Lodamine is the first broad–spectrum angiogenesis inhibitor for oral use
Developed by Dr. Ofra Benny from Boston Children's Hospital, Lodamine is a new form of the delayed-release drug TNP-470, created about twenty years ago by an employee of the same laboratory, Dr. Donald Ingber. TNP-470 is one of the first angiogenesis inhibitors approved for clinical trials, in which it has demonstrated efficacy against an extremely wide range of malignant tumors, including metastatic forms. In some cases, taking the drug led to complete remission. In the 90s, clinical trials of the drug were suspended due to neurological side effects caused in some patients by high doses of TNP-470. However, today TNP-470 remains one of the angiogenesis inhibitors with the widest spectrum of action.
Lodamine has the effectiveness and broad spectrum of action of TNP-470 and does not cause a detectable neurotoxic effect. In addition, when taken orally, it is significantly more effective than TNP-470. Unlike currently available vascular growth inhibitors, such as Avastin, most of which act only on one of the angiogenesis factors, for example, vascular endothelial growth factor (VEGF) and are approved only for the treatment of a small number of specific types of cancer, Lodamine prevents capillary growth under the action of all tested angiogenesis stimulants. Moreover, in experiments on mice, Lodamine suppressed liver metastasis – a lethal complication of many types of cancer that has no effective treatment.
TNP-470 was first modified several years ago by Dr. Ronit Satchi-Fainaro, who attached a large polymer to the drug molecule that prevents the penetration of the complex through the blood-brain barrier. A new form of the drug, called Caplostatin, does not have a neurotoxic effect and is currently being prepared for clinical trials. The disadvantage of Caplostatin is the need for intravenous administration.
A new approach, which resulted in the appearance of Lodamine, consists in attaching two short chains of polymers to the TNP-470 molecule: polyethylene glycol and polylactate.
As a result of experiments with polymer chains of different lengths, the authors obtained stable nanoparticles in the form of spherical micelles, similar to a pompom for a knitted hat, the core of which is the TNP-470 molecule.
Polymers that have already been approved by the US Food and Drug Administration and are widely used for commercial purposes protect the drug from the acidic environment of the stomach, which makes it possible to take it orally.
In tests on mice, Lodamine demonstrated a significantly increased half-life, selective accumulation in tumors, the ability to block angiogenesis and significantly suppress the growth of primary tumors in mouse models of melanoma and lung cancer without side effects when taken at effective doses. Subsequent tests showed that Lodamine has an incredibly wide spectrum of action, the same as the original TNP-470.
The most unexpected effect of the drug was that Lodamine accumulated in the liver, without having a hepatotoxic effect and preventing tumor metastasis to the liver.
TNP-470 has a very interesting history, similar to the history of the discovery of penicillin. Initially, the fumagillin compound was isolated from a mold fungus with a powerful antiangiogenic effect. Ingber accidentally noticed that in the plates with a culture of endothelial cells contaminated with fungus, the cells acquired a rounded shape, which is a sign of inhibition of capillary growth. Contrary to the rules according to which infected cultures should be destroyed immediately, he cultivated the fungus, and then, together with the head of the laboratory Judah Folkman (Judah Folkman) with the help of the Japanese company Takeda Chemical Industries, synthesized an artificial analogue of fumagillin.
Thus, as a result of a peculiar evolution, fumagillin turned into Caplostatin and Lodamine, the rights to the clinical development of which were obtained by the Cambridge (Massachusetts)-based biotech company SynDevRx.
In case of successful clinical trials, the oral drug Lodamine can be used not only for the treatment of a wide range of tumors, but also as a preventive agent for people at high risk for various malignant diseases, as well as for the treatment of other diseases in which abnormal growth of blood vessels is observed, such as age-associated macular degeneration and arthritis.
Evgeniya Ryabtseva,
portal "Eternal youth" www.vechnayamolodost.ru based on the materials of ScienceDaily
03.07.2008