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Carbohydrate Polymers Aug 2023Breast cancer is one of the most threatening cancers that poses a great risk to women's health. The anti-tumor drug doxorubicin (DOX) is one of commonly used drugs in...
Breast cancer is one of the most threatening cancers that poses a great risk to women's health. The anti-tumor drug doxorubicin (DOX) is one of commonly used drugs in the treatment of breast cancer. However, the cytotoxicity of DOX has always been an urgent challenge to be solved. In this study, we report an alternative drug delivery system delivering DOX for reducing its physiological toxicity by using the yeast β-glucan particle (YGP) with a hollow and porous vesicle structure. Briefly, amino groups were grafted onto the surface of YGP with the silane coupling agent, then the oxidized hyaluronic acid (OHA) was attached by Schiff base reaction to get HA-modified YGP (YGP@N=C-HA), finally DOX was encapsulated into YGP@N=C-HA to get DOX-loaded YGP@N=C-HA (YGP@N=C-HA/DOX). In vitro release experiments exhibited the pH-responsive DOX release from YGP@N=C-HA/DOX. Cell experiments displayed that YGP@N=C-HA/DOX had good killing effect on both MCF-7 and 4T1 cells and could be internalized into these cells through CD44 receptors, showing targetability to cancer cells. Furthermore, YGP@N=C-HA/DOX could effectively inhibit tumor growth and reduce the physiological toxicity of DOX. Thus, the YGP-based vesicle provides an alternative strategy for lowering the physiological toxicity of DOX in the medical treatment of breast cancer.
Topics: Female; Humans; Breast Neoplasms; Hyaluronic Acid; Saccharomyces cerevisiae; beta-Glucans; Doxorubicin; Drug Delivery Systems; Nanoparticles; MCF-7 Cells
PubMed: 37173014
DOI: 10.1016/j.carbpol.2023.120907 -
Cell Death & Disease Jan 2021MicroRNAs play an important role in tumorigenesis and, among them, miR-21 is found to be aberrantly up-regulated in various tumors. The tumor-associated antigen, folate...
MicroRNAs play an important role in tumorigenesis and, among them, miR-21 is found to be aberrantly up-regulated in various tumors. The tumor-associated antigen, folate receptor alpha is a GPI-membrane protein overexpressed in many malignant tumors of epithelial origin, including ovarian and cervical cancers. Covalently bound octahedral DNA nanocages were functionalized with folate molecules and utilized as scaffolds to engineer four sequestering units with a miR-21 complementary sequence for obtaining biocompatible Fol-miR21-NC non-toxic nanostructures, to be able to selectively recognize folate receptor alpha-overexpressing cancer cells and sequester the oncogenic miR-21. qPCR assays showed that Fol-miR21-NCs reduce the miR-21 expression up to 80% in cancer cells in the first 2 days of treatment. Functional assays demonstrated that miR-21 sequestering leads to up-regulation of miR-21 tumor suppressor targets (i.e., PTEN and Pdcd4), reduction in cancer cell migration, reduction in proliferation, and increase in cell death. Fol-miR21-NCs can be efficiently loaded with the chemotherapeutic agent doxorubicin. Co-delivery of anti-miR-21 and doxorubicin showed additive cytotoxic effects on tumor cells, paving the way for their use as selective nucleic acid drugs.
Topics: DNA; Doxorubicin; HeLa Cells; Humans; MicroRNAs; Nanostructures; Neoplasms
PubMed: 33414439
DOI: 10.1038/s41419-020-03339-3 -
Cytotherapy Dec 2022The stimulatory natural killer-dendritic cell axis in the tumor microenvironment could play a critical role in stimulating cytotoxic T cells and driving immune responses...
γc cytokine-aided crosstalk between dendritic cells and natural killer cells together with doxorubicin induces a healer response in experimental lymphoma by downregulating FOXP3 and programmed cell death protein 1.
BACKGROUND AIMS
The stimulatory natural killer-dendritic cell axis in the tumor microenvironment could play a critical role in stimulating cytotoxic T cells and driving immune responses against cancer.
METHODS
We established a novel treatment protocol by adroitly combining chemotherapy with doxorubicin and immunotherapy with dendritic cells and natural killer cells against a highly aggressive and malignant lymphoma called Dalton's lymphoma.
