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1.
Theranostics ; 14(8): 3267-3281, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38855181

RESUMEN

Background: Myocardial infarction (MI) as a consequence of atherosclerosis-associated acute thrombosis is a leading cause of death and disability globally. Antiplatelet and anticoagulant drugs are standard therapies in preventing and treating MI. However, all clinically used drugs are associated with bleeding complications, which ultimately limits their use in patients with a high risk of bleeding. We have developed a new recombinant drug, targ-HSA-TAP, that combines targeting and specific inhibition of activated platelets as well as anticoagulation. This drug is designed and tested for a prolonged circulating half-life, enabling unique thromboprophylaxis without bleeding complications. Methods: Targ-HSA-TAP combines a single-chain antibody (scFv) that targets activated glycoprotein IIb/IIIa on activated platelets, human serum albumin (HSA) for prolonged circulation, and tick anticoagulant peptide (TAP) for coagulation FX inhibition. A non-binding scFv is employed as a non-targeting control (non-targ-HSA-TAP). Its efficacy was investigated in vivo using murine models of acute thrombosis and cardiac ischemia-reperfusion (I/R) injury. Results: Our experiments confirmed the targeting specificity of targ-HSA-TAP to activated platelets and demonstrated effective prevention of platelet aggregation and thrombus formation, as well as FXa inhibition in vitro. Thromboprophylactic administration of targ-HSA-TAP subcutaneously in mice prevented occlusion of the carotid artery after ferric chloride injury as compared to non-targ-HSA-TAP and PBS-control treated mice. By comparing the therapeutic outcomes between targ-TAP and targ-HSA-TAP, we demonstrate the significant improvements brought by the HSA fusion in extending the drug's half-life and enhancing its therapeutic window for up to 16 h post-administration. Importantly, tail bleeding time was not prolonged with targ-HSA-TAP in contrast to the clinically used anticoagulant enoxaparin. Furthermore, in a murine model of cardiac I/R injury, mice administered targ-HSA-TAP 10 h before injury demonstrated preserved cardiac function, with significantly higher ejection fraction and fractional shortening, as compared to the non-targ-HSA-TAP and PBS control groups. Advanced strain analysis revealed reduced myocardial deformation and histology confirmed a reduced infarct size in targ-HSA-TAP treated mice compared to control groups. Conclusion: The inclusion of HSA represents a significant advancement in the design of targeted therapeutic agents for thromboprophylaxis. Our activated platelet-targeted targ-HSA-TAP is a highly effective antithrombotic drug with both anticoagulant and antiplatelet effects while retaining normal hemostasis. The long half-life of targ-HSA-TAP provides the unique opportunity to use this antithrombotic drug for more effective, long-lasting and safer anti-thrombotic prophylaxis. In cases where MI occurs, this prophylactic strategy reduces thrombus burden and effectively reduces cardiac I/R injury.


Asunto(s)
Plaquetas , Hemorragia , Albúmina Sérica Humana , Trombosis , Animales , Ratones , Trombosis/prevención & control , Trombosis/tratamiento farmacológico , Humanos , Hemorragia/prevención & control , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Modelos Animales de Enfermedad , Masculino , Anticoagulantes/farmacología , Anticoagulantes/uso terapéutico , Anticuerpos de Cadena Única/farmacología , Anticuerpos de Cadena Única/uso terapéutico , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Infarto del Miocardio/tratamiento farmacológico , Ratones Endogámicos C57BL , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico
2.
Arterioscler Thromb Vasc Biol ; 43(6): 1031-1040, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37078286

