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1.
Sci Adv ; 10(33): eado3919, 2024 Aug 16.
Article in English | MEDLINE | ID: mdl-39141742

ABSTRACT

Postoperative rehemorrhage following intracerebral hemorrhage surgery is intricately associated with a high mortality rate, yet there is now no effective clinical treatment. In this study, we developed a hemoglobin (Hb)-responsive in situ implantable DNA hydrogel comprising Hb aptamers cross-linked with two complementary chains and encapsulating deferoxamine mesylate (DFO). Functionally, the hydrogel generates signals upon postoperative rehemorrhage by capturing Hb, demonstrating a distinctive "self-diagnosis" capability. In addition, the ongoing capture of Hb mediates the gradual disintegration of the hydrogel, enabling the on-demand release of DFO without compromising physiological iron-dependent functions. This process achieves self-treatment by inhibiting the ferroptosis of neurocytes. In a collagenase and autologous blood injection model-induced mimic postoperative rehemorrhage model, the hydrogel exhibited a 5.58-fold increase in iron absorption efficiency, reducing hematoma size significantly (from 8.674 to 4.768 cubic millimeters). This innovative Hb-responsive DNA hydrogel not only offers a therapeutic intervention for postoperative rehemorrhage but also provides self-diagnosis feedback, holding notable promise for enhancing clinical outcomes.


Subject(s)
Cerebral Hemorrhage , Hemoglobins , Hydrogels , Cerebral Hemorrhage/diagnosis , Cerebral Hemorrhage/drug therapy , Hydrogels/chemistry , Hemoglobins/metabolism , Animals , Deferoxamine/pharmacology , Deferoxamine/therapeutic use , Deferoxamine/chemistry , DNA/metabolism , Humans , Male , Rats , Disease Models, Animal , Ferroptosis/drug effects , Iron/metabolism , Postoperative Hemorrhage/etiology , Postoperative Hemorrhage/diagnosis , Aptamers, Nucleotide/pharmacology , Aptamers, Nucleotide/chemistry
2.
Mol Pharm ; 21(9): 4324-4335, 2024 Sep 02.
Article in English | MEDLINE | ID: mdl-39164886

ABSTRACT

Positron emission tomography (PET) is a powerful tool for investigating the in vivo behavior of drug delivery systems. We aimed to assess the biodistribution of extracellular vesicles (EVs), nanosized vesicles secreted by cells isolated from various human cell sources using PET. EVs were isolated from mesenchymal stromal cells (MSCs) (MSC EVs), human macrophages (Mϕ EVs), and a melanoma cell line (A375 EVs) by centrifugation and were conjugated with deferoxamine for radiolabeling with Zr-89. PET using conjugated and radiolabeled EVs evaluated their in vivo biodistribution and tissue tropisms. Our study also investigated differences in mouse models, utilizing immunocompetent and immunocompromised mice and an A375 xenograft tumor model. Lastly, we investigated the impact of different labeling techniques on the observed EV biodistribution, including covalent surface modification and membrane incorporation. PET showed that all tested EVs exhibited extended in vivo circulation and generally low uptake in the liver, spleen, and lungs. However, Mϕ EVs showed high liver uptake, potentially attributable to the intrinsic tissue tropism of these EVs from the surface protein composition. MSC EV biodistribution differed between immunocompetent and immunodeficient mice, with increased spleen uptake observed in the latter. PET using A375 xenografts demonstrated efficient tumor uptake of EVs, but no preferential tissue-specific tropism of A375 EVs was found. Biodistribution differences between labeling techniques showed that surface-conjugated EVs had preferential blood circulation and low liver, spleen, and lung uptake compared to membrane integration. This study demonstrates the potential of EVs as effective drug carriers for various diseases, highlights the importance of selecting appropriate cell sources for EV-based drug delivery, and suggests that EV tropism can be harnessed to optimize therapeutic efficacy. Our findings indicate that the cellular source of EVs, labeling technique, and animal model can influence the observed biodistribution.


Subject(s)
Extracellular Vesicles , Mesenchymal Stem Cells , Positron-Emission Tomography , Animals , Humans , Extracellular Vesicles/metabolism , Tissue Distribution , Mice , Positron-Emission Tomography/methods , Cell Line, Tumor , Mesenchymal Stem Cells/metabolism , Macrophages/metabolism , Zirconium/chemistry , Zirconium/pharmacokinetics , Deferoxamine/chemistry , Deferoxamine/pharmacokinetics , Radioisotopes/chemistry , Radioisotopes/pharmacokinetics , Drug Delivery Systems/methods , Xenograft Model Antitumor Assays , Female , Melanoma/metabolism , Melanoma/diagnostic imaging
3.
Methods Enzymol ; 702: 121-145, 2024.
Article in English | MEDLINE | ID: mdl-39155108

ABSTRACT

Siderophores are low-molecular-weight organic bacterial and fungal secondary metabolites that form high affinity complexes with Fe(III). These Fe(III)-siderophore complexes are part of the siderophore-mediated Fe(III) uptake mechanism, which is the most widespread strategy used by microbes to access sufficient iron for growth. Microbial competition for limited iron is met by biosynthetic gene clusters that encode for the biosynthesis of siderophores with variable molecular scaffolds and iron binding motifs. Some classes of siderophores have well understood biosynthetic pathways, which opens opportunities to further expand structural and property diversity using precursor-directed biosynthesis (PDB). PDB involves augmenting culture medium with non-native substrates to compete against native substrates during metabolite assembly. This chapter provides background information and technical details of conducting a PDB experiment towards producing a range of different analogues of the archetypal hydroxamic acid siderophore desferrioxamine B. This includes processes to semi-purify the culture supernatant and the use of liquid chromatography-tandem mass spectrometry for downstream analysis of analogues and groups of constitutional isomers.


