Thesis (Ph. D.)--Uppsala University, 2000. / "Acta Universitatis Upsaliensis." Extra abstract sheet inserted. Includes bibliographical references (p. 42-46).

Thesis (Ph. D.)--University of Texas at Austin, 2002. / Vita. Includes bibliographical references. Available also from UMI Company.

Thesis (Ph. D.)--Drexel University, 2002. / Includes abstract and vita. Includes bibliographical references.

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: mass balance approach; bioavailability; drug delivery; dynamic modeling; partial differential equations; sensitivity analysis; dynamic simulations. Includes bibliographical references (p. 62-67).

published_or_final_version / Mechanical Engineering / Master / Master of Philosophy

Our ability to precisely manipulate size, shape, and composition of nanoscale carriers is essential for controlling their in-vivo transport, biodistribution, and drug release mechanism. Shape-specific, "smart" nanoparticles that deliver drugs or imaging agents to target tissues primarily in response to disease-specific or physiological signals could significantly improve therapeutic care of complex diseases. Current methods in nanoparticle synthesis do not allow such simultaneous control over particle size, shape, and environmentally-triggered drug release, especially at the sub-100 nm range. In this dissertation, we discuss the development of high-throughput nanofabrication techniques using synthetic and biological macromers (peptides) to produce highly monodisperse nanoparticles, as well as enzymatically-triggered nanoparticles, of precise sizes and shapes. We evaluated thermal nanoimprint lithography (ThNIL) and step and flash imprint lithography (SFIL) as two possible fabrication techniques. We successfully employed ThNIL and SFIL for fabricating nanoparticles and have extensively characterized the SFIL fabrication process, as well as the properties of the imprinted biopolymers. Particles as small as 50 nm were fabricated on silicon wafers and harvested directly into aqueous buffer using a biocompatible, one-step release technique. These methods provide a novel way to fabricate biocompatible nanoparticles with precise size and geometry. Furthermore, we developed an enzyme-degradable material system and demonstrated successful encapsulation and enzyme-triggered release of antibodies and nucleic acids from these imprinted nanoparticles; thus providing a potential means for disease-controlled delivery of biomolecules. Finally, we evaluated the bioactivity of the encapsulated therapeutics in-vitro. The development of the SFIL method for fabrication of biocompatible nanocarriers has great potential in the drug delivery field for its ability to create monodisperse particles of pre-designed geometry and size, and to incorporate stimulus-responsive release mechanisms. This research provides the potential to broaden the study of how particle size and shape affect the biodistribution of drugs within the body. / text

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This thesis presents an experimental study of the effect that particle size and shape have on nanoparticle magination and adhesion propensity in micro-capillaries. With the use of half elliptical cross-section microfluidic channels that were fabricated using photolithography as well as wet and dry etching techniques and geometrically mimetic of human microcirculation, particles ranging from 93 to 970 nm were flown and imaged individually adhering to the channel walls. The results show a significant increase in particle adhesion below 200 nm as well as the emergence of a critical particle diameter above which no particle adherence was observed. The volume delivery efficiency was also shown to increase below 200 nm, providing insight for the rational design of nanocarriers for targeted cancer therapeutics. / text

Cationic gemini surfactants have been used for delivery of DNA into cells. These cationic surfactants are known to strongly bind to DNA to form a complex. In the dilute regimen, when the gemini-DNA complexes are mixed with helper neutral lipids, they undergo spontaneous assembly to form particles that are able to transfect DNA into the cells. In this study, the structure of several gemini surfactants, gemini-DNA complexes and gemini-DNA-neutral lipids complexes were systematically examined by small angle x-ray scattering (SAXS). The gemini surfactants were found to form micelles of varying shapes and arrangements modulated by the nature of spacer region and tail lengths. This includes ellipsoidal and worm-like micelles (as in the case of the 12- s-12 series) and disk-shaped hexagonally packed micelles (as in the case of 16-3-16). In addition to the study of the gemini surfactants, the effect of varying the DNA: gemini charge ratio on the DNA-gemini assembly was studied. The scattering pattern has shown that in the presence of excess gemini surfactants, free unbound surfactants exist in the solution. Upon the addition of neutral lipids, DNA-gemini-neutral lipid complexes are formed. The scattering patterns of the latter showed evidence of a strong interaction of the neutral lipids with the free gemini surfactants and the overcharged DNA-gemini complexes. Effectively, overcharging DNA-gemini complexes seem to aid in its incorporation into the neutral lipid matrix. These findings shed the light on the structure of DNA-gemini-neutral lipid systems and provide insights into the factors that influence the spontaneity of the self-assembly process. More importantly, the presented work provides a general strategy that can be applied to the study of similar systems using small angle x-ray scattering. A helium and vacuum chambers were made to enable testing the feasibility of the technique at the Canadian Light Source. Further, a pipeline was written to automate the reduction and analysis of SAXS data.