Targeting Cancer and Bone Metastases with Novel Anti Angiogenic Polymer Therapeutics

The Invention A new strategy for cancer and bone metastases therapy was developed using combined targeted polymeric drug delivery system with angiogenesis inhibitors. The novel compounds are composed of three elements:
1. Water soluble synthetic copolymer (HPMA) as specific carrier enabling the molecules to internalize into the tumor leaky vessels. 2. The aminobisphosphonate alendronate (ALN) as a specific bone targeting moiety, that was demonstrated as an excellent candidate for targeting tumors confined to bony tissues. 3. Specific angiogenesis inhibitors, such as TNP-470, a low molecular weight analogue of Fumagilin, that was demonstrated as a selective inhibitor of angiogenesis, or known chemotherapy agents such as Paclitaxel (PTX), that were demonstrated as inhibitors of angiogenesis when given in an "anti-angiogenic dosing schedule" (administration of chemotherapy in low doses, well below the maximum tolerated dose, in close intervals for extended periods of time – “metronomic dosing”).

The Need Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is crucial in pathological processes such as tumor progression and bone metastases. Both tumor growth and metastases are highly dependent on oxygen and nutrients supplied by new angiogenic blood vessels which formation is stimulated by the tumor itself and its microenvironment.

Prostate and breast cancers are two of the most common cancers of males and females in industrialized countries. Most patients do not die due to primary tumor mass, but rather from complications caused by metastases to vital organs, mainly to the bones. Bone cancers also include few types of primary malignancies such as multiple myeloma and bone sarcomas. The most common type of primary bone cancer is osteosarcoma which develops in new tissue in growing bones. Osteosarcoma tends to occur more frequently in children and adolescents. Chemotherapy agents, hormonal deprivation and bisphosphonates are the common treatments for advanced metastatic disease and osteosarcoma. However, with time, the disease progresses to a phase when the standard therapy fails to control the malignancy and further progresses to a highly chemotherapy-resistant state.

Potential Applications Bone metastases develop in numerous cancer patients (except for those with skin cancers such as basal cell and squamous cell cancer) at some point in the course of the disease. The bone is the third most common site for metastases after lung and liver. Applications include treatment of various cancers including:
• Bone metastases
• Prostate cancer
• Breast cancer
• Primary bone cancers
• Osteosarcoma

Advantages A novel class of targeted polymeric drug delivery system - by conjugation of aminobisphosphonate and angiogenesis inhibitors to a soluble polymer backbone. Combination of antitumor and anti-angiogenesis treatment that demonstrates synergistic inhibitory effect. Specific targeting of bone metastases and tumors. The unique reversible addition-fragmentation chain transfer (RAFT) polymerization technique and conjugation facilitate high loading of ALN to the polymeric backbone, enabling rapid accumulation in bone tissue and enhanced antitumor activity. Multivalency of the polymers allows the conjugation of a combination of different drugs onto one polymeric backbone. Enables treatment with low doses of Paclitaxel, well below the maximum tolerated dose, thus avoiding acute toxicity and leading to drug administration for longer period.

Stage Cellular internalization analysis of HPMA copolymer-ALN-TNP-470 conjugate revealed its cytoplasmic uptake by human umbilical vein endothelial cells (HUVEC) and by Saos-2 and MG-63 human osteosarcoma cells. Free and conjugated ALN-TNP-470 demonstrated their synergistic anti-angiogenic and antitumor activity by inhibiting proliferation, migration and capillary-like tube formation of HUVEC and proliferation of osteosarcoma cells. In vivo evaluation of the bi-specific conjugate demonstrated its ability to reduce vascular hyperpermeability and to inhibit MG-63 human osteosarcoma tumor growth in mice.


The HPMA copolymer-PTX-ALN conjugate inhibited the proliferation of prostate carcinoma cells. Furthermore, the conjugate demonstrated anti-angiogenic effect on different steps of the angiogenic cascade such as proliferation, migration and tube-formation of endothelial cells.

Patent Two patent families are currently pending, covering composition of matter and the various applications. Tech Transfer Officer Dr. Tamar Raz Office: +972-3-6406580 Fax: +972-3-6406675 Mail: [email protected]

Inventor(s): Ronit Satchi-Fainaro, Jindrich Kopecek

Type of Offer: Licensing



Next Patent »
« More Pharmaceutical Patents

Share on      


CrowdSell Your Patent