosis mechanism. Animal experiment was used to detect antitumour effect of doxorubicin hydrochloride (Dox) combined with CD55-TMn in vivo. We firstly found that Dox promotes gene expression mediated by CEA-regulated OA and virus progeny replication by activating phosphorylation of Smad3, and Dox can enhance antitumour effect of CEA-regulated CD55-TMn by promoting cell apotopsis and cell pyroptosis. Thus, our results provide an experimental and theoretical basis on tumour therapy by combination treatment of the oncolytic virotherapy and chemotherapy and it is expected to become a novel strategy for liver cancer therapy.
Topics: Adenoviridae; Animals; Antibiotics, Antineoplastic; Apoptosis; Biomarkers; Carcinoembryonic Antigen; Caspase 3; Cell Line, Tumor; Cell Survival; Combined Modality Therapy; Disease Models, Animal; Doxorubicin; Female; Genetic Therapy; Genetic Vectors; Humans; Immunohistochemistry; Liver Neoplasms; Mice; Oncolytic Virotherapy; Oncolytic Viruses; Phosphorylation; Smad3 Protein; Xenograft Model Antitumor Assays
PubMed: 33251723
DOI: 10.1111/jcmm.15966 -
Lab on a Chip Mar 2024The current challenge in using extracellular vesicles (EVs) as drug delivery vehicles is to precisely control their membrane permeability, specifically in the ability to...
The current challenge in using extracellular vesicles (EVs) as drug delivery vehicles is to precisely control their membrane permeability, specifically in the ability to switch between permeable and impermeable states without compromising their integrity and functionality. Here, we introduce a rapid, efficient, and gentle loading method for EVs based on tonicity control (TC) using a lab-on-a-disc platform. In this technique, a hypotonic solution was used for temporarily permeabilizing a membrane ("on" state), allowing the influx of molecules into EVs. The subsequent isotonic washing led to an impermeable membrane ("off" state). This loading cycle enables the loading of different cargos into EVs, such as doxorubicin hydrochloride (Dox), ssDNA, and miRNA. The TC approach was shown to be more effective than traditional methods such as sonication or extrusion, with loading yields that were 4.3-fold and 7.2-fold greater, respectively. Finally, the intracellular assessments of miRNA-497-loaded EVs and doxorubicin-loaded EVs confirmed the superior performance of TC-prepared formulations and demonstrated the impact of encapsulation heterogeneity on the therapeutic outcome, signifying potential opportunities for developing novel exosome-based therapeutic systems for clinical applications.
Topics: Extracellular Vesicles; MicroRNAs; Exosomes; Cell Communication; Doxorubicin; Drug Delivery Systems
PubMed: 38436394
DOI: 10.1039/d3lc00830d -
Journal For Immunotherapy of Cancer Aug 2023Localized radiotherapy (RT) can cause a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade....
BACKGROUND
Localized radiotherapy (RT) can cause a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade. However, this effect is still clinically rare and improvements are highly desirable. We investigated whether triple combination with a low dose of clinically approved liposomal doxorubicin (Doxil) could augment abscopal responses compared with RT/αPD-1 and Doxil/αPD-1. We also investigated whether the enhanced abscopal responses depended on the mitochondrial DNA (mtDNA)/cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)/IFN-I pathway.
MATERIALS/METHODS
We used Doxil in combination with RT and αPD-1 in two tumor models (B16-CD133 melanoma and MC38 colon carcinoma) with mice bearing two tumors, only one of which was irradiated. Mechanistic studies on the role of the mtDNA/cGAS/STING/IFN-I axis were performed using inhibitors and knockout cells in vitro as well as in mice.