Subject(s)
Siderophores , Siderophores/biosynthesis , Siderophores/chemistry , Siderophores/metabolism , Tandem Mass Spectrometry/methods , Deferoxamine/metabolism , Deferoxamine/chemistry , Chromatography, Liquid/methods , Biosynthetic Pathways , Multigene Family , Iron/metabolism , Iron/chemistry , Culture Media/chemistry , Culture Media/metabolism
4.
Bioorg Med Chem ; 112: 117842, 2024 Oct 01.
Article in English | MEDLINE | ID: mdl-39173538

ABSTRACT

The decline of antibiotics efficacy worldwide has recently reached a critical point urging for the development of new strategies to regain upper hand on multidrug resistant bacterial strains. In this context, the raise of photodynamic therapy (PDT), initially based on organic photosensitizers (PS) and more recently on organometallic PS, offers promising perspectives. Many PS exert their biological effects through the generation of reactive oxygen species (ROS) able to freely diffuse into and to kill surrounding bacteria. Hijacking of the bacterial iron-uptake systems with siderophore-PS conjugates would specifically target pathogens. Here, we report the synthesis of unprecedented conjugates between the siderophore desferrioxamine B (DFOB) and an antibacterial iridium(III) PS. Redox properties of the new conjugates have been determined at excited states and compared to that of an antibacterial iridium PS previously reported by our groups. Tested on nosocomial pathogen Pseudomonas aeruginosa and other bacteria, these conjugates demonstrated significant inhibitory activity when activated with blue LED light. Ir(III) conjugate and iridium free DFOB-2,2'-dipyridylamine ligands were crystallized in complex with FoxA, the outer membrane transporter involved in DFOB uptake in P. aeruginosa and revealed details of the binding mode of these unprecedented conjugates.


Subject(s)
Anti-Bacterial Agents , Coordination Complexes , Deferoxamine , Iridium , Light , Microbial Sensitivity Tests , Pseudomonas aeruginosa , Siderophores , Iridium/chemistry , Iridium/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Deferoxamine/pharmacology , Deferoxamine/chemistry , Deferoxamine/chemical synthesis , Siderophores/chemistry , Siderophores/pharmacology , Siderophores/chemical synthesis , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Pseudomonas aeruginosa/drug effects , Molecular Structure , Structure-Activity Relationship , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/chemical synthesis , Dose-Response Relationship, Drug
5.
ACS Appl Mater Interfaces ; 16(33): 43892-43906, 2024 Aug 21.
Article in English | MEDLINE | ID: mdl-39046193

ABSTRACT

With the swift evolution of multidrug-resistant bacteria resulting from the intense and inappropriate use of antibiotics, there is a pressing need for innovative solutions. In this study, a thermosensitive hydrogel was developed for efficient bacterial inhibition and promotion of wound healing. The antibacterial chitosan (CS) thermosensitive hydrogel, cross-linked with two-dimensional photothermal nanomaterial black phosphorus (BP) nanosheets through electrostatic interactions, effectively encapsulates and sustains the release of angiogenic drug deferoxamine mesylate (DFO). This facilitates the acceleration of re-epithelialization and neovascularization by enhancing cell migration and proliferation. Following near-infrared (NIR) treatment, this hydrogel demonstrates rapid eradication of the most common multidrug-resistant bacteria encountered in clinical settings, achieved through physical disruption of bacterial membranes and photothermal therapies. Noteworthy is the significant upregulation of IL-19 expression via STAT3 signaling pathways by the BP/CS-DFO hydrogel in a full-thickness wound model. This results in the polarization of the anti-inflammatory M2 macrophage phenotype, altering the microenvironment to a pro-healing state and enhancing extracellular matrix deposition and blood vessel formation. In conclusion, the BP/CS-DFO hydrogel shows immense promise as a potential clinical candidate for wound healing and antimicrobial therapy. Its innovative design and multifunctional capabilities position it as a valuable asset in combating antibiotic resistance and enhancing efficiency in wound healing.


Subject(s)
Anti-Bacterial Agents , Chitosan , Deferoxamine , Hydrogels , Phosphorus , Wound Healing , Wound Healing/drug effects , Hydrogels/chemistry , Hydrogels/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Phosphorus/chemistry , Mice , Animals , Chitosan/chemistry , Chitosan/pharmacology , Deferoxamine/chemistry , Deferoxamine/pharmacology , Nanostructures/chemistry , RAW 264.7 Cells , Microbial Sensitivity Tests , Humans , Staphylococcus aureus/drug effects , Cell Proliferation/drug effects
6.
Lancet Oncol ; 25(8): 1015-1024, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38950555

ABSTRACT

BACKGROUND: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. METHODS: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. FINDINGS: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. INTERPRETATION: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. FUNDING: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.


