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Nature Communications Jun 2024Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ...
Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1). We report results on a cohort of 4 GBM patients and preclinical models treated with this approach. LIPU/MB increases the concentration of doxorubicin by 2-fold and 3.9-fold in the human and murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated blood-brain barrier disruption leads to a 6-fold and a 2-fold increase in aPD-1 concentrations in murine brains and peritumoral brain regions from GBM patients treated with pembrolizumab, respectively. Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells. Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages. Doxorubicin and aPD-1 delivered with LIPU/MB results in the long-term survival of most glioma-bearing mice, which rely on myeloid cells and lymphocytes for their efficacy. Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM.
Topics: Doxorubicin; Animals; Humans; Programmed Cell Death 1 Receptor; Mice; Blood-Brain Barrier; Brain Neoplasms; Microbubbles; Cell Line, Tumor; Glioma; Brain; Female; Drug Delivery Systems; Ultrasonic Waves; Glioblastoma; Male; Microglia; Mice, Inbred C57BL; Antibodies, Monoclonal, Humanized; Immune Checkpoint Inhibitors; Polyethylene Glycols
PubMed: 38844770
DOI: 10.1038/s41467-024-48326-w -
Supportive Care in Cancer : Official... Jun 2024Alopecia is a common side-effect of chemotherapy and can be extremely distressing to patients. Scalp cooling can be used to reduce hair loss, but the optimal duration of... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Alopecia is a common side-effect of chemotherapy and can be extremely distressing to patients. Scalp cooling can be used to reduce hair loss, but the optimal duration of cooling remains unclear. Our aim was to determine whether increasing the duration of scalp cooling improves hair preservation.
METHODS
Patients with HER2-negative, non-metastatic, breast cancer received scalp cooling during adjuvant chemotherapy: three cycles of epirubicin/cyclophosphamide (EC) followed by three cycles of paclitaxel. The patients were randomly assigned to two groups. Group A (n=18) wore a Paxman cooling cap during each infusion and for 30 min post-infusion while Group B (n=19) wore the cap from 30 min before to 2 h after each infusion. All patients were asked to complete a questionnaire recording hair loss/regrowth, adverse events, and quality of life. Success of treatment was defined as <50% hair loss.
RESULTS
The success rates after each of the three cycles did not differ significantly between the two groups (EC: Group A: 40%, Group B: 44%; paclitaxel: Group A: 50%, Group B: 36%; p>0.05). Hair regrowth was significantly higher in Group B at the 8-week follow-up, but not at the 6-month follow-up. Head discomfort affected more patients in Group B than in Group A during the first session (94% vs. 62%, respectively; p=0.039).
CONCLUSION
Long duration scalp cooling during chemotherapy might increase patients' discomfort and does not appear to improve hair preservation.
Topics: Humans; Alopecia; Female; Breast Neoplasms; Pilot Projects; Middle Aged; Chemotherapy, Adjuvant; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Paclitaxel; Adult; Scalp; Epirubicin; Quality of Life; Hypothermia, Induced; Time Factors; Aged; Surveys and Questionnaires
PubMed: 38839667
DOI: 10.1007/s00520-024-08579-z -
International Journal of Nanomedicine 2024The purpose of this study is to address the need for efficient drug delivery with high drug encapsulation efficiency and sustained drug release. We aim to create...
PURPOSE
The purpose of this study is to address the need for efficient drug delivery with high drug encapsulation efficiency and sustained drug release. We aim to create nanoparticle-loaded microgels for potential applications in treatment development.
METHODS
We adopted the process of ionic gelation to generate microgels from sodium alginate and carboxymethyl cellulose. These microgels were loaded with doxorubicin-conjugated amine-functionalized zinc ferrite nanoparticles (AZnFe-NPs). The systems were characterized using various techniques. Toxicity was evaluated in MCF-7 cells. In vitro release studies were conducted at different pH levels at 37 C, with the drug release kinetics being analyzed using various models.
RESULTS
The drug encapsulation efficiency of the created carriers was as high as 70%. The nanoparticle-loaded microgels exhibited pH-responsive behavior and sustained drug release. Drug release from them was mediated via a non-Fickian type of diffusion.
CONCLUSION
Given their high drug encapsulation efficiency, sustained drug release and pH-responsiveness, our nanoparticle-loaded microgels show promise as smart carriers for future treatment applications. Further development and research can significantly benefit the field of drug delivery and treatment development.
