PMID- 36172817
OWN - NLM
STAT- MEDLINE
DCOM- 20230703
LR  - 20230705
IS  - 1592-8721 (Electronic)
IS  - 0390-6078 (Print)
IS  - 0390-6078 (Linking)
VI  - 108
IP  - 7
DP  - 2023 Jul 1
TI  - Plasminogen activator-coated nanobubbles targeting cellbound beta2-glycoprotein I as 
      a novel thrombus-specific thrombolytic strategy.
PG  - 1861-1872
LID - 10.3324/haematol.2022.281505 [doi]
AB  - beta2-glycoprotein I (beta2-GPI) is a serum protein widely recognized as the main 
      target of antibodies present in patients with antiphospholipid syndrome (APS). 
      beta2-GPI binds to activated endothelial cells, platelets and leukocytes, key 
      players in thrombus formation. We developed a new targeted thrombolytic agent 
      consisting of nanobubbles (NB) coated with recombinant tissue plasminogen 
      activator (rtPA) and a recombinant antibody specific for cell-bound beta2-GPI. The 
      therapeutic efficacy of targeted NB was evaluated in vitro, using platelet-rich 
      blood clots, and in vivo in three different animal models: i) thrombosis 
      developed in a rat model of APS; ii) ferric chloride-induced mesenteric 
      thrombosis in rats, and iii) thrombotic microangiopathy in a mouse model of 
      atypical hemolytic uremic syndrome (C3-gain-of-function mice). Targeted NB bound 
      preferentially to platelets and leukocytes within thrombi and to endothelial 
      cells through beta2-GPI expressed on activated cells. In vitro, rtPA-targeted NB 
      (rtPA-tNB) induced greater lysis of platelet-rich blood clots than untargeted NB. 
      In a rat model of APS, administration of rtPA-tNB caused rapid dissolution of 
      thrombi and, unlike soluble rtPA that induced transient thrombolysis, prevented 
      new thrombus formation. In a rat model of ferric chloride triggered thrombosis, 
      rtPA-tNB, but not untargeted NB and free rtPA, induced rapid and persistent 
      recanalization of occluded vessels. Finally, treatment of C3-gain-of-function 
      mice with rtPA-tNB, that target beta2-GPI deposited in kidney glomeruli, decreased 
      fibrin deposition, and improved urinalysis data with a greater efficiency than 
      untargeted NB. Our findings suggest that targeting cell-bound beta2-GPI may 
      represent an efficient and thrombus-specific thrombolytic strategy in both 
      APS-related and APS-unrelated thrombotic conditions.
FAU - Macor, Paolo
AU  - Macor P
AD  - Department of Life Sciences, University of Trieste, 34127 Trieste. 
      pmacor@units.it.
FAU - Durigutto, Paolo
AU  - Durigutto P
AD  - Istituto Auxologico Italiano, IRCCS, Laboratory of Immuno-Rheumatology, Milan.
FAU - Argenziano, Monica
AU  - Argenziano M
AD  - Department of Scienza e Tecnologia del Farmaco, University of Turin, 10125 Turin.
FAU - Smith-Jackson, Kate
AU  - Smith-Jackson K
AD  - Translational and Clinical Research Institute, Faculty of Medical Sciences, 
      Newcastle University, Newcastle.
FAU - Capolla, Sara
AU  - Capolla S
AD  - Experimental and Clinical Pharmacology Unit, C.R.O.-IRCCS, 33081 Aviano.
FAU - Di Leonardo, Valeria
AU  - Di Leonardo V
AD  - Department of Life Sciences, University of Trieste, 34127 Trieste.
FAU - Marchbank, Kevin
AU  - Marchbank K
AD  - Translational and Clinical Research Institute, Faculty of Medical Sciences, 
      Newcastle University, Newcastle.
FAU - Tolva, Valerio Stefano
AU  - Tolva VS
AD  - Struttura Complessa di Chirurgia Vascolare, ASST GOM Niguarda. Milano.
FAU - Semeraro, Fabrizio
AU  - Semeraro F
AD  - Dipartimento di Scienze Biomediche e Oncologia Umana, Universita degli Studi di 
      Bari Aldo Moro, Bari.
FAU - Ammollo, Concetta T
AU  - Ammollo CT
AD  - Dipartimento di Scienze Biomediche e Oncologia Umana, Universita degli Studi di 
      Bari Aldo Moro, Bari.
FAU - Colucci, Mario
AU  - Colucci M
AD  - Dipartimento di Scienze Biomediche e Oncologia Umana, Universita degli Studi di 
      Bari Aldo Moro, Bari.
FAU - Cavalli, Roberta
AU  - Cavalli R
AD  - Department of Scienza e Tecnologia del Farmaco, University of Turin, 10125 Turin.
FAU - Meroni, Pierluigi
AU  - Meroni P
AD  - Istituto Auxologico Italiano, IRCCS, Laboratory of Immuno-Rheumatology, Milan.
FAU - Tedesco, Francesco
AU  - Tedesco F
AD  - Istituto Auxologico Italiano, IRCCS, Laboratory of Immuno-Rheumatology, Milan.
LA  - eng
PT  - Journal Article
DEP - 20230701
PL  - Italy
TA  - Haematologica
JT  - Haematologica
JID - 0417435
RN  - 0 (Fibrinolytic Agents)
RN  - U38V3ZVV3V (ferric chloride)
RN  - EC 3.4.21.68 (Tissue Plasminogen Activator)
RN  - 0 (beta 2-Glycoprotein I)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Rats
MH  - Fibrinolytic Agents/pharmacology/therapeutic use
MH  - Tissue Plasminogen Activator/pharmacology/therapeutic use
MH  - beta 2-Glycoprotein I
MH  - Endothelial Cells
MH  - *Thrombosis/drug therapy/etiology
MH  - *Thromboembolism
MH  - *Antiphospholipid Syndrome
PMC - PMC10316273
EDAT- 2022/09/30 06:00
MHDA- 2023/07/03 06:42
PMCR- 2022/09/29
CRDT- 2022/09/29 04:26
PHST- 2022/06/08 00:00 [received]
PHST- 2023/07/03 06:42 [medline]
PHST- 2022/09/30 06:00 [pubmed]
PHST- 2022/09/29 04:26 [entrez]
PHST- 2022/09/29 00:00 [pmc-release]
AID - 10.3324/haematol.2022.281505 [doi]
PST - epublish
SO  - Haematologica. 2023 Jul 1;108(7):1861-1872. doi: 10.3324/haematol.2022.281505.