Polymeric biomaterials have become ubiquitous in modern medical devices. ‘Smart’ materials, materials that respond to external stimuli, have been of particular interest for biomedical applications such as drug delivery. Poly(n-isopropylacrylamide) (pNIPAAm) is the best studied thermally responsive, biocompatible, ‘smart’ polymer and has been integrated into many potential drug delivery devices; however, the architectural design of the polymer in these devices is often overlooked. My research focus was the exploration of pNIPAAm architecture for biological applications. Two new biomaterials were synthesized as a result. Architectural modification of linear pNIPAAm was used to synthesize a well-defined homopolymer pNIPAAm with a sharp transition slightly above normal body temperature under isotonic conditions. This polymer required a combination of polymerization and control techniques including controlled radical polymerization, hydrogen bond induced tacticity, and end-group manipulation. The synthesis of this polymer opened up a variety of biomedical possibilities, one of which is the use of these polymers in a novel hydrogel system. Through the use of the controlled linear pNIPAAm synthesized through chain architectural modification, hydrogels with physiological transition temperatures were also synthesized. These hydrogels showed greater shrinking properties than traditional hydrogels synthesized in the same manner and showed physiological mechanical properties. Highly branched pNIPAAm was also optimized for biological applications. In this case, the branching reduced the efficacy of end-groups in transition temperature modification but increased the efficacy of certain copolymers. The resulting biomaterial was incorporated into a nanoparticle drug delivery system. By combining gold nanoparticles with highly branched pNIPAAm, which was designed to entrap small molecule drugs, a hybrid system was synthesized where heating of the nanoparticle through surface plasmon resonance can trigger drug release from the pNIPAAm. This system proved to be easy to synthesize, effective in loading, and controlled in release. As shown from the applications, architectural control of pNIPAAm can open up new possibilities with this polymer for biomedical applications. Small structural changes can lead to significant changes in the bulk properties of the polymer and should be considered in future pNIPAAm based medical devices.

Chronic pulmonary disorders, marked by excessive extracellular matrix deposition (ECM) or fibrosis, are the most resistant to present clinical therapies resulting in prognoses of 50% life expectancy three years from diagnosis. Inadequacies of current treatments may be attributable to limitations in non-invasive therapeutic administration modalities. However, with the use of polyketal microparticles (PKMs), a novel drug delivery vehicle, a myriad of therapeutic schemes may be explored. Polyketals are a new polymeric family characterized by tissue biocompatibility, rapid hydrolysis, and benign degradation byproducts making it attuned for pulmonary applications. Potential treatments such as siRNA, oligo nucleotides, enzymes and other biomolecules can be encapsulated within PKMs and administered non-invasively via inhalation. For this study, we selected a model therapeutic peptide, Ac-SDKP, with established anti-fibrotic properties as the load for PKMs. For lung dysfunctions accompanied by fibrotic scarring, Ac-SDKP possesses promise in restoring the normal ECM framework. To assess PKMs viability as a pulmonary drug delivery vehicle three objectives were initially defined: 1) Synthesize particles possessing aerodynamic properties conducive for aerosolization 2) Optimization of the therapeutic load, Ac-SDKP, in PKMs to levels that will translate to clinical dosing concentrations, and 3) Determine the biocompatibility of the PKMs in the lung. Optimization of the Ac-SKDP loading within PKMs and size analysis revealed that a solid in oil in water double emulsion particle synthesis technique produced the most ideal microspheres. Based on previous reports, the loading efficiency attained, when locally dispensed, should reach clinical dosing requirements. Synthesized particles were compatible with aerosolization criteria; i.e., diameters below 3 μm and low polydispersities. In addition, we evaluated PKM tissue biocompatibility using a murine lung model. Examination of bronchoalveolar lavage fluid demonstrated only a slight inflammatory response to intratracheal particle injections of PKMs whereas PLGA, a commonly used biomaterial, elicited a significantly higher response. Histological assessment of the lungs following particle injection verified PKMs biocompatibility superiority. In conclusion, small-diameter PKMs are a suitable delivery system for pulmonary drug delivery, capable of delivering small peptide therapeutics and evading the local inflammatory response. The present work will enable expansion of therapeutic avenues capable of combating chronic lung disease.