Topics: Doxorubicin; Humans; Delayed-Action Preparations; Drug Liberation; MCF-7 Cells; Ferric Compounds; Hydrogen-Ion Concentration; Microgels; Drug Carriers; Alginates; Amines; Carboxymethylcellulose Sodium; Nanoparticles; Zinc; Zinc Compounds; Cell Survival
PubMed: 38836007
DOI: 10.2147/IJN.S448594 -
Molecular Cancer Jun 2024The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in...
The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients.
Topics: Animals; Female; Humans; Male; Aclarubicin; Anthracyclines; Antineoplastic Agents; Leukemia, Myeloid, Acute; Treatment Outcome
PubMed: 38831402
DOI: 10.1186/s12943-024-02034-7 -
International Journal of Nanomedicine 2024The tumor microenvironment (TME) has attracted considerable attention as a potential therapeutic target for cancer. High levels of reactive oxygen species (ROS) in the...
INTRODUCTION
The tumor microenvironment (TME) has attracted considerable attention as a potential therapeutic target for cancer. High levels of reactive oxygen species (ROS) in the TME may act as a stimulus for drug release. In this study, we have developed ROS-responsive hyaluronic acid-bilirubin nanoparticles (HABN) loaded with doxorubicin (DOX@HABN) for the specific delivery and release of DOX in tumor tissue. The hyaluronic acid shell of the nanoparticles acts as an active targeting ligand that can specifically bind to CD44-overexpressing tumors. The bilirubin core has intrinsic anti-cancer activity and ROS-responsive solubility change properties.
METHODS & RESULTS
DOX@HABN showed the HA shell-mediated targeting ability, ROS-responsive disruption leading to ROS-mediated drug release, and synergistic anti-cancer activity against ROS-overproducing CD44-overexpressing HeLa cells. Additionally, intravenously administered HABN-Cy5.5 showed remarkable tumor-targeting ability in HeLa tumor-bearing mice with limited distribution in major organs. Finally, intravenous injection of DOX@HABN into HeLa tumor-bearing mice showed synergistic anti-tumor efficacy without noticeable side effects.
CONCLUSION
These findings suggest that DOX@HABN has significant potential as a cancer-targeting and TME ROS-responsive nanomedicine for targeted cancer treatment.
Topics: Hyaluronic Acid; Tumor Microenvironment; Animals; Reactive Oxygen Species; Humans; Doxorubicin; Nanoparticles; Mice; HeLa Cells; Nanomedicine; Hyaluronan Receptors; Bilirubin; Drug Liberation; Mice, Inbred BALB C; Mice, Nude; Xenograft Model Antitumor Assays; Drug Carriers; Antineoplastic Agents; Neoplasms
PubMed: 38828202
DOI: 10.2147/IJN.S460468 -
Cell Death & Disease Jun 2024Doxorubicin's antitumor effectiveness may be constrained with ineffective tumor penetration, systemic adverse effects, as well as drug resistance. The co-loading of...
Doxorubicin's antitumor effectiveness may be constrained with ineffective tumor penetration, systemic adverse effects, as well as drug resistance. The co-loading of immune checkpoint inhibitors and doxorubicin into liposomes can produce synergistic benefits and address problems, including quick drug clearance, toxicity, and low drug penetration efficiency. In our previous study, we modified a nanobody targeting CTLA-4 onto liposomes (LPS-Nb36) to be an extremely potent CTLA-4 signal blocker which improve the CD8 T-cell activity against tumors under physiological conditions. In this study, we designed a drug delivery system (LPS-RGD-Nb36-DOX) based on LPS-Nb36 that realized the doxorubicin and anti-CTLA-4 Nb co-loaded and RGD modification, and was applied to antitumor therapy. We tested whether LPS-RGD-Nb36-DOX could targets the tumor by in vivo animal photography, and more importantly, promote cytotoxic T cells proliferation, pro-inflammatory cytokine production, and cytotoxicity. Our findings demonstrated that the combination of activated CD8 T cells with doxorubicin/anti-CTLA-4 Nb co-loaded liposomes can effectively eradicate tumor cells both in vivo and in vitro. This combination therapy is anticipated to have synergistic antitumor effects. More importantly, it has the potential to reduce the dose of chemotherapeutic drugs and improve safety.
Topics: Doxorubicin; Animals; CTLA-4 Antigen; Mice; Drug Delivery Systems; Liposomes; Humans; Cell Line, Tumor; CD8-Positive T-Lymphocytes; Female; Mice, Inbred BALB C; Mice, Inbred C57BL
PubMed: 38824143
DOI: 10.1038/s41419-024-06776-6 -
Pharmacological Research Jul 2024Doxorubicin (Dox) is an anti-tumor drug with a broad spectrum, whereas the cardiotoxicity limits its further application. In clinical settings, liposome delivery...
