Osteogenic and Angiogenic Properties of Heparin as a System for Delivery of Biomolecules for Bone Bioengineering: a Brief Critical Review

Литвинова, Л. С.; Yurova, K. A.; Хазиахматова, О. Г.; Khlusova, M. Yu.; Малащенко, В. В.; Shunkin, E. O.; Тодосенко, Н. М.; Норкин, И. К.; Ivanov, Pavel A.; Хлусов, И. А.

doi:10.1134/s1990750821020050

Cited by 6 publications

(4 citation statements)

References 45 publications

(59 reference statements)

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“…НМГ, в отличие от НФГ, обладают более высокой биодоступностью, лучше дозируются и вызывают меньше побочных эффектов [46,103]. Антикоагулянтные эффекты гепарина нами подробнее рассматривались ранее [56], далее речь пойдет преимущественно о неантикоагулянтных эффектах. Разнообразие подобных эффектов привело к разработке альтернативных препаратов на основе гепарина, не проявляющих антикоагулянтную активность [17]…”

Section: гепарины (характеристики гепарина и его производных)unclassified

Potential targets of heparin during progression and metastasis of malignant neoplasms

Malashchenko,

Khlusov,

Yurova

et al. 2023

Med. immunol.

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In the modern world, oncological diseases occupy the leading positions in the structure of mortality. An integrated approach to oncotherapy is not only aimed at immediate affection of malignant tumors, but also directed at reducing the risk of tumor recurrence and metastasis, as well as alleviating side effects of chemotherapy and radiotherapy of the disease. In oncologic disorders, blood viscosity increases, thus being associated with hypercoagulation syndrome. To prevent its consequences, the direct and indirect anticoagulants, especially heparin and its derivatives, are actively used. Biological functions and structural features of heparin make it a potential universal platform of a drug development for broad application, including oncology. With the advent of heparin fractionation technology and preparation of low-molecular weight forms and their derivatives, it has become possible to focus not only on anticoagulant activity but also to obtain fractions with targeted pharmacological activity. Usage of the anticoagulants has shown their antitumor activity in some cases, thus providing a basis for a more detailed study of pharmacotherapeutic effects of this group of drugs. Currently, some data suggest various pathways of interaction between heparin and tumor cells. There are multiple common features in development of a primary tumor and formation of secondary distant metastases, which may be attributed to similar molecular cellular mechanisms. The molecules mediating intercellular interactions, both between the tumor cells and between malignant cells and tumor-associated immune cells (e.g., lymphocytes and macrophages) may serve as targets for heparin thus helping the tumor to evade immune surveillance. The cytokines that stimulate tumor angiogenesis represent another important therapeutic target. Heparin derivatives are able to suppress tumor activity and prevent metastatic processes at various stages by inhibiting heparanase, P-/L-selectin, and angiogenesis activity, modulating the CXCL12-CXCR4 chemokine axis, and regulating OAM activity.This brief review addresses the current understanding and application of the potentially antimetastatic properties of heparin and its derivatives in malignant bone tumors since the heparin-based drugs are used as anticoagulants in arthroplasty of large joints and bone defects in patients with osteosarcoma.

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Section: гепарины (характеристики гепарина и его производных)unclassified

Potential targets of heparin during progression and metastasis of malignant neoplasms

Malashchenko,

Khlusov,

Yurova

et al. 2023

Med. immunol.

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“…It is found to be effective when applied topically, as it promotes tissue repair in rabbit trachea [ 24 ]. The property of heparin binding to its growth factor makes it a potential candidate for several therapeutic purposes [ 25 , 26 ]. Heparin was incorporated in alginate and arginyl-glycyl-aspartic acid (RGD) hydrogel for the purpose of increasing angiogenesis [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Heparin-Loaded Alginate Hydrogels: Characterization and Molecular Mechanisms of Their Angiogenic and Anti-Microbial Potential

et al. 2022

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Background: Chronic wounds continue to be a global concern that demands substantial resources from the healthcare system. The process of cutaneous wound healing is complex, involving inflammation, blood clotting, angiogenesis, migration and remodeling. In the present study, commercially available alginate wound dressings were loaded with heparin. The purpose of the study was to enhance the angiogenic potential of alginate wound dressings and analyze the antibacterial activity, biocompatibility and other relevant properties. We also aimed to conduct some molecular and gene expression studies to elaborate on the mechanisms through which heparin induces angiogenesis. Methods: The physical properties of the hydrogels were evaluated by Fourier transform infrared spectroscopy (FTIR). Swelling ability was measured by soaking hydrogels in the Phosphate buffer at 37 °C, and cell studies were conducted to evaluate the cytotoxicity and biocompatibility of hydrogels in NIH3T3 (fibroblasts). Real-time PCR was conducted to check the molecular mechanisms of heparin/alginate-induced angiogenesis. The physical properties of the hydrogels were evaluated by Fourier transform infrared spectroscopy (FTIR). Results: FTIR confirmed the formation of heparin-loaded alginate wound dressing and the compatibility of both heparin and alginate. Among all, 10 µg/mL concentration of heparin showed the best antibacterial activity against E. coli. The swelling was considerably increased up to 1500% within 1 h. Alamar Blue assay revealed no cytotoxic effect on NIH3T3. Heparin showed good anti-microbial properties and inhibited the growth of E. coli in zones with a diameter of 18 mm. The expression analysis suggested that heparin probably exerts its pro-angiogenetic effect through VEGF and cPGE. Conclusions: We report that heparin-loaded alginate dressings are not cytotoxic and offer increased angiogenic and anti-bacterial potential. The angiogenesis is apparently taken through the VEGF pathway.

