OC 43.4 - Novel synthetic sulfonate-based di- and triblock polymers with anticoagulant activity: mechanism of action, efficacy and safety

Monday, June 24, 2024

15:30 – 15:45 ICT

Room: Ballroom B3

Co-Author(s)

JS

Justyna Swieton

PhD Student
Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland
Bialystok, Podlaskie, Poland
JM

Joanna Miklosz

Associate Professor
Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland
Bialystok, Podlaskie, Poland
NB

Natalia Bielicka

Associate Professor
Department of Biopharmacy and Radiopharmacy, Medical University of Bialystok, Bialystok, Poland
Bialystok, Podlaskie, Poland
AF

Aleksandra Frackiewicz

PhD Student
Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland
Bialystok, Podlaskie, Poland
KD

Karol Depczynski

Student
Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland
Bialystok, Podlaskie, Poland
MS

Marta Stolarek

PhD Student
Faculty of Chemistry, Jagiellonian University, Krakow, Poland
Krakow, Malopolskie, Poland
PB

Piotr Bonarek

Associate Professor
Faculty of Chemistry, Jagiellonian University, Krakow, Poland
Krakow, Malopolskie, Poland
KK

Kamil Kaminski

Associate Professor
Faculty of Chemistry, Jagiellonian University, Krakow, Poland
Krakow, Malopolskie, Poland
SY

Shin-Ichi Yusa

Professor
Department of Applied Chemistry, University of Hyogo, Hyogo, Japan
Hyogo, Hyogo, Japan
AG

Anna Gromotowicz-Poplawska

Associate Professor
Department of Biopharmacy and Radiopharmacy, Medical University of Bialystok, Bialystok, Poland
Bialystok, Podlaskie, Poland
KS

Krzysztof Szczubialka

Professor
Faculty of Chemistry, Jagiellonian University, Krakow, Poland
Krakow, Malopolskie, Poland
DP

Dariusz Pawlak

Professor
Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland
Bialystok, Podlaskie, Poland
Andrzej Mogielnicki, PhD

Associate Professor
Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland
Bialystok, Podlaskie, Poland

Presenting Author(s)

Bartlomiej Kalaska, PhD

Associate Professor
Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland
Bialystok, Podlaskie, Poland

Background: Despite targeting different coagulation cascade sites, all anticoagulants present an elevated risk of bleeding, including life-threatening intracranial hemorrhage. Many preclinical and clinical trials are focusing on developing safer anticoagulants.

Aims: The aim of this study was to synthesize di- and triblock polymers designed to inhibit coagulation by incorporating sulfonate blocks and to identify the most efficient and safe polymer through comprehensive in vitro and in vivo investigations.

Methods: Five polymers, synthesized via radical addition-fragmentation chain transfer polymerization, were composed of a poly(sodium styrenesulfonate) (PSSS) block for anticoagulation, and either poly(ethylene glycol) (PEG) block or poly(acrylic acid) block to minimize toxicity. Their anticoagulant activity and toxicity were evaluated in the in vitro assays measuring aPTT, blood counts, cell viability, and hemolysis rate, and in vivo assessment of cardiorespiratory parameters. The lead polymer underwent testing in the total thrombus-formation analysis system (T-TAS), electrically-induced arterial thrombosis model (rats), and laser-induced thrombosis model (mice). Coagulation times, fibrinogen level, binding to antithrombin and prothrombin, and impact on coagulation factors were analyzed to elucidate potential targets of action. Animal procedures were ethically approved by the Local Committee.

Results: All polymers exhibited anticoagulant properties by prolonging aPTT in vitro. PEG47-PSSS32, a polymer with degrees of polymerization of PEG and PSSS blocks equal to 47 and 32, respectively, displayed the most promising efficacy/safety profile. It significantly prolonged aPTT without impacting blood count, cell viability, hemolysis, and cardiorespiratory parameters. The anticoagulant activity of PEG47-PSSS32 was further confirmed in T-TAS and animal thrombosis models (Figure 1A-D). No effect on platelet-dependent thrombus formation was observed (Figure 1E). PEG47-PSSS32 acts by interactions with antithrombin and coagulation factors, including fibrinogen reduction.

Conclusion(s): PEG47-PSSS32 demonstrated promising effectiveness and safety, positioning it as a potential candidate for a new anticoagulant. Further research is needed to fully explore its therapeutic applications.

Funding: Medical University of Bialystok, 2024.