Doxorubicin (Dox) is an anti-tumor drug with a broad spectrum, whereas the cardiotoxicity limits its further application. In clinical settings, liposome delivery vehicles are used to reduce Dox cardiotoxicity. Here, we substitute extracellular vesicles (EVs) for liposomes and deeply investigate the mechanism for EV-encapsulated Dox delivery. The results demonstrate that EVs dramatically increase import efficiency and anti-tumor effects of Dox in vitro and in vivo, and the efficiency increase benefits from its unique entry pattern. Dox-loading EVs repeat a "kiss-and-run" motion before EVs internalization. Once EVs touch the cell membrane, Dox disassociates from EVs and directly enters the cytoplasm, leading to higher and faster Dox import than single Dox. This unique entry pattern makes the adhesion between EVs and cell membrane rather than the total amount of EV internalization the key factor for regulating the Dox import. Furthermore, we recognize ICAM1 as the molecule mediating the adhesion between EVs and cell membranes. Interestingly, EV-encapsulated Dox can induce ICAM1 expression by irritating IFN-γ and TNF-α secretion in TME, thereby increasing tumor targeting of Dox-loading EVs. Altogether, EVs and EV-encapsulated Dox synergize via ICAM1, which collectively enhances the curative effects for tumor treatment.
Topics: Doxorubicin; Animals; Humans; Intercellular Adhesion Molecule-1; Extracellular Vesicles; Antibiotics, Antineoplastic; Cell Line, Tumor; Mice, Inbred BALB C; Mice; Female; Neoplasms; Cell Adhesion; Drug Delivery Systems; Mice, Nude; Tumor Necrosis Factor-alpha
PubMed: 38821149
DOI: 10.1016/j.phrs.2024.107244 -
Asian Pacific Journal of Cancer... May 2024ATP Binding Cassette Transporters (ABCB1) gene plays an important role in transport of different metabolites and anticancer drugs across the cell membrane. There is lack...
BACKGROUND
ATP Binding Cassette Transporters (ABCB1) gene plays an important role in transport of different metabolites and anticancer drugs across the cell membrane. There is lack of knowledge on ABCB1 gene polymorphism and its correlation with Adriamycin or paclitaxel based chemotherapy induced toxicity in breast cancer patients. Therefore in this study, we explored the correlation of ABCB1 polymorphisms gene on response and toxicity in adriamycin and paclitaxel based chemotherapy in breast cancer patients from Indian population.
METHODS
Two hundred BC patients receiving Adriamycin and paclitaxel chemotherapy were enrolled in this study and chemotherapy induced hematological and non-hematological toxicity reactions were noted. The polymorphisms in ABCB1 gene (C1236T, C3435T) were studied by PCR and RFLP analysis.
RESULTS
The univariate logistic regression analysis showed statistically significant negative association with protective effects of ABCB1 (C3435T) polymorphism with heterozygous genotype (OR=0.34, 95% CI: 0.13-0.89; p=0.027), homozygous variant genotype (OR=0.31, 95% CI: 0.10-0.99; p=0.049) and combined C/T+T/T genotypes (OR=0.33, 95% CI: 0.13-0.79; p=0.013) in relation with severe toxicity of chemotherapy induced nausea and vomiting in breast cancer patients treated with Adriamycin chemotherapy. The 3435 C>T polymorphism of ABCB1 gene with heterozygous C/T genotype showed significantly negative association (OR=0.37, 95% CI: 0.14-0.96; p=0.042) with peripheral neuropathy in patients treated primarily with paclitaxel thereafter Adriamycin.
CONCLUSION
The findings obtained from this study revealed significant association of ABCB1 3435 C>T polymorphisms with non-hematological toxicity in response to adriamycin and paclitaxel based chemotherapy.
Topics: Humans; Female; Breast Neoplasms; ATP Binding Cassette Transporter, Subfamily B; Doxorubicin; Middle Aged; Paclitaxel; Antineoplastic Combined Chemotherapy Protocols; Adult; Polymorphism, Single Nucleotide; Prognosis; Genotype; Follow-Up Studies; Aged; Treatment Outcome
PubMed: 38809628
DOI: 10.31557/APJCP.2024.25.5.1567 -
Asian Pacific Journal of Cancer... May 2024Several studies of multi-drug regimens for osteosarcoma have shown different efficacies and are still controversial. Meanwhile, chemotherapy options have remained... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Several studies of multi-drug regimens for osteosarcoma have shown different efficacies and are still controversial. Meanwhile, chemotherapy options have remained largely unchanged over a couple of decades. This study is designed to ascertain the outcome and safety of Methotrexate, Doxorubicin, and Cisplatin regimen for chemotherapy in osteosarcoma patients through the utilization of meta-analysis.
