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Journal of Nanobiotechnology Jan 2023Despite the development of therapeutic modalities to treat cancer, multidrug resistance (MDR) and incomplete destruction of deeply embedded lung tumors remain...
Despite the development of therapeutic modalities to treat cancer, multidrug resistance (MDR) and incomplete destruction of deeply embedded lung tumors remain long-standing problems responsible for tumor recurrence and low survival rates. Therefore, developing therapeutic approaches to treat MDR tumors is necessary. In this study, nanodrugs with enhanced intracellular drug internalization were identified by the covalent bonding of carbon nanotubes of a specific nano size and doxorubicin (DOX). In addition, carbon nanotube conjugated DOX (CNT-DOX) sustained in the intracellular environment in multidrug-resistant tumor cells for a long time causes mitochondrial damage, suppresses ATP production, and results in the effective therapeutic effect of drug-resistant tumors. This study identified that H69AR lung cancer cells, an adriamycin (DOX) drug-resistant tumor cell line, did not activate drug resistance function on designed nano-anticancer drugs with a specific nano size. In summary, this study identified that the specific size of the nanodrug in combination with DOX overcame multidrug-resistant tumors by inducing selective accumulation in tumor cells and inhibiting ATP by mitochondrial damage.
Topics: Humans; Nanotubes, Carbon; Drug Resistance, Neoplasm; Lung Neoplasms; Doxorubicin; Cell Line, Tumor; Nanoparticles; Adenosine Triphosphate
PubMed: 36635755
DOI: 10.1186/s12951-023-01768-8 -
Veterinary Medicine and Science Aug 2020Opioid receptor activation was shown to enhance the efficacy of anti-neoplastic drugs in several human cancer cell lines. In these cell lines, doxorubicin increased the...
Opioid receptor activation was shown to enhance the efficacy of anti-neoplastic drugs in several human cancer cell lines. In these cell lines, doxorubicin increased the number of opioid receptors and methadone concurrently enhanced cellular doxorubicin uptake. Triggered through lay press and media, animal owners started to challenge veterinary oncologists with questions about methadone use in anti-cancer therapy. Especially in veterinary medicine, where side effects of chemotherapy are tolerated to a lesser extent and hence smaller doses are given, agents potentiating chemotherapeutic agents would be an optimal approach to treatment. Canine transitional cell carcinoma cells (TCC, K9TCC), canine osteosarcoma cells (OSA, Abrams) and canine hemangiosarcoma cells (HSA, DAL-4) were incubated with different combinations of methadone, buprenorphine and doxorubicin, in order to test inhibition of cell proliferation. Opioid receptor density was assessed with fluorescence-activated cell sorting in drug native and doxorubicin pretreated cells. In TCC and OSA cell lines opioid receptor density increased after doxorubicin pretreatment. In combination treatment, however, we did not find significant potentiation of doxorubicin's inhibitory effect on proliferation in these cell lines. Neither was there a significant increase of the effect of doxorubicin when the opioids were added 24 hr before doxorubicin. Hence, we could not confirm the hypothesis that opioids increase the anti-proliferative effect of the anti-neoplastic drug doxorubicin in any of these canine tumour cell lines. The lack of effect on a cellular level does not warrant a clinical approach to use opioids together with doxorubicin in dogs with cancer.
Topics: Animals; Antineoplastic Agents; Buprenorphine; Cell Line, Tumor; Cell Proliferation; Dogs; Doxorubicin; Methadone
PubMed: 32306524
DOI: 10.1002/vms3.266 -
Advanced Science (Weinheim,... Sep 2022Effective pyroptosis induction is a promising approach to potentiate cancer immunotherapy. However, the actual efficacy of the present pyroptosis inducers can be...
Effective pyroptosis induction is a promising approach to potentiate cancer immunotherapy. However, the actual efficacy of the present pyroptosis inducers can be weakened by successive biological barriers. Here, a cascaded pH-activated supramolecular nanoprodrug (PDNP) with a stepwise size shrinkage property is developed as a pyroptosis inducer to boost antitumor immune response. PDNPs comprise multiple poly(ethylene glycol) (PEG) and doxorubicin (DOX) drug-polymer hybrid repeating blocks conjugated by ultra-pH-sensitive benzoic imine (bzi) and hydrazone (hyd) bonds. The PEG units endow its "stealth" property and ensure sufficient tumor accumulation. A sharp switch in particle size and detachment of PEG shielding can be triggered by the acidic extracellular pH to achieve deep intratumor penetration. Following endocytosis, second-stage size switching can be initiated by more acidic endolysosomes, and PDNPs disassociate into ultrasmall cargo to ensure accurate intracellular delivery. The cascaded pH activation of PDNPs can effectively elicit gasdermin E (GSDME)-mediated pyroptosis to enhance the immunological response. In combination with anti-PD-1 antibody, PDNPs can amplify tumor suppression and extend the survival of mice, which suggests a powerful immune adjuvant and pave the way for high-efficiency immune checkpoint blockade therapy.