RESULTS
Our data suggest that binary application of adoptive cell therapy and chemotherapy nearly cures (95%) early-stage experimental lymphoma. In the case of mid-stage cancer, the success rate was significantly lower but still impressive (75%). Our results demonstrated that the application of combination therapy in early-stage cancer significantly reduced the tumor volume and extended the lifespan of the experimental animal in addition to reinvigorating the immune system, including restoring the effector functions of dendritic cells and natural killer cells. The novel protocol limits the metastasis of tumor cells in vascularized organs and rearms the adaptive immune response mediated by dendritic cells and CD4 and CD8 T cells.
CONCLUSIONS
Combination therapy in the early stage alters the cytokine profile, increases interferon-γ and tumor necrosis factor-α in the serum of treated animals and downregulates programmed cell death protein 1 expression in CD8 T cells. Thus, cooperative and cognitive interactions between dendritic cells and natural killer cells in addition to therapy with doxorubicin promote the immune response and tumoricidal activities against lymphoma.
Topics: Animals; Programmed Cell Death 1 Receptor; Cytokines; CD8-Positive T-Lymphocytes; Lymphoma; Killer Cells, Natural; Doxorubicin; Dendritic Cells; Forkhead Transcription Factors; Tumor Microenvironment
PubMed: 36057496
DOI: 10.1016/j.jcyt.2022.07.012 -
Nanotechnology Jun 2022To improve the shortcomings of narrow therapeutic range and low bioavailability of traditional preparations, a composite drug carrier that combines the advantages of...
To improve the shortcomings of narrow therapeutic range and low bioavailability of traditional preparations, a composite drug carrier that combines the advantages of biological carriers and synthetic carriers was prepared in this project. The biomimetic nano-delivery system outer membrane vesicles-polydopamine-mesoporous silica nanoparticle (OMVs-PDA-MSN-DOX) for oral administration is composed of OMVs ofas shell and doxorubicin-loaded MSN modified by PDA as core. Several characterization techniques thoroughly examined the nano-drug delivery system to confirm its surface morphology and chemical property. OMVs-PDA-MSN-DOX with a particle size of 150 nm showed significant cell selectivity and safety. We demonstrated that OMVs are capable of protecting pH-sensitive nanostructure from the oral route of administration in the short term. Importantly, OMVs-PDA-MSN-DOX could facilitate intestinal adhesion and improve DOX bioavailability. Overall, the OMVs-cloaked nanocarrier provides an efficient delivery platform for the oral targeting treatment of cancer with pH-sensitive nano-formulations.
Topics: Doxorubicin; Drug Carriers; Drug Delivery Systems; Hydrogen-Ion Concentration; Indoles; Nanoparticles; Neoplasms; Polymers; Porosity; Silicon Dioxide
PubMed: 35576909
DOI: 10.1088/1361-6528/ac6fee -
Nanoscale Jul 2020Low biodegradability of graphene derivatives and related health risks are the main limiting factors for their in vivo biomedical applications. Here, we present the...
Low biodegradability of graphene derivatives and related health risks are the main limiting factors for their in vivo biomedical applications. Here, we present the synthesis of enzyme-functionalized graphene sheets with self-degrading properties under physiological conditions and their applications in tumor therapy. The synergistic enzyme cascade glucose oxidase and myeloperoxidase are covalently conjugated to the surface of graphene sheets and two-dimensional (2D) platforms are obtained that can produce sodium hypochlorite from glucose. The enzyme-functionalized graphene sheets with up to 289 nm average size are degraded into small pieces (≤40 nm) by incubation under physiological conditions for 24 h. Biodegradable graphene sheets are further loaded with doxorubicin and their ability for tumor therapy is evaluated in vitro and in vivo. The laser-triggered release of doxorubicin in combination with the enzymatic activity of the functionalized graphene sheets results in a synergistic antitumor activity. Taking advantage of their neutrophil-like activity, fast biodegradability, high photo- and chemotherapeutic effects, the novel two-dimensional nanoplatforms can be used for tumor therapeutic applications.
Topics: Coloring Agents; Doxorubicin; Graphite
PubMed: 32608434
DOI: 10.1039/d0nr02159h -
Colloids and Surfaces. B, Biointerfaces Aug 2023Due to the inability of nano-carriers to passively cross the cell membrane, cell penetration enhancers are used to accelerate cytoplasmic delivery of antineoplastic...