METHODS
We interrogated trials that compared the MAP regimen with other regimens as chemotherapy for osteosarcoma from several databases encompassing PubMed, Science Direct, and grey literature (Google Scholar) until December 2022. The analyzed outcomes including Event-Free Survival (EFS), Overall Survival (OS), Tumor Necrosis (TN) rate, and Adverse Event (AE) were then analyzed using RevMan 5.4 software in fixed or random effect models.
RESULTS
Our meta-analysis comprised 8 prospective articles that evaluated a cumulative number of 2920 OS patients. The analysis results indicated no meaningful difference in 5-year EFS (OR=0.99, 95% CI=0.77-1.27, [P = 0.91]) and neoadjuvant chemotherapy response (TN) (OR=0.76, 95% CI=0.49-1.17, [P = 0.22]) between the MAP and control groups. Furthermore, 5-year OS analysis revealed a significant association in the control group (OR=0.82, 95% CI=0.68-0.99, [P = 0.04]). However, the control group was associated with statistically meaningful AE compared to the MAP group, particularly in thrombocytopenia (OR=0.46, 95% CI=0.23-0.90, [P = 0.02]) and fever (OR=0.34, 95% CI=0.26-0.46, [P < 0.00001]).
CONCLUSION
The present meta-analysis showed that the MAP regimen remains preferable in treating osteosarcoma patients despite no significant outcome compared to the other regimens considering the less frequent AE in the MAP regimen.
Topics: Osteosarcoma; Humans; Methotrexate; Doxorubicin; Cisplatin; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Patient Safety; Prognosis; Survival Rate; Treatment Outcome
PubMed: 38809621
DOI: 10.31557/APJCP.2024.25.5.1497 -
Organogenesis Dec 2024This study is to investigate the therapeutical effect and mechanisms of human-derived adipose mesenchymal stem cells (ADSC) in relieving adriamycin (ADR)-induced...
This study is to investigate the therapeutical effect and mechanisms of human-derived adipose mesenchymal stem cells (ADSC) in relieving adriamycin (ADR)-induced nephropathy (AN). SD rats were separated into normal group, ADR group, ADR+Losartan group (20 mg/kg), and ADR + ADSC group. AN rats were induced by intravenous injection with adriamycin (8 mg/kg), and 4 d later, ADSC (2 × 10 cells/mouse) were administrated twice with 2 weeks interval time (i.v.). The rats were euthanized after the 6 weeks' treatment. Biochemical indicators reflecting renal injury, such as blood urea nitrogen (BUN), neutrophil gelatinase alpha (NGAL), serum creatinine (Scr), inflammation, oxidative stress, and pro-fibrosis molecules, were evaluated. Results demonstrated that we obtained high qualified ADSCs for treatment determined by flow cytometry, and ADSCs treatment significantly ameliorated renal injuries in DN rats by decreasing BUN, Scr and NGAL in peripheral blood, as well as renal histopathological injuries, especially protecting the integrity of podocytes by immunofluorescence. Furthermore, ADSCs treatment also remarkably reduced the renal inflammation, oxidative stress, and fibrosis in DN rats. Preliminary mechanism study suggested that the ADSCs treatment significantly increased renal neovascularization via enhancing proangiogenic VEGF production. Pharmacodynamics study using in vivo imaging confirmed that ADSCs via intravenous injection could accumulate into the kidneys and be alive at least 2 weeks. In a conclusion, ADSC can significantly alleviate ADR-induced nephropathy, and mainly through reducing oxidative stress, inflammation and fibrosis, as well as enhancing VEGF production.
Topics: Animals; Doxorubicin; Humans; Adipose Tissue; Rats, Sprague-Dawley; Male; Kidney Diseases; Rats; Mesenchymal Stem Cells; Neovascularization, Physiologic; Mesenchymal Stem Cell Transplantation; Oxidative Stress; Kidney; Fibrosis; Vascular Endothelial Growth Factor A; Stromal Cells; Angiogenesis
PubMed: 38796830
DOI: 10.1080/15476278.2024.2356339