Topics: Animals; Doxorubicin; Mice; Neoplasms; Polyethylene Glycols; Prodrugs; Pyroptosis
PubMed: 35869614
DOI: 10.1002/advs.202203353 -
Biomaterials Advances Feb 2023Although new strategies for breast cancer treatment have yielded promising results, most drugs can lead to serious side effects when applied systemically. Doxorubicin...
Although new strategies for breast cancer treatment have yielded promising results, most drugs can lead to serious side effects when applied systemically. Doxorubicin (DOX), currently the most effective chemotherapeutic drug to treat breast cancer, is poorly selective towards tumor cells and treatment often leads to the development of drug resistance. Recent studies have indicated that several fatty acids (FAs) have beneficial effects on inhibiting tumorigenesis. The saturated FA palmitic acid (PA) showed anti-tumor activities in several types of cancer, as well as effective repolarization of M2 macrophages towards the anti-tumorigenic M1 phenotype. However, water insolubility and cellular impermeability limit the use of PA in vivo. To overcome these limitations, here, we encapsulated PA into a poly(d,l-lactic co-glycolic acid) (PLGA) nanoparticle (NP) platform, alone and in combination with DOX, to explore PA's potential as mono or combinational breast cancer therapy. Our results showed that PLGA-PA-DOX NPs and PLGA-PA NPs significantly reduced the viability and migratory capacity of breast cancer cells in vitro. In vivo studies in mice bearing mammary tumors demonstrated that PLGA-PA-NPs were as effective in reducing primary tumor growth and metastasis as NPs loaded with DOX, PA and DOX, or free DOX. At the molecular level, PLGA-PA NPs reduced the expression of genes associated with multi-drug resistance and inhibition of apoptosis, and induced apoptosis via a caspase-3-independent pathway in breast cancer cells. In addition, immunohistochemical analysis of residual tumors showed a reduction in M2 macrophage content and infiltration of leukocytes after treatment of PLGA-PA NPs and PLGA-PA-DOX NPs, suggesting immunomodulatory properties of PA in the tumor microenvironment. In conclusion, the use of PA alone or in combination with DOX may represent a promising novel strategy for the treatment of breast cancer.
Topics: Animals; Mice; Palmitic Acid; Doxorubicin; Neoplasms; Lactic Acid; Nanoparticles; Tumor Microenvironment
PubMed: 36603405
DOI: 10.1016/j.bioadv.2022.213270 -
Journal of Otolaryngology - Head & Neck... Dec 2023Our research group in the early stage identified CD109 as the target of aptamer S3 in nasopharyngeal carcinoma (NPC). This study was to use S3 to connect DNA tetrahedron...
OBJECTIVE
Our research group in the early stage identified CD109 as the target of aptamer S3 in nasopharyngeal carcinoma (NPC). This study was to use S3 to connect DNA tetrahedron (DT) and load doxorubicin (Dox) onto DT to develop a targeted delivery system, and explore whether S3-DT-Dox can achieve targeted therapy for NPC.
METHODS
Aptamer S3-conjugated DT was synthesized and loaded with Dox. The effects of S3-DT-Dox on NPC cells were investigated with laser confocal microscopy, flow cytometry, and MTS assays. A nude mouse tumor model was established from NPC 5-8F cells, and the in vivo anti-tumor activity of S3-DT-Dox was examined by using fluorescent probe labeling and hematoxylin-eosin staining.
RESULTS
The synthesized S3-DT had high purity and stability. S3-DT specifically recognized 5-8F cells and NPC tissues in vitro. When the ratio of S3-DT to Dox was 1:20, S3-DT had the best Dox loading efficiency. The drug release rate reached the maximum (0.402 ± 0.029) at 48 h after S3-DT-Dox was prepared and mixed with PBS. S3-DT did not affect Dox toxicity to 5-8F cells, but reduced Dox toxicity to non-target cells. Meanwhile, S3-DT-Dox was able to specifically target the transplanted tumors and inhibit their growth in nude mice, with minor damage to normal tissues.
CONCLUSION
Our study highlights the ability and safety of S3-DT-Dox to target NPC cells and inhibit the development NPC.