HYPOTHESIS
Due to the inability of nano-carriers to passively cross the cell membrane, cell penetration enhancers are used to accelerate cytoplasmic delivery of antineoplastic drugs. In this regard, snake venom phospholipase A2 peptides are known for their ability to destabilize natural and artificial membranes. In this context, functionalized liposomes with peptide pEM-2 should favor the incorporation of doxorubicin and increase its cytotoxicity in HeLa cells compared to free doxorubicin, and doxorubicin encapsulated in non-functionalized liposomes.
EXPERIMENTS
Several characteristics were monitored, including doxorubicin loading capacity of the liposomes, as well as the release and uptake before and after functionalization. Cell viability and half-maximal inhibition concentrations were determined in HeLa cells.
FINDINGS
In vitro studies showed that functionalization of doxorubicin-loaded PC-NG liposomes with pEM-2 not only improved the amount of doxorubicin delivered compared to free doxorubicin or other doxorubicin-containing formulations, but also showed enhanced cytotoxicity against HeLa cells. The PC-NG liposomes loaded with doxorubicin improved treatment efficacy by reducing the IC value and incubation time. This increase in cell toxicity was directly related to the concentration of pEM-2 peptide bound to the liposomes. We conclude that the cytotoxicity observed in HeLa cells due to the action of doxorubicin was strongly favored when encapsulated in synthetic liposomes and functionalized with the pEM-2 peptide.
Topics: Humans; Liposomes; HeLa Cells; Doxorubicin; Peptides; Drug Delivery Systems; Cell Line, Tumor
PubMed: 37379702
DOI: 10.1016/j.colsurfb.2023.113420 -
Advanced Drug Delivery Reviews Nov 2021We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be... (Review)
Review
We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be utilized in human clinical trials. This class of compounds is designed to carry a payload of a cytotoxic agent and adequately circulate in order to accumulate at a tumor that is being heated. At the target the carrier is activated by heat and releases its contents at high concentrations. We summarize the preclinical and clinical experience of LTLD including its successes and challenges in the development process.
Topics: Animals; Antibiotics, Antineoplastic; Doxorubicin; Drug Delivery Systems; Drug Development; Drug Liberation; Humans; Hyperthermia; Hyperthermia, Induced; Polyethylene Glycols
PubMed: 34555486
DOI: 10.1016/j.addr.2021.113985 -
FEBS Open Bio Jan 2022DDB1 and CUL4 associated factor 13 (DCAF13) is a substrate receptor in the CUL4-DDB1 E3 ligase, and its expression is associated with the prognosis of certain cancers....
DDB1 and CUL4 associated factor 13 (DCAF13) is a substrate receptor in the CUL4-DDB1 E3 ligase, and its expression is associated with the prognosis of certain cancers. In the present study, we report evidence that DCAF13 is aberrantly overexpressed in human breast cancer and its expression is positively associated with cancer progression. Further analysis showed that the DCAF13 expression level is significantly higher in triple-negative breast cancer compared to non-triple-negative breast cancer, indicating a positive correlation between its expression and the aggressiveness of breast cancer. Subsequent studies revealed that DCAF13 regulates cancer cell migration, invasion and epithelial-mesenchymal transition in human breast cancer, whereas it has no significant impact on breast cancer cell proliferation, cell cycle progressionor apoptosis. Taken together, our results demonstrate that DCAF13 promotes the epithelial-mesenchymal transition in human breast cancer cells, indicating an involvement in breast cancer metastasis. Furthermore, we report that doxorubicin, a widely used chemotherapy drug, increases DCAF13 expression in breast cancer cells, leading to enhanced cancer cell migration and invasion. These results suggest that doxorubicin chemotherapy may increase the risk of metastasis of drug-resistant breast cancer cells, and future therapeutics targeting DCAF13 may help reduce the risk, especially for patients undergoing chemotherapy.
Topics: Cell Movement; Doxorubicin; Epithelial-Mesenchymal Transition; Humans; RNA-Binding Proteins; Triple Negative Breast Neoplasms
PubMed: 34775691
DOI: 10.1002/2211-5463.13330 -
Cell Biology International Oct 2022Hepatocellular carcinoma (HCC) is a common liver cancer that accounts for 90% of cases. Doxorubicin exhibits a broad spectrum of antitumor activity and is one of the...