Subject(s)
Intracellular Signaling Peptides and Proteins , Lung Neoplasms , Membrane Proteins , Positron Emission Tomography Computed Tomography , Prostatic Neoplasms , Radioisotopes , Zirconium , Humans , Male , Middle Aged , Aged , Membrane Proteins/immunology , Membrane Proteins/metabolism , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/immunology , Neuroendocrine Tumors/diagnostic imaging , Neuroendocrine Tumors/pathology , Neuroendocrine Tumors/immunology , Neuroendocrine Tumors/drug therapy , Female , Deferoxamine/chemistry , Immunoconjugates/pharmacokinetics , Neoplasm Grading , Radiopharmaceuticals , Adult , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/administration & dosage , Aged, 80 and over , Benzodiazepinones , Antibodies, Monoclonal, Humanized
7.
J Med Chem ; 67(14): 12143-12154, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-38907990

ABSTRACT

The pathogenic fungus Aspergillus fumigatus utilizes a cyclic ferrioxamine E (FOXE) siderophore to acquire iron from the host. Biomimetic FOXE analogues were labeled with gallium-68 for molecular imaging with PET. [68Ga]Ga(III)-FOXE analogues were internalized in A. fumigatus cells via Sit1. Uptake of [68Ga]Ga(III)-FOX 2-5, the most structurally alike analogue to FOXE, was high by both A. fumigatus and bacterial Staphylococcus aureus. However, altering the ring size provoked species-specific uptake between these two microbes: ring size shortening by one methylene unit (FOX 2-4) increased uptake by A. fumigatus compared to that by S. aureus, whereas lengthening the ring (FOX 2-6 and 3-5) had the opposite effect. These results were consistent both in vitro and in vivo, including PET imaging in infection models. Overall, this study provided valuable structural insights into the specificity of siderophore uptake and, for the first time, opened up ways for selective targeting and imaging of microbial pathogens by siderophore derivatization.


Subject(s)
Aspergillosis , Aspergillus fumigatus , Gallium Radioisotopes , Positron-Emission Tomography , Siderophores , Staphylococcus aureus , Aspergillus fumigatus/metabolism , Aspergillus fumigatus/chemistry , Positron-Emission Tomography/methods , Siderophores/chemistry , Siderophores/metabolism , Animals , Staphylococcus aureus/metabolism , Aspergillosis/diagnostic imaging , Aspergillosis/microbiology , Gallium Radioisotopes/chemistry , Species Specificity , Mice , Ferric Compounds/chemistry , Biomimetic Materials/chemistry , Biomimetic Materials/metabolism , Deferoxamine/chemistry , Peptides, Cyclic
8.
Mol Pharm ; 21(7): 3218-3232, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38885477

ABSTRACT

Squamous cell carcinoma (SCC) is a common nonmelanoma skin cancer. Radiotherapy plays an integral role in treating SCC due to its characteristics, such as diminished intercellular adhesion, heightened cell migration and invasion capabilities, and immune evasion. These problems lead to inaccurate tumor boundary positioning and radiotherapy tolerance in SCC treatment. Thus, accurate localization and enhanced radiotherapy sensitivity are imperative for effective SCC treatment. To address the existing limitations in SCC therapy, we developed monoglyceride solid lipid nanoparticles (MG SLNs) and enveloped them with the A431 cell membrane (A431 CM) to create A431@MG. The characterization results showed that A431@MG was spherical. Furthermore, A431@MG had specific targeting for A431 cells. In A431 tumor-bearing mice, A431@MG demonstrated prolonged accumulation within tumors, ensuring precise boundary localization of SCC. We further advanced the approach by preparing MG SLNs encapsulating 5-aminolevulinic acid methyl ester (MLA) and desferrioxamine (DFO) with an A431 CM coating to yield A431@MG-MLA/DFO. Several studies have revealed that DFO effectively reduced iron content, impeding protoporphyrin IX (PpIX) biotransformation and promoting PpIX accumulation. Simultaneously, MLA was metabolized into PpIX upon cellular entry. During radiotherapy, the heightened PpIX levels enhanced reactive oxygen species (ROS) generation, inducing DNA and mitochondrial damage and leading to cell apoptosis. In A431 tumor-bearing mice, the A431@MG-MLA/DFO group exhibited notable radiotherapy sensitization, displaying superior tumor growth inhibition. Combining A431@MG-MLA/DFO with radiotherapy significantly improved anticancer efficacy, highlighting its potential to serve as an integrated diagnostic and therapeutic strategy for SCC.


Subject(s)
Carcinoma, Squamous Cell , Cell Membrane , Nanoparticles , Radiation-Sensitizing Agents , Skin Neoplasms , Animals , Mice , Nanoparticles/chemistry , Humans , Cell Line, Tumor , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/radiotherapy , Radiation-Sensitizing Agents/chemistry , Radiation-Sensitizing Agents/pharmacology , Radiation-Sensitizing Agents/administration & dosage , Cell Membrane/metabolism , Aminolevulinic Acid/chemistry , Aminolevulinic Acid/pharmacology , Aminolevulinic Acid/administration & dosage , Lipids/chemistry , Xenograft Model Antitumor Assays , Deferoxamine/chemistry , Deferoxamine/pharmacology , Mice, Nude , Female , Mice, Inbred BALB C , Reactive Oxygen Species/metabolism , Apoptosis/drug effects , Liposomes
9.
ACS Appl Mater Interfaces ; 16(27): 34720-34731, 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38934381