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“…On the other hand, in the study of Cao [17] et al, routine subcutaneous injection of enoxaparin sodium increased the expression of BMP-2 and VEGF, resulting in better results and angiogenic activity. At the same time, low molecular weight heparin can be loaded into bone implants as an osteogenic delivery system to promote bone repair [18]. Enoxaparin sodium, as a kind of low molecular weight heparin, has the theoretical condition of promoting new bone formation in the process of bone repair.…”

Section: Introductionmentioning

confidence: 99%

Bone healing study of alendronate combined with enoxaparin sodium bone cement in rabbits with bone defects

Xiao

Zhang

et al. 2022

J Orthop Surg Res

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Background To observe the effect of enoxaparin sodium-polymethyl methacrylate (ES-PMMA) bone cement supplemented with alendronate (AN) on bone repair of bone defects in New Zealand rabbits. Methods Twenty-seven New Zealand rabbits were randomly divided into ES/AN, ES-PMMA and PMMA groups, with a total of 27 New Zealand rabbits. The drugs loaded in 40 g bone cement powder were as follows: ES/AN group 8000 AxaIU enoxaparin (ES) and 200 mg alendronate (AN), ES-PMMA group 8000 AxaIU enoxaparin (ES), PMMA group without drugs. A bone defect model with a length of 10 mm and a diameter of 5 mm was made from the left tibia of rabbits, and the prepared bone cement was placed in the tibia defect. At 4 weeks, 8 weeks and 12 weeks after the operation, 3 rabbits in each group were sacrificed, and left tibia samples were collected for histological scoring, HE staining and Masson staining. Bone mineral density and new bone volume were measured by imaging, and the related data were processed by one-way ANOVA and least significance difference (LSD) post hoc test. Results (1) Bone mineral density (BMD, mg/mm3) around the bone defect: at the 4th week, BMD in the ES/AN group was higher than that in the PMMA group; at the 8th week, the BMD in the ES/AN group was significantly higher than that in the other two groups; and at the 12th week, the BMD in the ES/AN group was significantly higher than that in the other two groups. (2) New bone volume (BV, mm3): at the 4th week, BV in the ES/AN group was significantly higher than that in the other two groups, BV in the ES/AN group was significantly higher than that in the other two groups at the 8th and 12th weeks, and BV in the ES-PMMA group was higher than that in the PMMA group. (3) Histological score: at the 4th and 8th weeks, the histological score of the ES/AN group was higher than that of the PMMA group, and at the 12th week, the histological score of the ES/AN group was higher than that of the other two groups. (4) Cortical bone thickness (μm): at the 4th, 8th and 12th weeks, the cortical bone thickness in the ES/AN group was higher than that in the other two groups, and the cortical bone thickness in the ES-PMMA group was higher than that in the PMMA group. (5) The percentage of mature area of new bone in the ES/AN group was higher than that in the other two groups at the 4th week, and at the 8th and 12th weeks, the percentage of mature area of new bone in the ES/AN group and ES-PMMA group was significantly higher than that in the PMMA group. Conclusion (1) Enoxaparin sodium bone cement supplemented with alendronate was superior to enoxaparin sodium bone cement and PMMA bone cement in promoting bone repair of tibial bone defects in New Zealand rabbits. (2) Enoxaparin sodium bone cement is superior to PMMA bone cement in promoting bone repair, showing a certain osteogenic potential.

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Osteogenic and Angiogenic Properties of Heparin as a System for Delivery of Biomolecules for Bone Bioengineering: a Brief Critical Review

Cited by 6 publications

References 45 publications

Potential targets of heparin during progression and metastasis of malignant neoplasms

Potential targets of heparin during progression and metastasis of malignant neoplasms

Heparin-Loaded Alginate Hydrogels: Characterization and Molecular Mechanisms of Their Angiogenic and Anti-Microbial Potential

Bone healing study of alendronate combined with enoxaparin sodium bone cement in rabbits with bone defects

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