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Anti-cancer Agents in Medicinal... 2021Doxorubicin (DOX) is widely used as a clinical first-line anti-cancer drug. However, its clinical application is severely limited due to the lack of tumor specificity of... (Review)
Review
Doxorubicin (DOX) is widely used as a clinical first-line anti-cancer drug. However, its clinical application is severely limited due to the lack of tumor specificity of the drug and severe side effects such as myelosuppression, nephrotoxicity, dose-dependent cardiotoxicity, and multi-drug resistance. To improve the bioavailability of DOX, maximize the therapeutic effect, and reduce its toxicity and side effects, many studies have been done on the nanoformulations of DOX, such as liposomes, polymer micelles, dendrimer, and nanogels. Herein, we review the latest progress of DOX nano-preparations and their anti-tumor effects, hoping to provide theoretical references and new research ideas for the development of new dosage forms of the drug and the technical methods available for clinical application.
Topics: Antibiotics, Antineoplastic; Cell Proliferation; Doxorubicin; Humans; Molecular Conformation; Nanoparticles; Neoplasms
PubMed: 33372884
DOI: 10.2174/1871520621666201229115612 -
Environmental Research Jun 2023Nanomedicine is a field that combines biology and engineering to improve disease treatment, particularly in cancer therapy. One of the promising techniques utilized in... (Review)
Review
Nanomedicine is a field that combines biology and engineering to improve disease treatment, particularly in cancer therapy. One of the promising techniques utilized in this area is the use of micelles, which are nanoscale delivery systems that are known for their simple preparation, high biocompatibility, small particle size, and the ability to be functionalized. A commonly employed chemotherapy drug, Doxorubicin (DOX), is an effective inhibitor of topoisomerase II that prevents DNA replication in cancer cells. However, its efficacy is frequently limited by resistance resulting from various factors, including increased activity of drug efflux transporters, heightened oncogenic factors, and lack of targeted delivery. This review aims to highlight the potential of micelles as new nanocarriers for delivering DOX and to examine the challenges involved with employing chemotherapy to treat cancer. Micelles that respond to changes in pH, redox, and light are known as stimuli-responsive micelles, which can improve the targeted delivery of DOX and its cytotoxicity by facilitating its uptake in tumor cells. Additionally, micelles can be utilized to administer a combination of DOX and other drugs and genes to overcome drug resistance mechanisms and improve tumor suppression. Furthermore, micelles can be used in phototherapy, both photodynamic and photothermal, to promote cell death and increase DOX sensitivity in human cancers. Finally, the alteration of micelle surfaces with ligands can further enhance their targeted delivery for cancer suppression.
Topics: Humans; Micelles; Cell Line, Tumor; Doxorubicin; Hydrogen-Ion Concentration
PubMed: 36948284
DOI: 10.1016/j.envres.2023.115722 -
Molecules (Basel, Switzerland) Jul 2022The scarcity of novel and effective therapeutics for the treatment of cancer is a pressing and alarming issue that needs to be prioritized. The number of cancer cases... (Review)
Review
The scarcity of novel and effective therapeutics for the treatment of cancer is a pressing and alarming issue that needs to be prioritized. The number of cancer cases and deaths are increasing at a rapid rate worldwide. Doxorubicin, an anticancer agent, is currently used to treat several types of cancer. It disrupts myriad processes such as histone eviction, ceramide overproduction, DNA-adduct formation, reactive oxygen species generation, Ca, and iron hemostasis regulation. However, its use is limited by factors such as drug resistance, toxicity, and congestive heart failure reported in some patients. The combination of doxorubicin with other chemotherapeutic agents has been reported as an effective treatment option for cancer with few side effects. Thus, the hybridization of doxorubicin and other chemotherapeutic drugs is regarded as a promising approach that can lead to effective anticancer agents. This review gives an update on hybrid compounds containing the scaffolds of doxorubicin and its derivatives with potent chemotherapeutic effects.
Topics: Antineoplastic Agents; DNA Damage; Doxorubicin; Histones; Humans
PubMed: 35889350
DOI: 10.3390/molecules27144478 -
International Journal of Molecular... Jun 2022Variable-Angle Total Internal Reflection Fluorescence Microscopy (VA-TIRFM) is applied in view of early detection of cellular responses to the cytostatic drug...
Variable-Angle Total Internal Reflection Fluorescence Microscopy (VA-TIRFM) is applied in view of early detection of cellular responses to the cytostatic drug doxorubicin. Therefore, we determined cell-substrate topology of cultivated CHO cells transfected with a membrane-associated Green Fluorescent Protein (GFP) in the nanometer range prior to and subsequent to the application of doxorubicin. Cell-substrate distances increased up to a factor of 2 after 24 h of application. A reduction of these distances by again a factor 2 was observed upon cell aging, and an influence of the cultivation time is presently discussed. Applicability of VA-TIRFM was supported by measurements of MCF-7 breast cancer cells after membrane staining and incubation with doxorubicin, when cell-substrate distances increased again by a factor ≥ 2. So far, our method needs well-defined cell ages and staining of cell membranes or transfection with GFP or related molecules. Use of intrinsic fluorescence or even light-scattering methods to various cancer cell lines could make this method more universal in the future, e.g., in the context of early detection of apoptosis.