ABSTRACT

Anti-inflammatory and angiogenesis are two important factors in wound healing. Wound dressings with anti-inflammation and vascularization are essential to address complex interventions, expensive treatments, and uncontrolled release mechanisms. Based on the above considerations, we designed a near-infrared (NIR)-responsive hydrogel dressing, which is composed of mPDA-DFO@LA nanoparticles (mPDA: dopamine hydrochloride nanoparticles, DFO: deferoxamine, LA: lauric acid), valsartan (abbreviated as Va), and dopamine-hyaluronic acid hydrogel. The hydrogel dressing demonstrated injectability, bioadhesive, and photothermal properties. The results indicated the obtained dressing by releasing Va can appropriately regulate macrophage phenotype transformation from M1 to M2, resulting in an anti-inflammatory environment. In addition, DFO encapsulated by LA can be sustainably released into the wound site by NIR irradiation, which further prevents excessive neovascularization. Notably, the results in vivo indicated the mPDA-DFO@LA/Va hydrogel dressing significantly enhanced wound recovery, achieving a healing rate of up to 96% after 11 days of treatment. Therefore, this NIR-responsive hydrogel dressing with anti-inflammation, vascularization, and on-demand programmed drug release will be a promising wound dressing for wound infection.


Subject(s)
Anti-Inflammatory Agents , Bandages , Hydrogels , Nanocomposites , Wound Healing , Animals , Mice , Angiogenesis/drug effects , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Deferoxamine/chemistry , Deferoxamine/pharmacology , Deferoxamine/therapeutic use , Dopamine/chemistry , Dopamine/pharmacology , Hydrogels/chemistry , Hydrogels/pharmacology , Infrared Rays , Lauric Acids/chemistry , Lauric Acids/pharmacology , Nanocomposites/chemistry , Nanocomposites/therapeutic use , RAW 264.7 Cells , Wound Healing/drug effects
10.
ACS Appl Mater Interfaces ; 16(19): 24384-24397, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38709640

ABSTRACT

Vascularization and inflammation management are essential for successful bone regeneration during the healing process of large bone defects assisted by artificial implants/fillers. Therefore, this study is devoted to the optimization of the osteogenic microenvironment for accelerated bone healing through rapid neovascularization and appropriate inflammation inhibition that were achieved by applying a tantalum oxide (TaO)-based nanoplatform carrying functional substances at the bone defect. Specifically, TaO mesoporous nanospheres were first constructed and then modified by functionalized metal ions (Mg2+) with the following deferoxamine (DFO) loading to obtain the final product simplified as DFO-Mg-TaO. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed that the product was homogeneously dispersed hollow nanospheres with large specific surface areas and mesoporous shells suitable for loading Mg2+ and DFO. The biological assessments indicated that DFO-Mg-TaO could enhance the adhesion, proliferation, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). The DFO released from DFO-Mg-TaO promoted angiogenetic activity by upregulating the expressions of hypoxia-inducible factor-1 (HIF-1α) and vascular endothelial growth factor (VEGF). Notably, DFO-Mg-TaO also displayed anti-inflammatory activity by reducing the expressions of pro-inflammatory factors, benefiting from the release of bioactive Mg2+. In vivo experiments demonstrated that DFO-Mg-TaO integrated with vascular regenerative, anti-inflammatory, and osteogenic activities significantly accelerated the reconstruction of bone defects. Our findings suggest that the optimized DFO-Mg-TaO nanospheres are promising as multifunctional fillers to speed up the bone healing process.


Subject(s)
Bone Regeneration , Deferoxamine , Magnesium , Mesenchymal Stem Cells , Oxides , Tantalum , Deferoxamine/chemistry , Deferoxamine/pharmacology , Bone Regeneration/drug effects , Tantalum/chemistry , Animals , Oxides/chemistry , Oxides/pharmacology , Magnesium/chemistry , Magnesium/pharmacology , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Osteogenesis/drug effects , Neovascularization, Physiologic/drug effects , Rats , Mice , Rats, Sprague-Dawley , Cell Proliferation/drug effects , Angiogenesis
11.
Biomed Mater ; 19(4)2024 May 21.
Article in English | MEDLINE | ID: mdl-38697149

ABSTRACT

To effectively address underlying issues and enhance the healing process of hard-to-treat soft tissue defects, innovative therapeutic approaches are required. One promising strategy involves the incorporation of bioactive substances into biodegradable scaffolds to facilitate synergistic tissue regeneration, particularly in vascular regeneration. In this study, we introduce a composite hydrogel design that mimics the extracellular matrix by covalently combining gelatin and hyaluronic acid (HA), with the encapsulation of deferoxamine nanoparticles (DFO NPs) for potential tissue regeneration applications. Crosslinked hydrogels were fabricated by controlling the ratio of HA in the gelatin-based hydrogels, resulting in improved mechanical properties, enhanced degradation ability, and optimised porosity, compared with hydrogel formed by gelatin alone. The DFO NPs, synthesized using a double emulsion method with poly (D,L-lactide-co-glycolide acid), exhibited a sustained release of DFO over 12 d. Encapsulating the DFO NPs in the hydrogel enabled controlled release over 15 d. The DFO NPs, composite hydrogel, and the DFO NPs loaded hydrogel exhibited excellent cytocompatibility and promoted cell proliferationin vitro. Subcutaneous implantation of the composite hydrogel and the DFO NPs loaded hydrogel demonstrated biodegradability, tissue integration, and no obvious adverse effects, evidenced by histological analysis. Furthermore, the DFO NPs loaded composite hydrogel exhibited accelerated wound closure and promoted neovascularisation and granular formation when tested in an excisional skin wound model in mice. These findings highlight the potential of our composite hydrogel system for promoting the faster healing of diabetes-induced skin wounds and oral lesions through its ability to modulate tissue regeneration processes.