RESULTS
Addition of a single low dose of Doxil to RT and αPD-1 strongly enhanced the RT/αPD-1-induced abscopal effect in both models. Complete cures of non-irradiated tumors were mainly observed in triple-treated mice. Triple therapy induced more cross-presenting dendritic cells (DCs) and more tumor-specific CD8 T cells than RT/αPD-1 and Doxil/αPD-1, particularly in non-irradiated tumors. Coincubation of Doxil-treated and/or RT-treated tumor cells with DCs enhanced DC antigen cross-presentation which is crucial for inducing CD8 T cells. CD8 T cell depletion or implantation of cGAS-deficient or STING-deficient tumor cells abolished the abscopal effect. Doxorubicin-induced/Doxil-induced IFNβ1 markedly depended on the cGAS/STING pathway. Doxorubicin-treated/Doxil-treated tumor cells depleted of mtDNA secreted less IFNβ1, of the related T cell-recruiting chemokine CXCL10, and ATP; coincubation with mtDNA-depleted tumor cells strongly reduced IFNβ1 secretion by DCs. Implantation of mtDNA-depleted tumor cells, particularly at the non-irradiated/abscopal site, substantially diminished the Doxil-enhanced abscopal effect and tumor infiltration by tumor-specific CD8 T cells.
CONCLUSIONS
These data show that single low-dose Doxil can substantially enhance the RT/αPD-1-induced abscopal effect, with a strong increase in cross-presenting DCs and CD8 tumor-specific T cells particularly in abscopal tumors compared with RT/αPD-1 and Doxil/αPD-1. Moreover, they indicate that the mtDNA/cGAS/STING/IFN-I axis is important for the immunogenic/immunomodulatory doxorubicin effects. Our findings may be helpful for the planning of clinical radiochemoimmunotherapy trials in (oligo)metastatic patients.
Topics: Animals; Mice; DNA, Mitochondrial; CD8-Positive T-Lymphocytes; Mitochondria; Doxorubicin
PubMed: 37640480
DOI: 10.1136/jitc-2022-006235 -
Journal of Liposome Research Sep 2020Combination therapy with conventional chemotherapeutic drugs strongly demonstrates a good approach to reduce cytotoxicity, resistance, and the dose of the potent...
Combination therapy with conventional chemotherapeutic drugs strongly demonstrates a good approach to reduce cytotoxicity, resistance, and the dose of the potent anticancer drugs. The purpose of this research was to design and characterize liposome incorporating celecoxib (CEL) and doxorubicin hydrochloride (DOX) and investigate the anti-tumor efficacy of this combination on different tumor cells. A simple comparison study had been performed for liposomes formulation using thin-film hydration method and pH-gradient method. HSPC-incorporated liposomes were chosen for encapsulation of both CEL and DOX. The formulations showed small particle size and polydispersity index with high encapsulation efficiency. DOX/CEL liposomes displayed the strongest cytotoxicity against B16 and MGC80-3 cells in comparison to the corresponding drug solutions. By incorporation of both agents, a significant reduction in IC50 from 0.927 to 0.198 µg/ml and from 0.81 to 0.535 µg/ml against B16 cells and MGC80-3 cells, respectively, was observed. CEL also significantly improved the intracellular retention and accumulation of DOX . Our data suggest that the developed liposomal formulation proved to be the most effective formulative strategy as a dual drug delivery system for incorporation of both doxorubicin HCL and CEL and could be considered a useful tool for enhancing the therapeutic efficacy of the anticancer drug.
Topics: Animals; Antineoplastic Agents; Celecoxib; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Screening Assays, Antitumor; Humans; Liposomes; Mice; Particle Size; Structure-Activity Relationship; Surface Properties; Tumor Cells, Cultured
PubMed: 31223044
DOI: 10.1080/08982104.2019.1634724 -
European Journal of Pharmaceutical... Sep 2022To evaluate the bioequivalence of a hybrid pegylated liposomal doxorubicin (PLD) hydrochloride injection with reference product Caelyx®. (Randomized Controlled Trial)
Randomized Controlled Trial
Bioequivalence of a hybrid pegylated liposomal doxorubicin hydrochloride injection and Caelyx®: A single-dose, randomized, multicenter, open-label, two-period crossover study in patients with advanced ovarian cancer.
OBJECTIVE
To evaluate the bioequivalence of a hybrid pegylated liposomal doxorubicin (PLD) hydrochloride injection with reference product Caelyx®.
METHODS
This multicenter, open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover, bioequivalence study was conducted in female patients aged ≥18 years and ≤75 years with ovarian cancer, whose disease progressed or recurred after platinum-based chemotherapy, and who were scheduled to start PLD therapy. Patients were intravenously infused drugs over 1 h at 50 mg/m dose two hours after breakfast on the first day of the chemotherapy cycle in period-I and crossed over to the other arm in period-II (day 29). Pharmacokinetic (PK) analyses were performed using two separate, validated liquid chromatography-mass spectrometry methods for encapsulated and unencapsulated doxorubicin.
