Photoactivatable Anticancer Prodrug
In oncology non-resectable, non-metastasized tumor treatment currently relies on chemotherapy, radiation therapy, or photodynamic therapy (PDT). Chemotherapy can be effective but it can be done because of side effects (neuron damage, pain, fatigue, etc.). Radiation therapy and PDT are more local and lower systemic toxicity but they require dioxygen in the irradiated tissues to be efficient. Hypoxic tumors, subset or tumors with high volume or hypoxic, poorly vascularized tissues, low prognosis for the patient.
The present invention is a form of photoactivated chemotherapy (PACT) that combines the advantages of well-defined target (PDT) and PDT (local activation by light and lower side effects). It is more specifically aimed at treating hypoxic tumors.
The technology relies on the photochemical breakage of a chemical bond. In the prodrug form) a toxic, thioether-containing microtubule polymerization inhibitor is coordinated to a non-toxic ruthenium (II) caging complex. In the dark, the coordination bond between Ru 2+ and the sulfur atom is stable, but under light irradiation is broken, and the non-toxic caging group.
Details and State of Development:
- Collaboration between Leiden University, NL, and Texas State University, USA.
- Uncaged microtubule inhibitor patented by Prof. Alexander Kornienko from Texas State University, USA
- Synthesis, photochemistry, dark stability, and microtubule polymerization inhibition upon light irradiation, have been demonstrated
Chromatography-free synthesis available
- Low dark toxicity and high toxicity in vitro in 2D human cancer cell monolayers demonstrated both in normoxic (21% O 2 ) and hypoxic (1% O 2 ) conditions
- Low dark toxicity and high toxicity in vitro in A549 lung cancer 3D tumor spheroids
- Preliminary results in vivodemonstrate 30% tumor volume reduction under green light irradiation in A549 lung tumor xenografts in nude mice, and no toxicity in the dark, after intraperitoneal injection at 1 mg / kg and with a green light dose of 38 J / cm 2 .
Market for photoactivated chemotherapy includes brain, liver, head and neck, non-melanoma skin, and eye cancer (Market study available). Best application for tumors with a high ratio of hypoxic to normoxic volume, for which currently available therapies (PDT, radiation, surgery) do not work or are impossible (non-resectable tumors).
The researchers are looking for partners in the field of research, which would be extensive in vivo (mouse model) studies.
- Unlike the uncured (free) microtubule inhibitor, the caged prodrug is unable to interact with microtubules, leading to low toxicity in the dark.
- The photo-uncuring reaction is independent of the presence of dioxygen, so that activation in vitro or in vivo can happen both in normoxic and hypoxic conditions.
- Activation can be achieved using green light (532 nm), which is poorly toxic to cells, penetrates better in biological tissues than blue or UV light, and is well suited for the PDT treatment of flat tumors (bladder, eye, skin, etc.). ).
- The molecule does not produce oxygen, nor does it reduce inflammation, pain, and tissue necrosis in vivo.
- Caging of the inhibitor with ruthenium provides good water solubility.
Luris reference numberST181212-2300-14190
The rigidin analogues have been patented by New Mexico Tech and Texas State University jointly, while jointly is jointly filed at Texas State University and Leiden University.