Subject(s)
Biomimetic Materials , Deferoxamine , Gelatin , Hyaluronic Acid , Hydrogels , Nanoparticles , Gelatin/chemistry , Deferoxamine/chemistry , Deferoxamine/pharmacology , Animals , Hydrogels/chemistry , Hyaluronic Acid/chemistry , Nanoparticles/chemistry , Mice , Biomimetic Materials/chemistry , Cell Proliferation/drug effects , Wound Healing/drug effects , Tissue Engineering/methods , Tissue Scaffolds/chemistry , Biocompatible Materials/chemistry , Humans , Porosity , Regeneration , Biomimetics
12.
ACS Appl Mater Interfaces ; 16(22): 28209-28221, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38778020

ABSTRACT

Diabetic chronic wounds are notoriously difficult to heal as a result of their susceptibility to infection. To address this issue, we constructed an innovated and adaptable solution in the form of injectable chitosan (CS) hydrogel, denoted as CCOD, with enhanced antibacterial and anti-inflammatory properties. This hydrogel is created through a Schiff base reaction that combines chitosan-grafted chlorogenic acid (CS-CGA) and oxidized hyaluronic acid (OHA) with deferoxamine (DFO) as a model drug. The combination of CS and CGA has demonstrated excellent antibacterial and anti-inflammatory properties, while grafting played a pivotal role in making these positive effects stable. These unique features make it possible to customize injectable hydrogel and fit any wound shape, allowing for more effective and personalized treatment of complex bacterial infections. Furthermore, the hydrogel system is not only effective against inflammation and bacterial infections but also possesses antioxidant and angiogenic abilities, making it an ideal solution for the repair of chronic wounds that have been previously thought of as unmanageable.


Subject(s)
Anti-Bacterial Agents , Anti-Inflammatory Agents , Chitosan , Chlorogenic Acid , Deferoxamine , Hyaluronic Acid , Hydrogels , Wound Healing , Animals , Humans , Mice , Angiogenesis , Angiogenesis Inducing Agents/chemistry , Angiogenesis Inducing Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Chitosan/chemistry , Chitosan/pharmacology , Chlorogenic Acid/chemistry , Chlorogenic Acid/pharmacology , Deferoxamine/chemistry , Deferoxamine/pharmacology , Hyaluronic Acid/chemistry , Hyaluronic Acid/pharmacology , Hydrogels/chemistry , Hydrogels/pharmacology , Neovascularization, Physiologic/drug effects , Oxidation-Reduction , Staphylococcus aureus/drug effects , Wound Healing/drug effects
13.
Appl Radiat Isot ; 210: 111379, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38815448

ABSTRACT

This study aimed to carry out the preclinical studies of [89Zr]Zr-DFO-Bevacizumab. The radiolabeled compound was prepared with radiochemical purity >99% (ITLC), and a specific activity of 74 GBq/g. Cellular studies indicated the great capability of [89Zr]Zr-DFO-Bevacizumab for binding to SKOV3 cell lines. High accumulation was observed in the tumor. The liver and spleen received the highest absorbed dose with 1.12 and 0.72 mGy/MBq, respectively. This radiopharmaceutical can be considered as a suitable PET agent for VEGF-expressing ovarian cancer imaging.


Subject(s)
Bevacizumab , Ovarian Neoplasms , Positron-Emission Tomography , Radiopharmaceuticals , Vascular Endothelial Growth Factor A , Zirconium , Bevacizumab/pharmacokinetics , Bevacizumab/chemistry , Positron-Emission Tomography/methods , Animals , Humans , Female , Zirconium/chemistry , Radiopharmaceuticals/pharmacokinetics , Cell Line, Tumor , Vascular Endothelial Growth Factor A/metabolism , Ovarian Neoplasms/diagnostic imaging , Ovarian Neoplasms/metabolism , Mice , Tissue Distribution , Radioisotopes , Deferoxamine/chemistry
14.
ACS Biomater Sci Eng ; 10(6): 3946-3957, 2024 06 10.
Article in English | MEDLINE | ID: mdl-38701357

ABSTRACT

Elevated levels of ROS, bacterial infection, inflammation, and improper regeneration are the factors that need to be addressed simultaneously for achieving effective wound healing without scar formation. This study focuses on the fabrication of electrospun ROS-responsive selenium-containing polyurethane nanofibers incorporating deferoxamine mesylate (Def), indomethacin (Indo), and gold nanorods (AuNRs) as proangiogenesis, anti-inflammatory, and antibacterial agents for synchronized delivery to a full-thickness wound in vivo. The structure of the fabricated nanofibers was analyzed by various techniques. Toxicity was checked by CCK-8 and hemolytic assays. The efficiency of wound healing in vitro was verified by a transwell assay and cell scratch assay. The wound healing efficiency of the nanofibers was assayed in full-thickness wounds in a rat model. The multifunctional nanofibers had a porous structure, enhanced antioxidation, antibacterial activity, and promoted wound healing. They eradicated TNF-α and IL-6, increased IL-10 expression, and revealed the angiogenic potential by increased expression of HIF-1α, VEGF, and CD31.