RESULTS
Both the test and reference formulations were well-tolerated and safe. The pharmacokinetic analysis for both encapsulated and unencapsulated doxorubicin was conducted in 50 patients and PK parameters were found to be comparable between test and reference products. The geometric mean ratios (90% confidence interval) of hybrid PLD/Caelyx® were; maximum measured plasma concentration (C): 91.94-97.28%, area under the plasma concentration versus time from time 0 to t (AUC): 95.19-103.67% AUC from time 0 to ∞ (AUC): 95.13-103.66% for encapsulated doxorubicin and for unencapsulated doxorubicin C: 92.08-116.46% AUC: 91.91-108.28% AUC: 93.45-110.05%.
CONCLUSION
The PLD formulation was found to be bioequivalent to Caelyx®.
Topics: Adolescent; Adult; Area Under Curve; Cross-Over Studies; Doxorubicin; Female; Humans; Ovarian Neoplasms; Polyethylene Glycols; Tablets; Therapeutic Equivalency
PubMed: 35777616
DOI: 10.1016/j.ejps.2022.106248 -
Clinical Therapeutics Apr 2022This study examined real-world treatment patterns with curative intent, adverse events, and health care resource utilization and costs in patients with relapsed or...
PURPOSE
This study examined real-world treatment patterns with curative intent, adverse events, and health care resource utilization and costs in patients with relapsed or refractory large B-cell lymphoma (LBCL) to understand the unmet medical need in the United States.
METHODS
Adult patients with ≥2 LBCL diagnoses between January 1, 2012, and March 31, 2019, were identified (index date was the date of the earliest LBCL diagnosis) from MarketScan® Commercial and Medicare Supplemental Databases. Patients had ≥1 claim for any LBCL treatment, ≥6 months of data before (baseline) and ≥12 months of data after (follow-up period) the index date, and no baseline LBCL diagnosis. Treatment patterns, adverse events, and all-cause and LBCL-related health care resource utilization and costs were examined. All patients had received first-line therapy of cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab; etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride with or without rituximab; or regimens with anthracycline and second-line therapy with stem cell transplant (SCT)-intended intensive therapy or platinum-based chemotherapy. Patients who received an SCT-intended second-line regimen or received an SCT regardless of second-line regimen were considered SCT eligible.
FINDINGS
A total of 188 patients met the criteria of eligibility for SCT. Among the 119 patients who received a second-line regimen intended for SCT, only 22.7% received an SCT. Patients eligible for SCT started first-line therapy within 1 month of their LBCL index date, and the mean duration of first-line therapy was 4.1 months. The mean gap in therapy between first- and second-line therapy was 6.6 months, and the mean duration of second-line therapy was 3.0 months. During the second-line therapy treatment window (mean duration with SCT, 12.4 months; mean duration without SCT, 4.8 months), the most common regimens for patients eligible for SCT were ifosfamide, carboplatin, and etoposide with or without rituximab and gemcitabine and oxaliplatin with or without rituximab; the top 4 most common treatment-related adverse events were febrile neutropenia (56.4%), anemia (49.5%), thrombocytopenia (42.6%), and nausea and vomiting (36.2%), which were similar regardless of receipt of SCT; mean (SD) per-patient-per-month all-cause costs were $46,174 ($49,057) for patients with SCT and $45,780 ($52,813) for patients without SCT.
IMPLICATIONS
Treatment patterns among patients with relapsed or refractory LBCL eligible for SCT were highly varied. Only 22.7% of patients who received an SCT-preparative regimen ultimately received SCT, which highlights the magnitude of unmet needs in this population. The occurrence of treatment-related adverse events was similar regardless of SCT status. Per-patient-per-month all-cause costs were also similar with upfront SCT costs averaged during a longer follow-up.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cost of Illness; Cyclophosphamide; Doxorubicin; Etoposide; Humans; Lymphoma, Large B-Cell, Diffuse; Medicare; Prednisone; Rituximab; United States; Vincristine
PubMed: 35241295
DOI: 10.1016/j.clinthera.2022.02.004