The neutralization of heparan sulfate by heparin-binding copolymer as a potential therapeutic target

Kałaska, Bartłomiej; Mikłosz, Joanna; Kamiński, Kamil; Musielak, Bogdan; Yusa, Shin‐ichi; Pawlak, Dariusz; Nowakowska, Maria; Szczubiałka, Krzysztof; Mogielnicki, Andrzej

doi:10.1039/c8ra09724k

Cited by 9 publications

(8 citation statements)

References 63 publications

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“…It has been noted that for long range interactions with proteins, this charge is important in attracting proteins to HS via charged binding sites in lysine and arginine residues ( Rabenstein, 2002 ; Meneghetti et al, 2015 ). The zeta potential of free HS in PBS solution lies at −10 mV ( Kalaska et al, 2019 ), so the polysaccharide is somewhat less strongly negatively charged than in our case of surface-bound heparan sulfate. This may be explained by the fact that the actual charge on polyelectrolytic polymers depends on the conformation of the polymer strands.…”

Section: Resultsmentioning

confidence: 65%

“…However, there is a difference in the absolute values, where the zeta potential of the HS-decorated fibers measured after the release experiments is only slightly more negative (differences Δζ range from 5 to 10 mV). Potentially, HS protects the fibers from strong degradation either due to sterical reasons, as HS may cover the surface of the fibers, or due to the acidic character of the glycosaminoglycan ( Rabenstein, 2002 ; Kalaska et al, 2019 ). In contrast to base-catalyzed ester hydrolysis, acidic catalysis takes place more slowly and reversibly.…”

Section: Resultsmentioning

confidence: 99%

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Development of Neuronal Guidance Fibers for Stimulating Electrodes: Basic Construction and Delivery of a Growth Factor

Wille

Harre

Oehmichen

et al. 2022

Front. Bioeng. Biotechnol.

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State-of-the-art treatment for sensorineural hearing loss is based on electrical stimulation of residual spiral ganglion neurons (SGNs) with cochlear implants (CIs). Due to the anatomical gap between the electrode contacts of the CI and the residual afferent fibers of the SGNs, spatial spreading of the stimulation signal hampers focused neuronal stimulation. Also, the efficiency of a CI is limited because SGNs degenerate over time due to loss of trophic support. A promising option to close the anatomical gap is to install fibers as artificial nerve guidance structures on the surface of the implant and install on these fibers drug delivery systems releasing neuroprotective agents. Here, we describe the first steps in this direction. In the present study, suture yarns made of biodegradable polymers (polyglycolide/poly-ε-caprolactone) serve as the basic fiber material. In addition to the unmodified fiber, also fibers modified with amine groups were employed. Cell culture investigations with NIH 3T3 fibroblasts attested good cytocompatibility to both types of fibers. The fibers were then coated with the extracellular matrix component heparan sulfate (HS) as a biomimetic of the extracellular matrix. HS is known to bind, stabilize, modulate, and sustainably release growth factors. Here, we loaded the HS-carrying fibers with the brain-derived neurotrophic factor (BDNF) which is known to act neuroprotectively. Release of this neurotrophic factor from the fibers was followed over a period of 110 days. Cell culture investigations with spiral ganglion cells, using the supernatants from the release studies, showed that the BDNF delivered from the fibers drastically increased the survival rate of SGNs in vitro. Thus, biodegradable polymer fibers with attached HS and loaded with BDNF are suitable for the protection and support of SGNs. Moreover, they present a promising base material for the further development towards a future neuronal guiding scaffold.

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Section: Resultsmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Development of Neuronal Guidance Fibers for Stimulating Electrodes: Basic Construction and Delivery of a Growth Factor

Wille

Harre

Oehmichen

et al. 2022

Front. Bioeng. Biotechnol.