Subject(s)
Gold , Nanofibers , Polyurethanes , Reactive Oxygen Species , Selenium , Wound Healing , Wound Healing/drug effects , Polyurethanes/chemistry , Polyurethanes/pharmacology , Animals , Nanofibers/chemistry , Selenium/chemistry , Selenium/pharmacology , Reactive Oxygen Species/metabolism , Gold/chemistry , Gold/pharmacology , Rats , Nanotubes/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Deferoxamine/pharmacology , Deferoxamine/chemistry , Rats, Sprague-Dawley , Humans , Indomethacin/pharmacology , Male , Neovascularization, Physiologic/drug effects , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry
15.
Eur J Nucl Med Mol Imaging ; 51(11): 3202-3214, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38730087

ABSTRACT

PURPOSE: ATG-101, a bispecific antibody that simultaneously targets the immune checkpoint PD-L1 and the costimulatory receptor 4-1BB, activates exhausted T cells upon PD-L1 crosslinking. Previous studies demonstrated promising anti-tumour efficacy of ATG-101 in preclinical models. Here, we labelled ATG-101 with 89Zr to confirm its tumour targeting effect and tissue biodistribution in a preclinical model. We also evaluated the use of immuno-PET to study tumour uptake of ATG-101 in vivo. METHODS: ATG-101, anti-PD-L1, and an isotype control were conjugated with p-SCN-Deferoxamine (Df). The Df-conjugated antibodies were radiolabelled with 89Zr, and their radiochemical purity, immunoreactivity, and serum stability were assessed. We conducted PET/MRI and biodistribution studies on [89Zr]Zr-Df-ATG-101 in BALB/c nude mice bearing PD-L1-expressing MDA-MB-231 breast cancer xenografts for up to 10 days after intravenous administration of [89Zr]Zr-labelled antibodies. The specificity of [89Zr]Zr-Df-ATG-101 was evaluated through a competition study with unlabelled ATG-101 and anti-PD-L1 antibodies. RESULTS: The Df-conjugation and [89Zr]Zr -radiolabelling did not affect the target binding of ATG-101. Biodistribution and imaging studies demonstrated biological similarity of [89Zr]Zr-Df-ATG-101 and [89Zr]Zr-Df-anti-PD-L1. Tumour uptake of [89Zr]Zr-Df-ATG-101 was clearly visualised using small-animal PET imaging up to 7 days post-injection. Competition studies confirmed the specificity of PD-L1 targeting in vivo. CONCLUSION: [89Zr]Zr-Df-ATG-101 in vivo distribution is dependent on PD-L1 expression in the MDA-MB-231 xenograft model. Immuno-PET with [89Zr]Zr-Df-ATG-101 provides real-time information about ATG-101 distribution and tumour uptake in vivo. Our data support the use of [89Zr]Zr-Df-ATG-101 to assess tumour and tissue uptake of ATG-101.


Subject(s)
Antibodies, Bispecific , B7-H1 Antigen , Zirconium , Animals , Zirconium/chemistry , Mice , B7-H1 Antigen/metabolism , Antibodies, Bispecific/pharmacokinetics , Antibodies, Bispecific/chemistry , Antibodies, Bispecific/immunology , Tissue Distribution , Humans , Cell Line, Tumor , Radioisotopes/chemistry , Deferoxamine/chemistry , Deferoxamine/analogs & derivatives , Positron-Emission Tomography , Female , Isotope Labeling , Mice, Inbred BALB C , Isothiocyanates
16.
J Labelled Comp Radiopharm ; 67(8): 280-287, 2024 Jun 30.
Article in English | MEDLINE | ID: mdl-38744538

ABSTRACT

A key aspect for the applicability of 89Zr-radioimmunoconjugates is inert modification and radiolabeling. The two commercially available bifunctional variants of the siderophore desferrioxamine (DFO), Fe-DFO-N-suc-TFP-ester and p-NCS-Bz-DFO, are most often used for clinical 89Zr-immuno-PET. The use of Fe-DFO-N-suc-TFP-ester is advantageous with regard to higher radiolysis stability and more facile assessment of radiochemical purity as well as chelator-to-mAb ratio. However, not all mAbs withstand the Fe-removal step at relatively low pH (4-4.5) using EDTA, which is needed after conjugation to allow 89Zr labeling. In this study, it was investigated whether hydroxybenzyl ethylenediamine (HBED) or the clinically approved deferiprone (DFP) can serve as an alternative for EDTA to establish a pH-independent mild method for Fe-removal and thereby broaden the applicability of Fe-DFO-N-suc-TFP-ester. Carrier-added [59Fe]Fe-DFO-N-suc-TFP-ester was used for mAb modification to enable direct tracking of the Fe-removal efficiency under various conditions. Whereas incomplete Fe-removal with HBED was observed at pH 5 or higher, Fe-removal with DFP was possible at a broad pH range (4-9). This provides a mild, pH-independent method for Fe-removal, improving the applicability and attractiveness of Fe-DFO-N-suc-TFP-ester for 89Zr-mAb preparation.


