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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 -
In Vitro Cellular & Developmental... Jan 2022Melanoma is the most dangerous type of skin cancer and is responsible for 75% of deaths from skin cancers. For an accurate evaluation of potential treatment efficacy, it...
Melanoma is the most dangerous type of skin cancer and is responsible for 75% of deaths from skin cancers. For an accurate evaluation of potential treatment efficacy, it is important to use study models as close as possible to the in vivo conditions. A 3D model consisting of B16F10 spheroids was developed using liquid overlay technique on plates coated with 1% agarose, in the presence of 1% methylcellulose and L929-conditioned medium. The model is suitable and can be further used for more complex in vitro drug testing than the classical 2D approach. For exemplification, the behavior of a well-known cytostatic, doxorubicin (DOX), was evaluated in spheroids as compared to classical 2D culture conditions. Fluorescence imaging was used to visualize DOX uptake by B16F10 spheroids at different periods of time. The results showed that a much higher DOX concentration is necessary to produce similar effects compared with the monolayer. The fluorescence images revealed that at least 4 h of stimulation is needed for a sufficient DOX uptake. The 3D model developed in this study was suitable to investigate drug penetration in time. Our findings may explain the decrease of the doxorubicin therapeutical effect, suggesting the need of maintaining the drug concentration at the tumoral place for at least 2 h upon administration. Similar or more advanced studies can lead to a better understanding of drug delivery kinetics and distribution upon administration, conducing toward a better performance in designing suitable delivery systems for obtaining the optimum dose-response effect.
Topics: Animals; Cell Line, Tumor; Doxorubicin; Melanoma; Optical Imaging; Spheroids, Cellular
PubMed: 34981409
DOI: 10.1007/s11626-021-00636-9 -
Doxorubicin chemomyectomy: injection of monkey orbicularis oculi results in selective muscle injury.Investigative Ophthalmology & Visual... Dec 1988Doxorubicin was injected into the preseptal portion of the orbicularis oculi of one lower eyelid in each of two cynomolgus monkeys at a dose of 2 mg. One monkey was...
Doxorubicin was injected into the preseptal portion of the orbicularis oculi of one lower eyelid in each of two cynomolgus monkeys at a dose of 2 mg. One monkey was observed for 4 days and the other for 68 days after doxorubicin injection. Although some skin ulceration was seen, it was completely healed by 3 weeks postinjection. The preseptal portion of the orbicularis oculi in both monkeys showed extensive signs of injury. At 4 days after doxorubicin injection many necrotic muscle fibers could be seen. Very few muscle fibers in the preseptal portion of the muscle remained by 68 days after injection. The pretarsal portion of the injected orbicularis oculi was relatively normal, with little evidence of injury. It appears that doxorubicin injection into the lower lid resulted in a gradient of muscle injury, with increasing severity at decreasing distances from the injection site. The extent of muscle injured is related to the dose and injection site and indicates the ability to selectively control the injury within a muscle. The ramifications of this effect on the use of doxorubicin for permanent treatment of blepharospasm and other related diseases are discussed in this first report of the injection of this drug into the eyelids of nonhuman primates.
Topics: Animals; Blepharospasm; Doxorubicin; Eyelids; Injections, Intramuscular; Macaca fascicularis; Muscles; Necrosis; Skin Diseases
PubMed: 3192375
DOI: No ID Found -
Biomaterials Science Mar 2022Despite the remarkable tumor inhibition effect of doxorubicin (DOX), its cardiotoxicity severely limits the clinical dosage and further impairs the chemotherapy...
Despite the remarkable tumor inhibition effect of doxorubicin (DOX), its cardiotoxicity severely limits the clinical dosage and further impairs the chemotherapy efficacy. To improve the biosafety and effectiveness of conventional chemotherapy, we propose a strategy to co-deliver DOX and ART to supplement apoptosis with ferroptosis. To this end, ART and DOX were incorporated into ferrous LiMOFs to develop a nanoreactor, utilizing ferrous ions as a catalyst to decompose ART into radicals and thus to induce efficient ferroptosis. Further, DOX can induce another form of death, apoptosis, which in combination enhances tumor inhibition. The synthesized nanoreactor (DOX/ART@LiMOFs) possesses a size of ∼100 nm and maintains a regular crystal structure. The pH-responsive disassociation endows it with acid-sensitive drug-releasing kinetics, and the liposomal bilayers bring about a sustained release feature (up to 12 h). The cellular ROS assay indicated that the supply of ferrous ions dramatically increased the ROS mediated by ART and led to markedly enhanced tumor inhibition in animal tests accompanied by the apoptosis of DOX. Consequently, this work presents an innovative strategy to synchronously induce potent ferroptosis and apoptosis, promoting conventional cancer chemotherapy.