Topics: Animals; Cell Membrane; Cricetinae; Cricetulus; Doxorubicin; Green Fluorescent Proteins; Microscopy, Fluorescence
PubMed: 35682954
DOI: 10.3390/ijms23116277 -
Nature Communications Mar 2024Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC...
Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.
Topics: Humans; Myeloid-Derived Suppressor Cells; Glutamine; Hematologic Neoplasms; Adenosine Triphosphate; Doxorubicin; Succinates
PubMed: 38555305
DOI: 10.1038/s41467-024-47096-9 -
Bioorganic Chemistry Mar 2022Doxorubicin belongs to the anthracycline chemical class of the drug and is one of the widely used anticancer drugs. The common side effects of doxorubicin include... (Review)
Review
Doxorubicin belongs to the anthracycline chemical class of the drug and is one of the widely used anticancer drugs. The common side effects of doxorubicin include vomiting, hair loss, rashes to serious side-effects such as irreversible cardiotoxicity, and drug-induced leukemia. This led many researchers around the globe to develop methods aimed to achieve higher efficacy and lower toxicity for doxorubicin. The present review article provides a detailed account of the design strategies i.e., chemical modifications and conjugate formation adopted by various research groups to minimize the side effects without compromising with the significant anticancer profile of the drug doxorubicin. Chemical modification of the drug includes alteration at C4' hydroxyl and C3' amine groups present in the sugar part. The pH-sensitive drug delivery system is covered highlighting use of theranostic tantalum oxide to the traditional approach of conjugating with acyl hydrazine and thiourea. Methods adopted to increase the bioavailability of the drugs inside the cancer cells viz., conjugation with humanized monoclonal antibody and other peptides along with their promising results are also discussed. The review further discusses works from recent years comprising of different nanoforms of doxorubicin for the targeted delivery of drugs inside the tumor cells. Few of the articles targeting nucleus or mitochondria as one of the effective cancer treatments are reported. The brain is inaccessible to the drug and it was modified through galactoxyloglucan-modified gold nanocarrier or conjugated with lactoferrin with enhanced permeability through the blood-brain barrier. Prodrug has particularly been used to target tumor tissues without affecting other tissue organs. The present review article offer clear advantages of one method over another adopted to target the cancer cells and may provide an insight for the researchers working in this area.
Topics: Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Galactose; Glucans; Nanoparticles
PubMed: 35030480
DOI: 10.1016/j.bioorg.2022.105599 -
Drug Development and Industrial Pharmacy Apr 2022Thermosensitive liposomes loaded with cisplatin and doxorubicin composed of DPPC, DSPC, and DPPE-PEG5000 with different ratios were prepared by thin film hydration...
Thermosensitive liposomes loaded with cisplatin and doxorubicin composed of DPPC, DSPC, and DPPE-PEG5000 with different ratios were prepared by thin film hydration method. The Differential Scanning Calorimetry (DSC) curves showed that the liposomes composed of DPPC-DSPC-DPPE-PEG5000 with phospholipid ratio 95:5:0.05 were a suitable formulation as thermosensitive liposomes with a DSC peak at 42.1 °C. The effect of doxorubicin and cisplatin encapsulated non-thermosensitive and thermosensitive liposomes on cellular proliferation and IC50 in SKBR3 & MDA-MB-231 breast cancer and PC-3 & LNcaP prostate cancer cell lines was investigated. The results showed that doxorubicin loaded into thermosensitive liposomes showed 20-fold decrease in the IC50 at 42 °C while comparing it with the same at 37 °C. Also, the results showed a more than 35-fold and 12-fold decrease in the IC50 of cisplatin thermosensitive liposomes at 42 °C, while compared with free cisplatin and cisplatin thermosensitive liposomes at any temperature. The results showed that the effect of doxorubicin encapsulated thermosensitive liposomes at hyperthermic conditions during the treatment as the tumor growth inhibition was measured 1.5-fold higher than any of the liposomal formulations of doxorubicin. It was also noticed that the tumor volume reduced to 150 mm in doxorubicin thermosensitive liposomes (G8) after 3 weeks during the treatment, but increased to 196 mm after 4 weeks. The Kaplan-Meir curve showed the 100% survival of the animals from G8 (thermosensitive liposomes containing doxorubicin plus hyperthermia) after 12 weeks. The flow cytometry data revealed more than 25% apoptotic cells and 6.25% necrotic cells in the tumor cells from the tissues of the G8 group of the animals. The results clearly indicate the superior efficacy of doxorubicin and cisplatin containing thermosensitive liposomes treatment during hyperthermia.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Doxorubicin; Liposomes; Male; Neoplasms; Phospholipids
PubMed: 35834369
DOI: 10.1080/03639045.2022.2102648 -
Advanced Materials (Deerfield Beach,... Apr 2024In osteosarcoma, immunotherapy often faces hurdles posed by cancer-associated fibroblasts (CAFs) that secrete dense extracellular matrix components and cytokines....