RESUMEN

BACKGROUND: Current clinical imaging of thromboembolic diseases often relies on indirect detection of thrombi, which may delay diagnosis and ultimately the institution of beneficial, potentially lifesaving treatment. Therefore, the development of targeting tools that facilitate the rapid, specific, and direct imaging of thrombi using molecular imaging is highly sought after. One potential molecular target is FXIIa (factor XIIa), which initiates the intrinsic coagulation pathway but also activates the kallikrein-kinin system, thereby initiating coagulation and inflammatory/immune responses. As FXII (factor XII) is dispensable for normal hemostasis, its activated form (FXIIa) represents an ideal molecular target for diagnostic and therapeutic approaches, the latter combining diagnosis/identification of thrombi and effective antithrombotic therapy. METHODS: We conjugated an FXIIa-specific antibody, 3F7, to a near-infrared (NIR) fluorophore and demonstrated binding to FeCl3-induced carotid thrombosis with 3-dimensional fluorescence emission computed tomography/computed tomography and 2-dimensional fluorescence imaging. We further demonstrated ex vivo imaging of thromboplastin-induced pulmonary embolism and detection of FXIIa in human thrombi produced in vitro. RESULTS: We demonstrated imaging of carotid thrombosis by fluorescence emission computed tomography/computed tomography and measured a significant fold increase in signal between healthy and control vessels from mice injected with 3F7-NIR compared with mice injected with nontargeted probe (P=0.002) ex vivo. In a model of pulmonary embolism, we measured increased NIR signal in lungs from mice injected with 3F7-NIR compared with mice injected with nontargeted probe (P=0.0008) and healthy lungs from mice injected with 3F7-NIR (P=0.021). CONCLUSIONS: Overall, we demonstrate that FXIIa targeting is highly suitable for the specific detection of venous and arterial thrombi. This approach will allow direct, specific, and early imaging of thrombosis in preclinical imaging modalities and may facilitate monitoring of antithrombotic treatment in vivo.


Asunto(s)
Trombosis de las Arterias Carótidas , Embolia Pulmonar , Trombosis , Ratones , Humanos , Animales , Coagulación Sanguínea , Trombosis/diagnóstico por imagen , Factor XII/metabolismo , Factor XIIa/metabolismo , Imagen Molecular
3.
Small ; 18(31): e2200967, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35710979

RESUMEN

Atherosclerosis is a major cause of mortality and morbidity worldwide. Left undiagnosed and untreated, atherosclerotic plaques can rupture and cause cardiovascular complications such as myocardial infarction and stroke. Atherosclerotic plaques are composed of lipids, including oxidized low-density lipoproteins and cholesterol crystals, and immune cells, including macrophages. 2-Hydroxypropyl-beta-cyclodextrin (CD) is FDA-approved for capturing, solubilizing, and delivering lipophilic drugs in humans. It is also known to dissolve cholesterol crystals and decrease atherosclerotic plaque size. However, its low retention time necessitates high dosages for successful therapy. This study reports CD delivery via air-trapped polybutylcyanoacrylate nanoparticles (with diameters of 388 ± 34 nm) loaded with CD (CDNPs). The multimodal contrast ability of these nanoparticles after being loaded with IR780 dye in mice is demonstrated using ultrasound and near-infrared imaging. It is shown that CDNPs enhance the cellular uptake of CD in murine cells. In an ApoE-/- mouse model of atherosclerosis, treatment with CDNPs significantly improves the anti-atherosclerotic efficacy of CD. Ultrasound triggering further improves CD uptake, highlighting that CDNPs can be used for ultrasound imaging and ultrasound-responsive CD delivery. Thus, CDNPs represent a theranostic nanocarrier for potential application in patients with atherosclerosis.


Asunto(s)
Aterosclerosis , Ciclodextrinas , Nanopartículas , Placa Aterosclerótica , Animales , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/tratamiento farmacológico , Colesterol , Humanos , Ratones , Imagen Multimodal , Nanopartículas/química , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/tratamiento farmacológico , Medicina de Precisión , Ultrasonografía
4.
Adv Drug Deliv Rev ; 179: 113998, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34662671

RESUMEN

Gene therapy has been widely investigated for the treatment of genetic, acquired, and infectious diseases. Pioneering work utilized viral vectors; however, these are suspected of causing serious adverse events, resulting in the termination of several clinical trials. Non-viral vectors, such as lipid nanoparticles, have attracted significant interest, mainly due to their successful use in vaccines in the current COVID-19 pandemic. Although they allow safe delivery, they come with the disadvantage of off-target delivery. The application of ultrasound to ultrasound-sensitive particles allows for a direct, site-specific transfer of genetic materials into the organ/site of interest. This process, termed ultrasound-targeted gene delivery (UTGD), also increases cell membrane permeability and enhances gene uptake. This review focuses on the advances in ultrasound and the development of ultrasonic particles for UTGD across a range of diseases. Furthermore, we discuss the limitations and future perspectives of UTGD.


Asunto(s)
Técnicas de Transferencia de Gen , Terapia Genética/métodos , Terapia Molecular Dirigida/métodos , Ultrasonido , Animales , COVID-19 , Humanos , Liposomas , Nanopartículas
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