Topics: Animals; Mice; Nasopharyngeal Carcinoma; Mice, Nude; Cell Line, Tumor; Doxorubicin; DNA; Nasopharyngeal Neoplasms
PubMed: 38087297
DOI: 10.1186/s40463-023-00673-2 -
International Journal of Molecular... Aug 2022Carbon nanomaterials have received increasing attention in drug-delivery applications because of their distinct properties and structures, including large surface areas,...
Carbon nanomaterials have received increasing attention in drug-delivery applications because of their distinct properties and structures, including large surface areas, high conductivity, low solubility in aqueous media, unique chemical functionalities, and stability at the nano-scale size. Particularly, they have been used as nano-carriers and mediators for anticancer drugs such as Cisplatin, Camptothecin, and Doxorubicin. Cancer has become the most challenging disease because it requires sophisticated therapy, and it is classified as one of the top killers according to the World Health Organization records. The aim of the current work is to study and investigate the mechanism of combination between single-walled carbon nanotubes (SWCNTs) and fullerene derivatives (CN-[OH]β) as mediators, and anticancer agents for photodynamic therapy directly to destroy the infected cells without damaging the normal ones. Here, we obtain a bio-medical model to determine the efficiency of the usefulness of Doxorubicin (DOX) as an antitumor agent conjugated with SWCNTs with variant radii and fullerene derivative (CN-[OH]β). The two sub-models are obtained mathematically to evaluate the potential energy arising from the DOX-SWCNT and DOX-(CN-[OH]β) interactions. DOX modelled as two-connected spheres, small and large, each interacting with different SWCNTs (variant radii ) and fullerene derivatives CN-[OH]β, formed based on the number of carbon atoms (N) and the number of hydroxide molecules (OH) (β), respectively. Based on our obtained results, we find that the most favorable carbon nanomaterial is the SWCNT ( = 15.27 Å), followed by fullerene derivatives CN-(OH)22, CN-(OH)20, and CN-(OH)24, with minimum energies of -38.27, -33.72, -32.95, and -29.11 kcal/mol.
Topics: Antineoplastic Agents; Doxorubicin; Fullerenes; Hydroxides; Nanotubes, Carbon; Neoplasms; Pharmaceutical Preparations
PubMed: 36077042
DOI: 10.3390/ijms23179646 -
Biomedicine & Pharmacotherapy =... Feb 2021pH-sensitive liposomes are interesting carriers for drug-delivery, undertaking rapid bilayer destabilization in response to pH changes, allied to tumor accumulation, a...
pH-sensitive liposomes are interesting carriers for drug-delivery, undertaking rapid bilayer destabilization in response to pH changes, allied to tumor accumulation, a desirable behavior in the treatment of cancer cells. Previously, we have shown that pH-sensitive liposomes accumulate in tumor tissues of mice, in which an acidic environment accelerates drug delivery. Ultimately, these formulations can be internalized by tumor cells and take the endosome-lysosomal route. However, the mechanism of doxorubicin release and intracellular traffic of pH-sensitive liposomes remains unclear. To investigate the molecular mechanisms underlying the intracellular release of doxorubicin from pH-sensitive liposomes, we followed HeLa cells viability, internalization, intracellular trafficking, and doxorubicin's intracellular delivery mechanisms from pH-sensitive (SpHL-DOX) and non-pH-sensitive (nSpHL-DOX) formulations. We found that SpHL-DOX has faster internalization kinetics and intracellular release of doxorubicin, followed by strong nuclear accumulation compared to nSpHL-DOX. The increased nuclear accumulation led to the activation of cleaved caspase-3, which efficiently induced apoptosis. Remarkably, we found that chloroquine and E64d enhanced the cytotoxicity of SpHL-DOX. This knowledge is paramount to improve the efficiency of pH-sensitive liposomes or to be used as a rational strategy for developing new formulations to be applied in vivo.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Caspase 3; Cell Survival; Chloroquine; Doxorubicin; Drug Compounding; Drug Delivery Systems; HeLa Cells; Humans; Hydrogen-Ion Concentration; Intracellular Space; Leucine; Liposomes; Mice
PubMed: 33348307
DOI: 10.1016/j.biopha.2020.110952 -
Cell Cycle (Georgetown, Tex.) 2015Genomic screens of doxorubicin toxicity in S. cerevisiae have identified numerous mutants in amino acid and carbon metabolism which express increased doxorubicin...
