Therapeutic uses of heparin beyond its traditional role as an anticoagulant

doi:10.1016/S0165-6147(00)89022-7

Trends in Pharmacological Sciences

Volume 16, Issue 6, June 1995, Pages 198-204

https://doi.org/10.1016/S0165-6147(00)89022-7 Get rights and content

Abstract

A number of physiological effects have been ascribed to heparin since its discovery almost 80 years ago, many of which are independent from its first-described and best-characterized activity as an anticoagulant. Heparin and heparan sulphate are believed to possess many biological activities that include the ability to modulate embryonic development, neurite outgrowth, tissue homeostasis, wound healing, metastasis, cell differentation, cell proliferation and inflammation. In this review, David Tyrrell, Stephen Kilfeather and Clive Page examine some of the activities of heparin (and heparin derivatives) beyond its effects as an anticoagulant, and discuss the therapeutic potential of this old, but certainly not antiquated, drug.

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Heparin is a glycosaminoglycans (GAGs) member and well-known FDA-approved anticoagulant that has been widely used in the clinic for 100 years. It has also been evaluated in various fields for further clinical applications, such as in anti-cancer or anti-inflammatory therapy beyond its anticoagulant effect. Here, we sought to utilize heparin molecules as drug carriers by directly conjugating the anticancer drug doxorubicin to the carboxyl group of unfractionated heparin. Given the molecular action of doxorubicin in intercalating DNA, it is expected to be less effective when structurally combined with other molecules. However, by utilizing doxorubicin molecules to produce reactive oxygen species (ROS), we found that the heparin–doxorubicin conjugates have significant cytotoxic ability to kill CT26 tumor cells with low anticoagulant activity. Several doxorubicin molecules were bound to heparin to provide sufficient cytotoxic capability and self-assembly ability due to their amphiphilic properties. The self-assembled formation of these nanoparticles was demonstrated through DLS, SEM and TEM. The cytotoxic ROS-generating doxorubicin-conjugated heparins could inhibit tumor growth and metastasis in CT26-bearing Balb/c animal models. Our results demonstrate that this cytotoxic doxorubicin-based heparin conjugate can significantly inhibit tumor growth and metastasis, thus showing promise as a potential new anti-cancer therapeutic.
Fabrication of pH-sensitive magnetic metal-organic framework for controlled-release of heparin
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Citation Excerpt :
Heparin, a naturally occurring glycosaminoglycan, is traditionally used as a clinical anticoagulant and antithrombotic drug, also has antitumor, anti-inflammatory, antiviral, and other pharmacological activities [1,2]. It is widely used in treating cerebrovascular, cardiovascular, obstetric, kidney and pulmonary diseases, and cancer [3–5]. However, heparin suffers from short serum half-life, poor oral absorption, low tissue permeability, and the risk of overdose [6,7].
Heparin, the most widely used anticoagulant drug in the world today, suffers from the risk of overdose and a short serum half-life, limiting its clinical applications. Concerning the controlled, sustained, and targeted release of heparin, a delivery system was fabricated in this research using the layered composites of Fe₃O₄ magnetic particles and pH-sensitive metal-organic framework, Fe₃O₄@ZIF-8. The composite demonstrated a high loading capacity for the heparin, 66.8 mg/g. The composite had a saturation magnetization of 1.5 emu/g and thus owned a magnetic targeting function, i.e. drug can be centered at a certain point using an external magnetic field. The anticoagulant activity was assessed by monitoring their activated partial thromboplastin time. The results showed that the pH-responsive and sustained release of the heparin reduced the systemic adverse effects associated with high concentrations. Moreover, control over the dose exhibited excellent anticoagulant features with fewer side effects.
In situ hydrogel dressing loaded with heparin and basic fibroblast growth factor for accelerating wound healing in rat
2020, Materials Science and Engineering C
In order to accelerate the healing of chronic wound, a hydrogel dressing encapsulating with heparin and basic fibroblast growth factor is prepared by the Michael addition of 4-arm acrylated polyethylene glycol and dithiothreitol. As-prepared hydrogel dressing can combine the advantages of wet healing theory and exogenous growth factor supplement. Furthermore, the encapsulated heparin can play a role in diminishing inflammation and accelerating wound healing in addition to its well-known function of stabilizing basic fibroblast growth factor. In vitro release test shows the hydrogel network is able to sustainably release basic fibroblast growth factor within 10 days by the regulation of heparin, while released growth factor can significantly promote fibroblast's proliferation in vitro. Moreover, the wound healing in rat shows that as-prepared hydrogel dressing could accelerate wound healing in vivo much more effectively compared with blank hydrogel dressing and negative control. Hematoxylin-eosin and Masson's Trichrome staining exhibit the formation of complete and uniform epidermis. Immunohistochemical staining exhibits heparin can help hydrogel dressing to possess low inflammation in early stage, which is beneficial for accelerating wound healing as well as preventing the production of scar tissue. The enzyme-linked immunosorbent assay results demonstrate the exogenous bFGF in hydrogel can significantly upgrade the expressing of vascular endothelial growth factor and transforming growth factor-β in wound site, which indicate better angiogenesis, and better on-site cell proliferation in wound site, respectively. Those results are further demonstrated by immunohistochemical and immunofluorescence staining. Consequently, as-prepared hydrogel dressing shows promising potential to perform better therapy efficacy in clinic for accelerating wound healing.
