Site Directed Delivery of Chemotherapy and Non-Anticoagulant Sulfated Heparin in Breast Cancer

There is substantial literature support for the use of low molecular weight heparins (LMWH) for treating coagulation disorders in cancer patients. Recent prospective and retrospective clinical trials have also demonstrated that they provide significant advantages in terms of progression-free and overall survival in certain cancers and in certain subgroups of patients. LMWH treatments are often associated with increased bleeding, constituting a dose-limiting effect. We have developed novel non-anticoagulant heparin (NACH) compounds that have minimal effects on hemostasis (El-Naggar and Mousa, US Patents 6,908,907 B2, (2005), and 10, 667,216, (2003). We have evaluated them for efficacy vs. tumor growth and metastasis and have begun to investigate the mechanisms involved in anti-tumor activities. Modified sulfated LMWH with weak or no anticoagulant activities were still highly effective in inhibiting angiogenesis and metastasis, demonstrating that anticoagulation is not essential for attenuation of angiogenesis or metastasis. The modified heparins were characterized with respect to their ability to release endothelial tissue factor pathway inhibitor (TFPI) and inhibit selectin-mediated interactions, molecular components that have been shown to modulate tumor growth, tumor angiogenesis and metastasis. One of these modified heparin compounds that showed significant activity in a selectin-mediated tumor cell adhesion assay was also highly effective in reducing tumor burden in mice with MC-38 colon carcinoma and B16-BL6 melanoma (>70%) and in reducing the number of metastatic foci (>65%) in these animals. We also investigated the efficacy of NACH compounds on growth factor-induced angiogenesis in a mouse Matrigel model in which new vessel growth was quantified by measuring hemoglobin concentration extracted from the Matrigel plug. Values are Means ± SEM. Matrigel alone: 0.57± 0.12; bFGF + Matrigel: 7.27 ± 1.18; NAC-S-S: 0.86 ± 0.10. This sulfated compound which demonstrated no anticoagulant activity in aPTT and TEG assays, reduced capillary formation to baseline levels. These data demonstrate that non-anticoagulant heparin compounds exhibit a profile of anti-tumor activities without disrupting normal hemostasis. Site-directed therapy with non-anticoagulant heparins (NACH) and chemotherapy would allow for optimization of treatments in the tumor microenvironment. In studies that are currently underway, we are targeting the sites of tumor neovascularization using a biodegradable nanoparticulate system made up of a blend of MPEG-PLGA (methoxy-polyethyleneglycol-poly (lactide-co-glycolide) and maleimide-PEG-PLGA. These nanoparticles have their surfaces conjugated to alpha-v beta-3 antibody and contain chemotherapeutic agent Doxorubicin, with or without NACH. Preliminary data indicate that repeated administration of sulfated non-anticoagulant heparin compound at 10 mg/kg S.C. daily for up to 14 days in conjunction with doxorubicin caused no bruising at the injection site, whereas Enoxaparin showed injection site bruising in >50% of the mice. The use of NACH agents that are co-encapsulated with chemotherapeutic agents could minimize the toxic side effects of the chemotherapy while delivering a combination of effective therapeutic agents directly to the tumor.

Managing Complications of Anticoagulant Therapy

Understanding the frequency, risk factors, and management of anticoagulant-induced adverse events will assist clinicians in optimizing patient outcomes. The most frequent adverse event of all anticoagulants is major bleeding. Risk factors for major bleeding have been identified with the heparin compounds, the direct thrombin inhibitors (DTIs), fondaparinux, and warfarin therapy. Understanding these risk factors can help prevent bleeding events. For cases of clinically significant bleeding, reversal agents exist primarily for heparin and warfarin. Although less common, nonbleeding adverse events of anticoagulant therapy can also be life threatening. The heparin compounds are associated with the development of heparin-induced thrombocytopenia (HIT) and osteoporosis. HIT can result in life-threatening thrombosis and is usually managed with a DTI. Nonbleeding adverse events with warfarin therapy include skin reactions and the development of venous limb gangrene. Appropriate initiation of warfarin therapy may decrease the risk of venous limb gangrene.