Subject(s)
Deferoxamine , Iron , Positron-Emission Tomography , Radioisotopes , Zirconium , Zirconium/chemistry , Deferoxamine/chemistry , Radioisotopes/chemistry , Iron/chemistry , Positron-Emission Tomography/methods , Pyridones/chemistry , Deferiprone/chemistry , Immunoconjugates/chemistry , Radiopharmaceuticals/chemistry , Antibodies, Monoclonal/chemistry
17.
Bioconjug Chem ; 35(5): 633-637, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38656148

ABSTRACT

Zirconium-89 is the most widely used radioisotope for immunoPET because its physical half-life (78.2 h) suits the one of antibodies. Desferrioxamine B (DFO) is the standard chelator for the complexation of zirconium(IV), and its bifunctional version, containing a phenylisothiocyanate function, is the most commonly used for the conjugation of DFO to proteins. However, preliminary results have shown that the thiourea link obtained from the conjugation of isothiocyanate and lysines is sensitive to the ionizing radiation generated by the radioisotope, leading to the rupture of the link and the release of the chelator/radiometal complex. This radiolysis phenomenon could produce nonspecific signal and prevent the detection of bone metastasis, as free zirconium accumulates into the bones. The aim of this work was to study the stability of a selection of conjugation linkers in 89Zr-labeled immunoconjugates. We have synthesized several DFO-based bifunctional chelators appended with an isothiocyanate moiety, a bicyclononyne, or a squaramate ester. Two antibodies (trastuzumab and rituximab) were conjugated and radiolabeled with zirconium-89. The effect of increasing activities of zirconium-89 on the integrity of the bioconjugate bearing thiourea links was evaluated as well as the impact of the presence of a radioprotectant. The stability of the radiolabeled antibodies was studied over 7 days in PBS and human plasma. Radioconjugates' integrity was evaluated using iTLC and size-exclusion chromatography. This study shows that the nature of the linker between the chelator and biomolecule can have a strong impact on the stability of the 89Zr-labeled conjugates, as well as on the aggregation of the conjugates.


Subject(s)
Immunoconjugates , Isothiocyanates , Radioisotopes , Zirconium , Zirconium/chemistry , Immunoconjugates/chemistry , Isothiocyanates/chemistry , Radioisotopes/chemistry , Chelating Agents/chemistry , Humans , Deferoxamine/chemistry
18.
Acc Chem Res ; 57(9): 1421-1433, 2024 05 07.
Article in English | MEDLINE | ID: mdl-38666539

ABSTRACT

Molecular imaging with antibodies radiolabeled with positron-emitting radionuclides combines the affinity and selectivity of antibodies with the sensitivity of Positron Emission Tomography (PET). PET imaging allows the visualization and quantification of the biodistribution of the injected radiolabeled antibody, which can be used to characterize specific biological interactions in individual patients. This characterization can provide information about the engagement of the antibody with a molecular target such as receptors present in elevated levels in tumors as well as providing insight into the distribution and clearance of the antibody. Potential applications of clinical PET with radiolabeled antibodies include identifying patients for targeted therapies, characterization of heterogeneous disease, and monitoring treatment response.Antibodies often take several days to clear from the blood pool and localize in tumors, so PET imaging with radiolabeled antibodies requires the use of a radionuclide with a similar radioactive half-life. Zirconium-89 is a positron-emitting radionuclide that has a radioactive half-life of 78 h and relatively low positron emission energy that is well suited to radiolabeling antibodies. It is essential that the zirconium-89 radionuclide be attached to the antibody through chemistry that provides an agent that is stable in vivo with respect to the dissociation of the radionuclide without compromising the biological activity of the antibody.This Account focuses on our research using a simple derivative of the bacterial siderophore desferrioxamine (DFO) with a squaramide ester functional group, DFO-squaramide (DFOSq), to link the chelator to antibodies. In our work, we produce conjugates with an average ∼4 chelators per antibody, and this does not compromise the binding of the antibody to the target. The resulting antibody conjugates of DFOSq are stable and can be easily radiolabeled with zirconium-89 in high radiochemical yields and purity. Automated methods for the radiolabeling of DFOSq-antibody conjugates have been developed to support multicenter clinical trials. Evaluation of several DFOSq conjugates with antibodies and low molecular weight targeting agents in tumor mouse models gave PET images with high tumor uptake and low background. The promising preclinical results supported the translation of this chemistry to human clinical trials using two different radiolabeled antibodies. The potential clinical impact of these ongoing clinical trials is discussed.The use of DFOSq to radiolabel relatively low molecular weight targeting molecules, peptides, and peptide mimetics is also presented. Low molecular weight molecules typically clear the blood pool and accumulate in target tissue more rapidly than antibodies, so they are usually radiolabeled with positron-emitting radionuclides with shorter radioactive half-lives such as fluorine-18 (t1/2 ∼ 110 min) or gallium-68 (t1/2 ∼ 68 min). Radiolabeling peptides and peptide mimetics with zirconium-89, with its longer radioactive half-life (t1/2 = 78 h), could facilitate the centralized manufacture and distribution of radiolabeled tracers. In addition, the ability to image patients at later time points with zirconium-89 based agents (e.g. 4-24 h after injection) may also allow the delineation of small or low-uptake disease sites as the delayed imaging results in increased clearance of the tracer from nontarget tissue and lower background signal.