Topics: Animals; Apoptosis; Cell Line, Tumor; Doxorubicin; Ferroptosis; Nanotechnology; Neoplasms
PubMed: 35171184
DOI: 10.1039/d2bm00079b -
Circulation Jul 2013
Topics: Animals; Cardiotonic Agents; Chemical Engineering; Doxorubicin; Female; Humans; Male; Myocytes, Cardiac; Neuregulin-1
PubMed: 23757311
DOI: 10.1161/CIRCULATIONAHA.113.003688 -
Drug Development Research May 2022In this work, five Man-DOX conjugates with different linkers were developed for targeted DOX delivery. The five Man-DOX conjugates with different linkers were...
In this work, five Man-DOX conjugates with different linkers were developed for targeted DOX delivery. The five Man-DOX conjugates with different linkers were characterized by H NMR, HRMS, HPLC, UV-vis, and fluorescence spectroscopy. Man-Suc-DOX, Man-TDG-DOX, and Man-DG-DOX can self-assemble into near-spherical nanoparticles with hydrodynamic diameters of 150-200 nm and negative zeta potentials in deionized water, whereas Man-SS-DOX and Man-SeSe-DOX are hardly dispersed in deionized water. The self-assembly behaviors of Man-Suc-DOX, Man-TDG-DOX, and Man-DG-DOX were studied by dissipative particle dynamics simulation and the results show that Man-Suc-DOX, Man-TDG-DOX, and Man-DG-DOX all self-assemble into spherical particles with Man and linkers on the surfaces and DOX in the interiors. The in vitro drug release study shows that Man-Suc-DOX, Man-TDG-DOX, and Man-DG-DOX exhibit limited drug release, while Man-SS-DOX and Man-SeSe-DOX exhibit glutathione-responsive drug release. The cellular uptake study shows that Man-DG-DOX exhibits the highest cellular uptake amount on HepG2 cells. Finally, Man-DG-DOX exhibits the best in vitro antitumor effect against HepG2 cells among the five Man-DOX conjugates with different linkers. Although the in vitro antitumor activity of Man-DG-DOX is still lower than free DOX, Man-DG-DOX shows significant selectivity toward HepG2 cells. Man-DG-DOX might achieve selective DOX delivery for mannose receptor overexpressed tumors.
Topics: Doxorubicin; Drug Delivery Systems; Drug Liberation; Humans; Mannose; Nanoparticles; Water
PubMed: 34730851
DOI: 10.1002/ddr.21896 -
Cells Jun 2022Leukemia is a non-solid cancer which features the malignant proliferation of leukocytes. Excessive leukocytes of lesions in peripheral blood will infiltrate organs,...
Leukemia is a non-solid cancer which features the malignant proliferation of leukocytes. Excessive leukocytes of lesions in peripheral blood will infiltrate organs, resulting in intumescence and weakening treatment efficiency. In this study, we proposed a novel approach for targeted clearance of the leukocytes in the peripheral blood ex vivo, which employed magnetic nanochains to selectively destroy the leukocytes of the lesions. The nanochains were doxorubicin-loaded nanochains of FeO nanoparticles which were fabricated by the solvent exchange method combined with magnetic field-directed self-assembly. Firstly, the nanochains were added into the peripheral blood during extracorporeal circulation and subjected to a rotational magnetic field for actuation. The leukocytes of the lesion were then conjugated by the nanochains via folic acid (FA) targeting. Finally, the rotational magnetic field actuated the nanochains to release the drugs and effectively damage the cytomembrane of the leukocytes. This strategy was conceptually shown in vitro (K562 cell line) and the method's safety was evaluated in a rat model. The preliminary results demonstrate that the nanochains are biocompatible and suitable as drug carriers, showing direct lethal action to the leukemic cells combined with a rotational magnetic field. More importantly to note is that the nanochains can be effectively kept from entry into the body. We believe this extracorporeal circulation-based strategy by activating nanochains magnetically could serve as a potential method for leukemia treatment in the future.
Topics: Animals; Doxorubicin; Drug Carriers; Extracorporeal Circulation; Leukemia; Nanoparticles; Rats
PubMed: 35805091
DOI: 10.3390/cells11132007 -
Journal of Materials Chemistry. B Aug 2020Stimuli-responsive and targetable nanomedicine systems have been widely applied as effective modalities for drug delivery and tumor therapeutics. Particle shape is also...
