Targeting cancer therapy: using protease cleavage sequences to develop more selective and effective cancer treatments

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dc.contributor.author Basel, Matthew T.
dc.date.accessioned 2012-07-25T14:54:33Z
dc.date.available 2012-07-25T14:54:33Z
dc.date.issued 2012-07-25
dc.identifier.uri http://hdl.handle.net/2097/14087
dc.description.abstract This paper describes two methods for utilizing cancer associated proteases for targeting cancer therapy to the tumor. The first method is designing a drug delivery system based on liposomes that are sensitive to cancer associated proteases. Upon contact with the protease, the liposome releases its contents. The second method is designing a prodrug that is based on a porin isolated from Mycobacterium smegmatis. The porin is modified with protease consensus sequences, inhibiting its toxicity. Upon contact with the protease, the drug is activated. Protease sensitive liposomes were synthesized that were sensitive to urokinase plasminogen activator. This was done by synthesizing a cholesterol-anchored, uPA consensus – sequence-containing, acrylic acid block copolymer and using it to form a covalently bound polymer cage around the outside of a hypertonic liposome. Liposomes were synthesized that had a diameter of 136 nm. Upon addition of the polymer the diameter increased by 2.69 nm, indicating it had successfully embedded into the liposome membrane. After crosslinking with either a short peptide containing a lysine (so that it is a diamine) or ethylenediamine, the diameter increased between 5.33 nm and 14.1 nm (depending on the type and amount of the crosslinked). Fluorescence release assays showed that the polymer cage could add in excess of thirty atmospheres of osmotic pressure resistance, and, under isobaric conditions, would prevent release of much of the liposomal contents. Upon treatment with uPA, the polymer caged liposomes released a significantly larger amount of their contents making the liposomes protease sensitive. MspA was shown to be a very stable protein able to be imaged by AFM. AFM imaging demonstrated that MspA is able to form native pore structures in membranes making it a good imitator of the membrane attack complex. MspA was demonstrated to be highly cytotoxic, but poor at distinguishing between cells. Pro-MspA was synthesized by adding a hydrophilic peptide to MspA that prevents insertion. A uPA cleavage sequence embedded causes the MspA to become activated at the cancer site. This was demonstrated in tests against uPA and non-uPA producing cell lines. en_US
dc.language.iso en_US en_US
dc.publisher Kansas State University en
dc.subject Urokinase plasmin activator (uPA) en_US
dc.subject Liposome en_US
dc.subject MspA en_US
dc.subject Cancer en_US
dc.title Targeting cancer therapy: using protease cleavage sequences to develop more selective and effective cancer treatments en_US
dc.type Dissertation en_US
dc.description.degree Doctor of Philosophy en_US
dc.description.level Doctoral en_US
dc.description.department Department of Chemistry en_US
dc.description.advisor Stefan H. Bossmann en_US
dc.subject.umi Chemistry (0485) en_US
dc.date.published 2010 en_US
dc.date.graduationmonth May en_US

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