pH-activatable polymeric nanodrugs enhanced tumor chemo/antiangiogenic combination therapy through improving targeting drug release
2019, Journal of Colloid and Interface Science
Citation Excerpt :
Moreover, the tumor inhibition rates of LMWH-UOA and sLMWH-UOA nanodrug were 2.04-fold and 1.52-fold than that of LMWH + UOA respectively, suggesting that LMWH-UOA and sLMWH-UOA nanodrug could further enhance the antitumor efficiency of LMWH + UOA. This might because that compared with LMWH + UOA group, both LMWH-UOA and sLMWH-UOA nanodrug could locate to tumor resulting into increased drug accumulation in tumor through EPR-effect induced passive tumor targeting ability and LMWH-mediated endocytosis [41]. More importantly, it was noted that sLMWH-UOA showed further significantly enhanced antitumor efficiency than LMWH-UOA (P < 0.01).
It was widely accepted that polymeric nanodrugs held superiority in enhancing antitumor efficacy, reducing side effect and achieving better long-term prognosis. However, there still existed disputes that whether their therapeutic efficiency was closely related to insure effective release of hydrophobic drug located in their hydrophobic core in tumor site. In order to investigate this controversy, we constructed two polymeric nanodrugs (pH-activatable sLMWH-UOA and non-sensitive LMWH-UOA) with low molecular weight heparin (LMWH) and ursolic acid (UOA) for chemo-and anti-angiogenic combination therapy in hepatocellular carcinoma. The degradation ratio of pH-activatable sLMWH-UOA increased by 33% compared with non-sensitive LMWH-UOA in in vitro degradation study. Besides, confocal microscopy captured that sLMWH-UOA could effectively release drug in acidic microenvironment of lysosome while LMWH-UOA nearly could not. More importantly, in contrast with LMWH-UOA, sLMWH-UOA presented pH-dependent cytotoxicity, indicating that promoting drug release played a key role in enhancing the cytotoxicity of polymeric nanodrugs. Additionally, in vivo pharmacodynamic evaluation showed that although non-sensitive LMWH-UOA had benefited from enhanced tumor targeting drug delivery ability to achieve absolute advantage over free drug combination therapy in antitumor combination therapy, sLMWH-UOA could acquire further optimized combined therapeutic effect with better drug release in tumor. All above, application of tumor-triggered chemical bonds to construct polymeric nanodrugs held vast prospect for improving the therapeutic efficiency for tumor cells.
Dose-reduction antiangiogenic curcumin-low molecular weight heparin nanodrugs for enhanced combinational antitumor therapy
2018, European Journal of Pharmaceutical Sciences
Curcumin (CUR) is a natural diketone with diverse bioactivities of inhibiting angiogenesis and tumor growth. However, its clinical application for cancer treatment was severely hindered by poor aqueous solubility and chemical instability. To overcome these drawbacks and achieve enhanced antitumor efficiency, low molecular weight heparin (LMWH) was conjugated to CUR via the one-step esterification reaction to yield LMWH-CUR (LCU) nanodrugs with the size of 180 nm, which exhibited enhanced accumulation within tumor site by EPR effect and long circulating capacity by LMWH hydrophilic shell. The solubility of conjugated CUR was increased to 0.12 mg/mL (equivalent of CUR) in comparison with 0.006 mg/mL of free CUR. The bioactivities of CUR were guaranteed because of the improved stability of LCU nanodrugs in low pH condition. Moreover, the stronger anti-angiogenesis efficacy of LCU nanodrugs than LMWH monotherapy was also verified. Notably, at a rather low dose of equivalent LMWH (5 mg/kg) and CUR (0.3 mg/kg), the tumor inhibition rate of LCU nanodrugs were much higher than that of LMWH (10 times) and LMWH plus CUR mixture (3.8 times) respectively, indicating its excellent in vivo antitumor efficacy. Overall, our study managed to obtain the novel nanodrugs with potent anti-angiogenesis and antitumor effects whereas avoiding tedious and complicated synthetic procedures. These results also suggested that LCU nanodrugs could be considered as a promising targeted delivery system for cancer treatment.
Effects of fucoidans and heparin on reactions of neutrophils induced by IL-8 and C5a
2017, Carbohydrate Polymers
Citation Excerpt :
Heparins are not only potent antithrombotics, but exhibit a broad spectrum of biological activities including several effects resulting in anti-inflammatory potency (Lever & Page, 2012; Tyrell, Kilfeather, & Page, 1995).
Fucose-containing sulfated polysaccharides (fucoidans) from brown algae exhibit anti-inflammatory activity in vivo, however, there is only limited knowledge about their mode of action. Potential targets may be the chemokine interleukin 8 (IL-8) and the anaphylatoxin C5a, as they are closely linked to inflammatory processes. In this study, two fucoidans from Saccharina latissima and Fucus vesiculosus, and unfractionated heparin (UFH) were examined for their binding properties to IL-8 and C5a and their effects on IL-8- and C5a-induced reactions of polymorphonuclear neutrophils (PMN).
As proved by a competitive sulfated polysaccharide-coating-ELISA, both fucoidans bind to IL-8 and C5a, whereby they showed higher affinity to IL-8. Whereas UFH displayed only moderate effects, the fucoidans concentration-dependently reduced the IL-8- and C5a-induced intracellular calcium release, Erk1/2 phosphorylation and chemotaxis of PMN. Their inhibitory potency is dependent on the target protein, but also other aspects than the binding turned out to play a role.

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Trends in Pharmacological Sciences

ReviewTherapeutic uses of heparin beyond its traditional role as an anticoagulant

Abstract

J. Cell. Biochem.

Isr. J. Med. Sci.

Blood

Cancer Res.

Biochemistry

Int. J. Cancer

Review
Therapeutic uses of heparin beyond its traditional role as an anticoagulant