Subject(s)
Deferoxamine , Positron-Emission Tomography , Quinine/analogs & derivatives , Radioisotopes , Zirconium , Zirconium/chemistry , Radioisotopes/chemistry , Deferoxamine/chemistry , Positron-Emission Tomography/methods , Animals , Humans , Mice , Radiopharmaceuticals/chemistry , Neoplasms/diagnostic imaging
19.
Eur J Nucl Med Mol Imaging ; 51(9): 2547-2557, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38625402

ABSTRACT

PURPOSE: Cadherin-17 (CDH17) is a calcium-dependent cell adhesion protein that is overexpressed in several adenocarcinomas, including gastric, colorectal, and pancreatic adenocarcinoma. High levels of CDH17 have been linked to metastatic disease and poor prognoses in patients with these malignancies, fueling interest in the protein as a target for diagnostics and therapeutics. Herein, we report the synthesis, in vitro validation, and in vivo evaluation of a CDH17-targeted 89Zr-labeled immunoPET probe. METHODS: The CDH17-targeting mAb D2101 was modified with an isothiocyanate-bearing derivative of desferrioxamine (DFO) to produce a chelator-bearing immunoconjugate - DFO-D2101 - and flow cytometry and surface plasmon resonance (SPR) were used to interrogate its antigen-binding properties. The immunoconjugate was then radiolabeled with zirconium-89 (t1/2 ~ 3.3 days), and the serum stability and immunoreactive fraction of [89Zr]Zr-DFO-D2101 were determined. Finally, [89Zr]Zr-DFO-D2101's performance was evaluated in a trio of murine models of pancreatic ductal adenocarcinoma (PDAC): subcutaneous, orthotopic, and patient-derived xenografts (PDX). PET images were acquired over the course of 5 days, and terminal biodistribution data were collected after the final imaging time point. RESULTS: DFO-D2101 was produced with a degree of labeling of ~ 1.1 DFO/mAb. Flow cytometry with CDH17-expressing AsPC-1 cells demonstrated that the immunoconjugate binds to its target in a manner similar to its parent mAb, while SPR with recombinant CDH17 revealed that D2101 and DFO-D2101 exhibit nearly identical KD values: 8.2 × 10-9 and 6.7 × 10-9 M, respectively. [89Zr]Zr-DFO-D2101 was produced with a specific activity of 185 MBq/mg (5.0 mCi/mg), remained >80% stable in human serum over the course of 5 days, and boasted an immunoreactive fraction of >0.85. In all three murine models of PDAC, the radioimmunoconjugate yielded high contrast images, with high activity concentrations in tumor tissue and low uptake in non-target organs. Tumoral activity concentrations reached as high as >60 %ID/g in two of the cohorts bearing PDXs. CONCLUSION: Taken together, these data underscore that [89Zr]Zr-DFO-D2101 is a highly promising probe for the non-invasive visualization of CDH17 expression in PDAC. We contend that this radioimmunoconjugate could have a significant impact on the clinical management of patients with both PDAC and gastrointestinal adenocarcinoma, most likely as a theranostic imaging tool in support of CDH17-targeted therapies.


Subject(s)
Cadherins , Radioisotopes , Zirconium , Animals , Humans , Mice , Cadherins/metabolism , Cell Line, Tumor , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/metabolism , Deferoxamine/chemistry , Adenocarcinoma/diagnostic imaging , Immunoconjugates/pharmacokinetics , Antibodies, Monoclonal/pharmacokinetics , Tissue Distribution , Positron-Emission Tomography
20.
Adv Healthc Mater ; 13(12): e2303134, 2024 05.
Article in English | MEDLINE | ID: mdl-38348511

ABSTRACT

The effective repair of large bone defects remains a major challenge due to its limited self-healing capacity. Inspired by the structure and function of the natural periosteum, an electrospun biomimetic periosteum is constructed to programmatically promote bone regeneration using natural bone healing mechanisms. The biomimetic periosteum is composed of a bilayer with an asymmetric structure in which an aligned electrospun poly(ε-caprolactone)/gelatin/deferoxamine (PCL/GEL/DFO) layer mimics the outer fibrous layer of the periosteum, while a random coaxial electrospun PCL/GEL/aspirin (ASP) shell and PCL/silicon nanoparticles (SiNPs) core layer mimics the inner cambial layer. The bilayer controls the release of ASP, DFO, and SiNPs to precisely regulate the inflammatory, angiogenic, and osteogenic phases of bone repair. The random coaxial inner layer can effectively antioxidize, promoting cell recruitment, proliferation, differentiation, and mineralization, while the aligned outer layer can promote angiogenesis and prevent fibroblast infiltration. In particular, different stages of bone repair are modulated in a rat skull defect model to achieve faster and better bone regeneration. The proposed biomimetic periosteum is expected to be a promising candidate for bone defect healing.


Subject(s)
Biomimetic Materials , Bone Regeneration , Periosteum , Polyesters , Bone Regeneration/drug effects , Animals , Periosteum/drug effects , Rats , Biomimetic Materials/chemistry , Biomimetic Materials/pharmacology , Polyesters/chemistry , Rats, Sprague-Dawley , Deferoxamine/pharmacology , Deferoxamine/chemistry , Gelatin/chemistry , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacology , Delayed-Action Preparations/pharmacokinetics , Osteogenesis/drug effects , Skull/drug effects , Skull/injuries , Male , Nanoparticles/chemistry , Tissue Engineering/methods , Cell Differentiation/drug effects , Tissue Scaffolds/chemistry
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