Hepatocellular carcinoma (HCC) is a common liver cancer that accounts for 90% of cases. Doxorubicin exhibits a broad spectrum of antitumor activity and is one of the most active agents in HCC. WW domain-containing protein 2 (WWP2) is highly expressed in HCC tissues and activates protein kinase B (AKT) signaling pathway to enhance tumor metastasis. However, the role of WWP2 in the glycolysis and antitumor effects of doxorubicin and the epigenetic alterations of WWP2 in HCC remain to be elucidated. The levels of WWP2 and N6-methyladenosine methyltransferase-like 3 (METTL3) in clinical samples and cells were investigated. WWP2 were silenced or overexpressed to study the role of WWP2 in regulating cell proliferation, colony formation, and glycolysis. RNA immunoprecipitation was performed to test m A levels. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blot were used to measure mRNA and protein, respectively. WWP2 silencing inhibits cell proliferation, colony formation, and glycolysis, while WWP2 overexpression has the inverse effects via the AKT signaling pathway. Silencing WWP2 enhances doxorubicin's antitumor effect, while WWP2 overexpression suppresses doxorubicin's antitumor effect. Data also support that METTL3 mediates WWP2 m6A modification, and m6A reader, IGF2BP2, binds to the methylated WWP2 to promote the stability of WWP2, leading to upregulation of WWP2. METTL3 mediates WWP2 m6A modification, which can be recognized and bound by IGF2BP2 to increase the stability of WWP2, leading to WWP2 overexpression which inhibits the antitumor effects of doxorubicin through METTL3/WWP2/AKT/glycolysis axis.
Topics: Carcinoma, Hepatocellular; Doxorubicin; Humans; Liver Neoplasms; Methyltransferases; Proto-Oncogene Proteins c-akt; RNA-Binding Proteins; Ubiquitin-Protein Ligases
PubMed: 35880837
DOI: 10.1002/cbin.11856 -
Journal of Labelled Compounds &... Aug 2023Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are promising treatments for unresectable liver tumours. Some recent studies suggested...
Development and physicochemical characterization of a biodegradable microspheres formulation loaded with samarium-153 and doxorubicin for chemo-radioembolization of liver tumours.
Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are promising treatments for unresectable liver tumours. Some recent studies suggested that combining TACE and TARE in one treatment course might improve treatment efficacy through synergistic cytotoxicity effects. Nonetheless, current formulations do not facilitate a combination of chemo- and radio-embolic agents in one delivery system. Therefore, this study aimed to synthesise a hybrid biodegradable microsphere loaded with both radioactive agent, samarium-153 ( Sm) and chemotherapeutic drug, doxorubicin (Dox) for potential radio-chemoembolization of advanced liver tumours. Sm and Dox-loaded polyhydroxybutyrate-co-3-hydroxyvalerate (PHBV) microspheres were prepared using water-in-oil-in-water solvent evaporation method. The microspheres were then sent for neutron activation in a neutron flux of 2 × 10 n/cm /s. The physicochemical properties, radioactivity, radionuclide purity, Sm retention efficiency, and Dox release profile of the Dox- Sm-PHBV microspheres were analysed. In addition, in vitro cytotoxicity of the formulation was tested using MTT assay on HepG2 cell line at 24 and 72 h. The mean diameter of the Dox- Sm-PHBV microspheres was 30.08 ± 2.79 μm. The specific radioactivity was 8.68 ± 0.17 GBq/g, or 177.69 Bq per microsphere. The Sm retention efficiency was more than 99%, tested in phosphate-buffered saline (PBS) and human blood plasma over 26 days. The cumulative release of Dox from the microspheres after 41 days was 65.21 ± 1.96% and 29.96 ± 0.03% in PBS solution of pH 7.4 and pH 5.5, respectively. The Dox- Sm-PHBV microspheres achieved a greater in vitro cytotoxicity effect on HepG2 cells (85.73 ± 3.63%) than Sm-PHBV (70.03 ± 5.61%) and Dox-PHBV (74.06 ± 0.78%) microspheres at 300 μg/mL at 72 h. In conclusion, a novel biodegradable microspheres formulation loaded with chemotherapeutic drug (Dox) and radioactive agent ( Sm) was successfully developed in this study. The formulation fulfilled all the desired physicochemical properties of a chemo-radioembolic agent and achieved better in vitro cytotoxicity on HepG2 cells. Further investigations are needed to evaluate the biosafety, radiation dosimetry, and synergetic anticancer properties of the formulation.
Topics: Humans; Liver Neoplasms; Microspheres; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Doxorubicin; Radioisotopes; Polyesters
PubMed: 37287213
DOI: 10.1002/jlcr.4046