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“…HBC is a diblock synthetic polymer that directly binds anticoagulant molecules and effectively neutralizes their effects in the living organism (Kalaska et al, 2016(Kalaska et al, , 2018(Kalaska et al, , 2019. In this work, we further explored the potential of HBC to safely reverse LMWHs widely used in the clinical practice, i.e., enoxaparin, nadroparin, dalteparin, and tinzaparin at in vivo conditions and human plasma.…”

Section: Downloaded Frommentioning

confidence: 99%

Heparin-Binding Copolymer as a Complete Antidote for Low-Molecular-Weight Heparins in Rats

Kałaska

Mikłosz

Kamiński

et al. 2020

J Pharmacol Exp Ther

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Bleeding resulting from the application of low-molecular-weight heparins (LMWHs) may be treated with protamine sulfate but lacks efficiency; its action against anti-factor Xa activity is limited to ~60%. Moreover, protamine sulfate can cause life-threatening hypersensitivity reactions. We developed diblock heparin-binding copolymer (HBC) that can neutralize the anticoagulant activity of parenteral anticoagulants. In the present study, we explored the safety profile of HBC and its potential to reverse enoxaparin, nadroparin, dalteparin, and tinzaparin in human plasma and at in vivo conditions. HBC-LMWHs complexes were characterized using zeta potential, isothermal titration calorimetry, and dynamic light scattering. The rat cardiomyocytes and human endothelial cells were used for the assessment of in vitro toxicity. Male Wistar rats were observed for up to 4 days after HBC administration for clinical evaluation, gross necropsy, and biochemistry and histopathological analysis. Rats were treated with LMWHs alone or followed by short-time intravenous infusion of HBC, and bleeding time and anti-factor Xa activity were measured. HBC completely reversed anti-factor Xa activity prolonged in vitro by all LMWHs with an optimal weight ratio of 2.5:1. The complexes of HBC-LMWHs were below 5 µm. We observed no effects on the viability of cardiovascular cells treated with HBC at concentrations up to 0.05 mg/mL. Single doses up to 20 mg/kg of HBC were well-tolerated by rats. HBC completely reversed the effects of LMWHs on bleeding time and anti-factor Xa activity in vivo after 20 minutes, and retained ~80% and ~60% of reversal activity after 1 hour and 2 hours, respectively. Well-documented efficacy and safety of HBC both in vitro and in vivo make this polymer a promising candidate for LMWHs reversal.

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“…17 Other small molecular systems have also been reported, such as surfen, delparantag, and foldamers. 18−21 Owing to their multivalency effects, cationic oligopeptides, 22,23 synthetic polymers, 24−27 and self-assembled systems 28−31 have drawn attention.…”

Section: Introductionmentioning

confidence: 99%

Serum Albumin–Peptide Conjugates for Simultaneous Heparin Binding and Detection

et al. 2019

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Heparin is a polysaccharide-based anticoagulant agent, which is widely used in surgery and blood transfusion. However, overdosage of heparin may cause severe side effects such as bleeding and low blood platelet count. Currently, there is only one clinically licensed antidote for heparin: protamine sulfate, which is known to provoke adverse effects. In this work, we present a stable and biocompatible alternative for protamine sulfate that is based on serum albumin, which is conjugated with a variable number of heparin-binding peptides. The heparin-binding efficiency of the conjugates was evaluated with methylene blue displacement assay, dynamic light scattering, and anti-Xa assay. We found that multivalency of the peptides played a key role in the observed heparin-binding affinity and complex formation. The conjugates had low cytotoxicity and low hemolytic activity, indicating excellent biocompatibility. Furthermore, a sensitive DNA competition assay for heparin detection was developed. The detection limit of heparin was 0.1 IU/mL, which is well below its therapeutic range (0.2–0.4 IU/mL). Such biomolecule-based systems are urgently needed for next-generation biocompatible materials capable of simultaneous heparin binding and sensing.

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The neutralization of heparan sulfate by heparin-binding copolymer as a potential therapeutic target

Abstract: The neutralization of heparan sulfate (HS) by a heparin-binding copolymer (HBC) could be a promising treating option for bacterial or viral infections or bleeding related to overproduction of HS in cancer or other diseases.

Cited by 9 publications

References 63 publications

Development of Neuronal Guidance Fibers for Stimulating Electrodes: Basic Construction and Delivery of a Growth Factor

Development of Neuronal Guidance Fibers for Stimulating Electrodes: Basic Construction and Delivery of a Growth Factor

Heparin-Binding Copolymer as a Complete Antidote for Low-Molecular-Weight Heparins in Rats

Serum Albumin–Peptide Conjugates for Simultaneous Heparin Binding and Detection

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