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Abstract
We have generated a library of over 500 degradable, poly(b-amino esters) for potential use as non-viral DNA vectors. To better understand structure/property relationships governing polymeric gene delivery, we synthesized polymers with 70 different primary structures, at 6 to 12 different molecular weights, using monomers previously identified as common to effective gene delivery polymers. This library was characterized by 1) molecular weight, 2) particle size upon complexation with DNA, 3) surface charge upon complexation with DNA, 4) optimal polymer/DNA ratio, 5) cytotoxicity and 6) transfection efficiency. The best performing polymer, C32, was tested in vivo for DNA delivery following intratumor (I.T.) and intramuscular (I.M.), and intra organ (I.O) injection. C32 delivered DNA I.T. ∼4-fold better than one of the best commercially available reagents, Jet PEI, and 26-fold better than naked DNA. C32 also shows the ability to effectively deliver DNA following I.O. injection. Conversely, the highest transfection levels following I.M. administration were achieved using naked DNA, followed by PEI; transfection was rarely observed with C32. C32-delivery of Dipetheria toxin A DNA to LNCaP xenografts suppressed tumor growth and even caused 40% of tumors to regress in size. Since C32 transfects tumors locally at high levels, transfects healthy muscle poorly, and displays no toxicity, it may provide a new vehicle for the local treatment of cancer.