Doctor of Philosophy
Matthew C.T. Hartman
There are many different types of targeted therapy for cancer treatment. The method of light mediated targeted therapy that we have developed uses photocaged molecules and photoswitchable peptides.
In photocaging, a biologically active molecule is made inactive by the attachment of a photocleavable blocking group. On exposure to UV radiation the photocleavable entity is removed and the biologically active molecule is released. Using this concept we have designed a prodrug that consists of a cell impermeable hydrophilic molecule attached to a photocaged doxorubicin. Upon irradiation with UV light the photosensitive group is removed and cytotoxic doxorubicin is released at the tumor site. This concept has been further modified by attaching receptor binding molecules to the photocaged entity to increase its specificity.
A peptide which consists of an azobenzene photoswitch has been used which, in the dark state is randomly coiled and cell impermeable but upon illumination becomes helical and cell permeable and can be used to deliver drugs into the cells. Upon illumination with UV light of suitable wavelength the azobenzene linker will change from a trans to a cis form and this will convert the randomly coiled cell impermeable peptide into an α helical permeable form. Thus a series of peptides have been designed with different arginine mutations which develop an arginine patch in the helical form. This arginine patch would help in cell permeability by interacting with cell surface glycans. The method could potentially be used to deliver drugs into cells in presence of light.
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Available for download on Sunday, December 08, 2019