Stimuli-responsive and targetable nanomedicine systems have been widely applied as effective modalities for drug delivery and tumor therapeutics. Particle shape is also important for the biodistribution and cellular uptake in drug delivery applications. Here, morphology tunable and acid-responsive dextran-doxorubicin conjugate assemblies of DD-M and DDF-V for targeted doxorubicin (DOX) delivery were constructed, which contain the following favorable advantages: (1) one-pot synthesis of the drug loaded system with a Schiff base reaction is a green chemistry method which is better than the conventional drug conjugation/encapsulation methods. (2) The morphology of the nanoparticles could be regulated from a micelle (DD-M) to vesicle (DDF-V) structure by either introducing folic acid (FA) or not. (3) The abundant hydroxyl groups and electronegativity give DD-M and DDF-V superior stability in the physiological environment. (4) Besides, the multifunctional DDF-V with its important merits including tumor-targeting ability and acid-responsiveness is specific for DOX delivery in cancer therapy. (5) Compared to free DOX and DD-M, DDF-V displayed enhanced anti-tumor efficacy both in vitro and in vivo without obvious systematic toxicity. The morphology tunable, acid-sensitive and targetable nanosystem could be a promising strategy for site-specific drug delivery and potential cancer therapy in the future.
Topics: Antineoplastic Agents; Cell Line, Tumor; Dextrans; Doxorubicin; Drug Carriers; Folic Acid; Humans; Hydrogen-Ion Concentration; Molecular Targeted Therapy
PubMed: 32400838
DOI: 10.1039/d0tb00746c -
Journal of Separation Science Feb 2023While histone deacetylase inhibitors, such as vorinostat, demonstrate a significant effect against hematological cancers, their application for solid tumor treatment is...
Box-Behnken assisted development and validation of high-performance liquid chromatography method for the simultaneous determination of doxorubicin and vorinostat in polymeric nanoparticles.
While histone deacetylase inhibitors, such as vorinostat, demonstrate a significant effect against hematological cancers, their application for solid tumor treatment is limited. However, there is strong evidence that combinatorial administration of vorinostat and genotoxic agents (e.g., doxorubicin) enhances the antitumoral action of both drugs against tumors. We developed a high-performance liquid chromatography method for the simultaneous determination of doxorubicin and vorinostat in polymeric nanoparticles designed to provide the parenteral administration of both drugs and increase their safety profile. We performed separation on Nucleodur C-18 Gravity column with a mixture of 10 mM potassium dihydrogen phosphate buffer pH 3.9:ACN (90:10 v/v) as mobile phase at 240 nm. The method was linear within the concentration range of 4.2-52.0 μg/ml for both drugs with limits of detection and quantification of 3.5 and 10.7 μg/ml for doxorubicin and 2.5 and 7.7 μg/ml for vorinostat, respectively. The method was precise and accurate over the concentration range of analysis. Drug loading was 5.4% for doxorubicin and 0.8% for vorinostat. Degradation of doxorubicin after irradiation was less than 5%, while the amount of vorinostat decreased at 88% under the same conditions. Thus, the validated method could be adopted for routine simultaneous analysis of doxorubicin and vorinostat in polymeric nanoparticles.
Topics: Humans; Vorinostat; Chromatography, High Pressure Liquid; Doxorubicin; Histone Deacetylase Inhibitors; Neoplasms; Pharmaceutical Preparations; Nanoparticles
PubMed: 36427291
DOI: 10.1002/jssc.202200731 -
Nanotechnology Nov 2022Feand 2-methylimidazole were selected to prepare tumor microenvironment targeted and regulated multifunctional drug carrier Fe-MOFs. The fact that Doxorubicin...
Tumor microenvironment targeting and regulating iron-based metal-organic framework for magnetic resonance imaging guided synergetic therapy of doxorubicin and hydroxyl radicals.
Feand 2-methylimidazole were selected to prepare tumor microenvironment targeted and regulated multifunctional drug carrier Fe-MOFs. The fact that Doxorubicin hydrochloride (DOX·HCl) release climbed 70% from 25% upon regulating the pH from 7.4 to 5.8 proved the pH responsive drug release of Fe-MOFs. Hydroxyl radicals (·OH) analysis proved that Fe-MOFs only generated hydroxyl radicals at pH 5.8, and dissolved oxygen performance showed the Owas produced during the process, which was expected to regulate hypoxia in tumor cells to increase anticancer effect. Cell viability experiments proved the selectivity of Fe-MOFs and the excellent performance of synergy therapy of DOX·HCl and hydroxyl radicals.magnetic resonance imaging experiments demonstrated excellent performance of positive images. All experiments showed that Fe-MOFs can be used for image-guided collaborative treatment to improve treatment efficiency and reduce side effects.
Topics: Metal-Organic Frameworks; Tumor Microenvironment; Hydroxyl Radical; Iron; Doxorubicin; Magnetic Resonance Imaging
PubMed: 36347034
DOI: 10.1088/1361-6528/aca0f8