Activated and Targeted Discharge of Anticancer Drugs (Bar Ilan)
Intravenous injection of chemotherapeutic drugs in cancer patients causes whole-body toxicity, while the drug molecules arrive to tumor sites at diluted concentrations which are less effective. “Stealth" liposomes, such as Doxil, which are at the vanguard of cancer treatment, are used as nanocarriers of chemotherapeutic drugs and help to prevent whole-body toxicity by aggregating at tumor sites because of the enhanced permeability and retention (EPR) effect near the cancer cells where the blood vessels are fenestrated. These liposomes also have long circulation times and evade the reticuloendothelial system because of their polyethylene glycol (PEG)-polymer coat. However, stealth liposomes do not allow for fast and effective release of the drug payload at the tumor site. There is thus a need for a liposomal delivery system with an efficient drug release mechanism for discharge of chemotherapeutics specifically at the site of tumor growth.In the present technology a proteinaceous nano-switch incorporated into liposomes acts as a gated nano-pore and opens up upon cleavage of engineered sites by factors which are over-expressed and secreted by cancer cells. To date, specific proteolytic cleavage sites have been inserted in a pore-forming protein. Following integration of the proteinaceous nano-switch into the lipid bilayer of proteoliposomes encapsulating a chemotherapeutic drug, the nano-switch was shown to undergo cleavage by the relevant cancer-specific enzyme. Release of payload from loaded liposomes was shown to be increased in the presence of the cancer-specific enzyme. Thus, partial activation of the release mechanism has been achieved in vitro and current focus is on demonstrating active release of anti-cancer drug as a result of tumor signals in vivo.
Patent pending
The most successful stealth liposomal drug currently used in cancer patients is Doxil, which consists of doxorubicin loaded PEGylated liposomes. Worldwide sales of Doxil are currently $600M and this will increase as the drug receives FDA approval for additional indications. Recognizing that the performance of Doxil can be improved by induction of controlled release, a method of ultrasound triggered release of the doxorubicin by causing liposome rupture at the cancer site is currently being tested clinically. By comparison, the “quick release” technology described here, which uses a built-in cancer activated nano-switch, has the potential of being a more effective drug release mechanism that would not require additional intervention by medical professionals. By incorporation into existing platforms, this technology has the potential to become an integral part of the “second generation” version of Doxil and other liposomal based drugs.
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