Genomic screens of doxorubicin toxicity in S. cerevisiae have identified numerous mutants in amino acid and carbon metabolism which express increased doxorubicin sensitivity. This work examines the effect of amino acid metabolism on doxorubicin toxicity. S. cerevisiae were treated with doxorubicin in combination with a variety of amino acid supplements. Strains of S. cerevisiae with mutations in pathways utilizing aspartate and other metabolites were examined for sensitivity to doxorubicin. S. cerevisiae cultures exposed to doxorubicin in minimal media showed significantly more toxicity than cultures exposed in rich media. Supplementing minimal media with aspartate, glutamate or alanine reduced doxorubicin toxicity. Cell cycle response was assessed by examining the budding pattern of treated cells. Cultures exposed to doxorubicin in minimal media arrested growth with no apparent cell cycle progression. Aspartate supplementation allowed cultures exposed to doxorubicin in minimal media to arrest after one division with a budding pattern and survival comparable to cultures exposed in rich media. Aspartate provides less protection from doxorubicin in cells mutant in either mitochondrial citrate synthase (CIT1) or NADH oxidase (NDI1), suggesting aspartate reduces doxorubicin toxicity by facilitating mitochondrial function. These data suggest glycolysis becomes less active and mitochondrial respiration more active following doxorubicin exposure.
Topics: Aspartic Acid; Cell Survival; Cells, Cultured; Doxorubicin; Growth Inhibitors; Mitochondria; Saccharomyces cerevisiae
PubMed: 26317891
DOI: 10.1080/15384101.2015.1087619 -
International Journal of Molecular... Jul 2022In this work, we report the fabrication and functional demonstration of a kind of dually responsive nanoparticles (NPs) as a potential drug delivery vector. The pH...
In this work, we report the fabrication and functional demonstration of a kind of dually responsive nanoparticles (NPs) as a potential drug delivery vector. The pH value, corresponding to the acidic microenvironment at the tumor site, and mannitol, to the extracellular trigger agent, were employed as the dually responsive factors. The function of dual responses was achieved by breaking the dynamic covalent bonds between phenylboronic acid (PBA) groups and diols at low pH value (pH 5.0) and/or under the administration of mannitol, which triggered the decomposition of the complex NPs and the concomitant release of anticancer drug of doxorubicin (DOX) loaded inside the NPs. The NPs were composed of modified chitosan (PQCS) with quaternary ammonium and PBA groups on the side chains, heparin (Hep), and poly(vinyl alcohol) (PVA), in which quaternary ammonium groups offer the positive charge for the cell-internalization of NPs, PBA groups serve for the formation of dynamic bonds in responding to pH change and mannitol addition, PVA furnishes the NPs with diol groups for the interaction with PBA groups and the formation of dynamic NPS, and Hep plays the roles of reducing the cytotoxicity of highly positively-charged chitosan and forming of complex NPs for DOX up-loading. A three-step fabrication process of drug-loaded NPs was described, and the characterization results were comprehensively demonstrated. The sustained drug release from the drug-loaded NPs displayed obvious pH and mannitol dependence. More specifically, the cumulative DOX release was increased more than 1.5-fold at pH 5.0 with 20 mg mL mannitol. Furthermore, the nanoparticles were manifested with effective antitumor efficient and apparently enhanced cytotoxicity in response to the acidic pH value and/or mannitol.
Topics: Ammonium Compounds; Chitosan; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Hydrogen-Ion Concentration; Mannitol; Nanoparticles
PubMed: 35806347
DOI: 10.3390/ijms23137342 -
ACS Applied Materials & Interfaces Dec 2023Microglial cells play a critical role in glioblastoma multiforme (GBM) progression, which is considered a highly malignant brain cancer. The activation of microglia can...
Microglial cells play a critical role in glioblastoma multiforme (GBM) progression, which is considered a highly malignant brain cancer. The activation of microglia can either promote or inhibit GBM growth depending on the stage of the tumor development and on the microenvironment conditions. The current treatments for GBM have limited efficacy; therefore, there is an urgent need to develop novel and efficient strategies for drug delivery and targeting: in this context, a promising strategy consists of using nanoplatforms. This study investigates the microglial response and the therapeutic efficacy of dual-cell membrane-coated and doxorubicin-loaded hexagonal boron nitride nanoflakes tested on human microglia and GBM cells. Obtained results show promising therapeutic effects on glioma cells and an M2 microglia polarization, which refers to a specific phenotype or activation state that is associated with anti-inflammatory and tissue repair functions, highlighted through proteomic analysis.
Topics: Humans; Microglia; Proteomics; Glioblastoma; Doxorubicin; Brain Neoplasms; Cell Membrane; Tumor Microenvironment; Cell Line, Tumor
PubMed: 38051559
DOI: 10.1021/acsami.3c17097