In osteosarcoma, immunotherapy often faces hurdles posed by cancer-associated fibroblasts (CAFs) that secrete dense extracellular matrix components and cytokines. Directly removing CAFs may prove ineffective and even promote tumor metastasis. To address this challenge, a sequential nanocomposite hydrogel that reshapes CAF behavior is developed, enhancing tumor-infiltrating T-cells in osteosarcoma. The approach utilizes an injectable blend of carboxymethyl chitosan and tetrabasic polyethylene glycol, forming a hydrogel for controlled release of a potent CAF suppressor (Nox4 inhibitor, Nox4i) and liposomal Doxorubicin (L-Dox) to induce immunogenic cell death (ICD) upon in situ administration. Nox4i effectively counters CAF activation, overcoming T-cell exclusion mechanisms, followed by programmed L-Dox release for ICD induction in stroma-rich osteosarcoma models. Combining the co-delivery gel with αPD-1 checkpoint inhibitor further enhances its effectiveness in an orthotopic osteosarcoma model. Immunophenotyping data underscore a significant boost in tumor T-cell infiltration and favorable anti-tumor immunity at the whole-animal level.
Topics: Animals; Nanogels; Cancer-Associated Fibroblasts; Osteosarcoma; Doxorubicin; Hydrogels; Bone Neoplasms; Immunotherapy; Cell Line, Tumor; Tumor Microenvironment; Polyethylene Glycols
PubMed: 38113900
DOI: 10.1002/adma.202309591 -
Bioconjugate Chemistry Dec 2023Bioorthogonal prodrug therapies offer an intriguing two-component system that features enhanced circulating stability and controlled activation on demand. Current...
Bioorthogonal prodrug therapies offer an intriguing two-component system that features enhanced circulating stability and controlled activation on demand. Current strategies often deliver either the prodrug or its complementary activator to the tumor with a monomechanism targeted mechanism, which cannot achieve the desired antitumor efficacy and safety profile. The orchestration of two distinct and orthogonal mechanisms should overcome the hierarchical heterogeneity of solid tumors to improve the delivery efficiency of both components simultaneously for bio-orthogonal prodrug therapies. We herein developed a dual-mechanism targeted bioorthogonal prodrug therapy by integrating two orthogonal, receptor-independent tumor-targeting strategies. We first employed the endogenous albumin transport system to generate the albumin-bound, bioorthogonal-caged doxorubicin prodrug with extended plasma circulation and selective accumulation at the tumor site. We then employed enzyme-instructed self-assembly (EISA) to specifically enrich the bioorthogonal activators within tumor cells. As each targeted delivery mode induced an intrinsic pharmacokinetic profile, further optimization of the administration sequence according to their pharmacokinetics allowed the spatiotemporally controlled prodrug activation on-target and on-demand. Taken together, by orchestrating two discrete and receptor-independent targeting strategies, we developed an all-small-molecule based bioorthogonal prodrug system for dual-mechanism targeted anticancer therapies to maximize therapeutic efficacy and minimize adverse drug reactions for chemotherapeutic agents.
Topics: Humans; Prodrugs; Doxorubicin; Neoplasms; Albumins; Cell Line, Tumor
PubMed: 37955377
DOI: 10.1021/acs.bioconjchem.3c00404 -
Biomaterials Jul 2023Multicellular clustering provides cancer cells with survival advantages and facilitates metastasis. At the tumor migration front, cancer cell clusters are surrounded by...
Multicellular clustering provides cancer cells with survival advantages and facilitates metastasis. At the tumor migration front, cancer cell clusters are surrounded by an aligned stromal topography. It remains unknown whether aligned stromal topography regulates the resistance of migrating cancer cell clusters to therapeutics. Using a hybrid nanopatterned model to characterize breast cancer cell clusters at the migration front with aligned stromal topography, we demonstrate that topography-induced migrating cancer cell clusters exhibit upregulated cytochrome P450 family 1 (CYP1) drug metabolism and downregulated glycolysis gene signatures, which correlates with unfavorable prognosis. Screening on approved oncology drugs shows that cancer cell clusters on aligned stromal topography are more resistant to diverse chemotherapeutics. Full-dose drug testings further indicate that topography induces drug resistance of hormone receptor-positive breast cancer cell clusters to doxorubicin and tamoxifen and triple-negative breast cancer cell clusters to doxorubicin by activating the aryl hydrocarbon receptor (AhR)/CYP1 pathways. Inhibiting the AhR/CYP1 pathway restores reactive oxygen species-mediated drug sensitivity to migrating cancer cell clusters, suggesting a plausible therapeutic direction for preventing metastatic recurrence.
Topics: Humans; Female; Breast Neoplasms; Drug Resistance, Neoplasm; Triple Negative Breast Neoplasms; Doxorubicin; Cell Line, Tumor
PubMed: 37121102
DOI: 10.1016/j.biomaterials.2023.122128