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The delivery of biomolecules by cell penetrating peptides (CPPs) is an innovative therapeutic strategy. However delivery efficiency is hindered by the entrapment of CPPs in vesicles, degradation, or recycling out of cells, which limits their delivery into the cell cytoplasm and nucleus. To overcome these barriers, we investigated a bacterial protein domain derived from Pseudomonas aeruginosa, Exotoxin A (ETA, residues 253-412) that is able to exit vesicular compartments. A series of CPP-ETA(253-412) fusion proteins were constructed, expressed, and purified. Confocal microscopy and flow cytometry confirmed the internalization at 37oC of constructs containing CPPs (poly-arginine or TAT). In addition, constructs containing CPP-ETA(253-412)-eGFP were shown to relocate from endosomes to the cytosol. CPP-ETA(253-412) constructs were also able to act as carriers of DNA cargos facilitating their delivery to the cytosol. The ETA(253-412) translocation domain may prove useful for the intracellular delivery of drugs, protein therapeutics, siRNA delivery, and vaccine formulations.

The delivery of biomolecules by cell penetrating peptides (CPPs) is an innovative therapeutic strategy. However delivery efficiency is hindered by the entrapment of CPPs in vesicles, degradation, or recycling out of cells, which limits their delivery into the cell cytoplasm and nucleus. To overcome these barriers, we investigated a bacterial protein domain derived from Pseudomonas aeruginosa, Exotoxin A (ETA, residues 253-412) that is able to exit vesicular compartments. A series of CPP-ETA(253-412) fusion proteins were constructed, expressed, and purified. Confocal microscopy and flow cytometry confirmed the internalization at 37oC of constructs containing CPPs (poly-arginine or TAT). In addition, constructs containing CPP-ETA(253-412)-eGFP were shown to relocate from endosomes to the cytosol. CPP-ETA(253-412) constructs were also able to act as carriers of DNA cargos facilitating their delivery to the cytosol. The ETA(253-412) translocation domain may prove useful for the intracellular delivery of drugs, protein therapeutics, siRNA delivery, and vaccine formulations.

There exists a demand to re-engineer pre-existing pharmaceuticals to provide improved drug delivery, new dosage forms and increased drug safety and efficacy. Furthermore, the development of novel methods and formulations allows for the patent life of pre-existing drugs to be extended, which has obvious economic benefits for pharmaceutical companies. Dense gas technology provides a means to achieve these aims and to overcome the distinct limitations of traditional technologies. A novel formulation of the antifungal drug itraconazole has been developed using gas antisolvent processes. The new itraconazole-polymer formulation displayed a significant improvement in dissolution rate achieving 89.8 % dissolution compared to 52.5 % for the commercial formulation. The results of this study demonstrate the great opportunity to use dense gases for the creation of novel drug-polymer composite formulations with improved dissolution properties. The impregnation of an active ingredient into a polymer matrix is another method that can be used to improve the dissolution of poorly water soluble drugs. Dense gas technology has been incorporated into traditional methods for the formation of porous polymer matrices decreasing process residence times. However, some issues still need to be overcome including high operating temperatures and the use of class 3 solvents. A novel dense gas process for the formation of a porous polymer hydrogel matrix has been developed to improve upon current methodologies; Dense Gas Solvent Exchange Process (DGSEP). The Dense Gas Solvent Exchange Process was used to create a porous chitosan hydrogel impregnated with a stable amorphous form of the drug griseofulvin. Furthermore, the process was extended to include a hydrophilic polymer into the matrix. The resulting formulation had a dramatically improved dissolution rate achieving complete dissolution within 70 minutes compared with the commercial formulation which achieved less than 40 %dissolution in the same time. There is great potential for DGSEP to be applied to the formation of a variety of polymer hydrogels impregnated with active ingredients and incorporating polymers and other compounds. The significance of these results is that a simple and effective processing method has been developed to produce hydrogel systems that are suitable for the development of a diverse range of drug delivery systems.

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 245-259). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph. D.)--Ohio State University, 2004. / Title from first page of PDF file. Document formatted into pages; contains xv, 172 p.; also includes graphics (some col.). Includes bibliographical references (p. 161-172).

Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Pharmaceutical Science." Includes bibliographical references (p. 191-199).

Thesis (Ph. D.)--University of Texas at Austin, 1998. / Vita. Includes bibliographical references (leaves 271-296). Available also in a digital version from Dissertation Abstracts.