Introduction: Embolic agents are used to block blood flow of hypervascular tumours, ultimately resulting in target tissue necrosis. However, this therapy is limited by the formation of new blood vessels within the tumour, a process known as angiogenesis. Targeting angiogenesis led to the discovery of anti-angiogenic factors, large molecular weight proteins that can block the angiogenic process. The aim of this research is development of poly (vinyl alcohol) (PVA) aqueous solutions that cross-link in situ to form a hydrogel that functions as an embolic agent for delivery of macromolecular drugs. Methods: PVA (14 kDa, 83% hydrolysed), functionalised by 7 acrylamide groups per chain, was used to prepare 10, 15, and 20wt% non-degradable hydrogels, cured by UV or redox initiation. Structural properties were characterised and the release of FITCDextran (20kDa) was quantified. Degradable networks were then prepared by attaching to PVA (83% and 98 % hydrolysed) ester linkages with an acrylate end group. The effect on degradation profiles was assessed by varying parameters such as macromer concentration, cross-linking density, polymer backbone and curing method. To further enhance the technology, radiopaque degradable PVA was synthesised, and degradation profiles were determined. Cell growth inhibition of modified PVA and degradable products were also investigated. Results: Redox initiation resulted in non-degradable PVA networks of well-controlled structural properties. Increasing the solid content from 10 to 20wt% prolonged the release time from few hours to ~ 2 days but had no effect on the percent release, with only a maximum release of 65% achieved. Ester attachment to the PVA allowed flexibility in designing networks of variable swelling behaviors and degradation times allowing ease of tailoring for specific clinical requirements. Synthesis of radiopaque degradable PVA hydrogels was successful without affecting the polymer solubility in water or its ability to polymerize by redox. This suggested that this novel hydrogel is a potential liquid embolic with enhanced X-ray visibility. Degradable products had negligible cytotoxicity. Conclusion: Novel non-degradable and radiopaque degradable PVA hydrogels cured by redox initiation were developed in this research. The developed PVA hydrogels showed characteristics in vitro that are desirable for the in vivo application as release systems for anti-angiogenic factors.

Introduction: Embolic agents are used to block blood flow of hypervascular tumours, ultimately resulting in target tissue necrosis. However, this therapy is limited by the formation of new blood vessels within the tumour, a process known as angiogenesis. Targeting angiogenesis led to the discovery of anti-angiogenic factors, large molecular weight proteins that can block the angiogenic process. The aim of this research is development of poly (vinyl alcohol) (PVA) aqueous solutions that cross-link in situ to form a hydrogel that functions as an embolic agent for delivery of macromolecular drugs. Methods: PVA (14 kDa, 83% hydrolysed), functionalised by 7 acrylamide groups per chain, was used to prepare 10, 15, and 20wt% non-degradable hydrogels, cured by UV or redox initiation. Structural properties were characterised and the release of FITCDextran (20kDa) was quantified. Degradable networks were then prepared by attaching to PVA (83% and 98 % hydrolysed) ester linkages with an acrylate end group. The effect on degradation profiles was assessed by varying parameters such as macromer concentration, cross-linking density, polymer backbone and curing method. To further enhance the technology, radiopaque degradable PVA was synthesised, and degradation profiles were determined. Cell growth inhibition of modified PVA and degradable products were also investigated. Results: Redox initiation resulted in non-degradable PVA networks of well-controlled structural properties. Increasing the solid content from 10 to 20wt% prolonged the release time from few hours to ~ 2 days but had no effect on the percent release, with only a maximum release of 65% achieved. Ester attachment to the PVA allowed flexibility in designing networks of variable swelling behaviors and degradation times allowing ease of tailoring for specific clinical requirements. Synthesis of radiopaque degradable PVA hydrogels was successful without affecting the polymer solubility in water or its ability to polymerize by redox. This suggested that this novel hydrogel is a potential liquid embolic with enhanced X-ray visibility. Degradable products had negligible cytotoxicity. Conclusion: Novel non-degradable and radiopaque degradable PVA hydrogels cured by redox initiation were developed in this research. The developed PVA hydrogels showed characteristics in vitro that are desirable for the in vivo application as release systems for anti-angiogenic factors.

Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--Lund University.

Thesis (Ph. D.)--Lund University.

Thesis (Ph.D)--Biomedical Engineering, Georgia Institute of Technology, 2009. / Committee Chair: Murthy, Niren; Committee Member: Bellamkonda, Ravi; Committee Member: Davis, Michael; Committee Member: May, Sheldon; Committee Member: Milam, Valeria. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 213-223).

A major drawback of chemotherapy is the lack of selectively leading to damage in healthy tissue, which results in severe acute side effects to cancer patients. The use of nanoparticles as a drug delivery system has emerged as novel strategy to overcome the barriers of immunogenic response, controlled release of therapeutic, and targeting the toxicity only to cancerous cells. In this study, polymeric nanoparticles composed of transition metals and particles derived from natural biopolymers have been generated via self-assembly. For example, nanoparticles composed of cobalt crosslinked with albumin (Co-alb NPs) via Co-amine coordination chemistry of lysine residue were syntheisized in various sizes. The method to generate Co-alb NPs involves no thermal heat, organic solvent or any surfactants, which is ideal for the production of large amounts in a timely manner. The Co-alb NPs displayed exceptional stability under physiological conditions (pH 7.4) for several days with minor changes in size; however degradation could be triggered by reductant (reduced glutathione (GSH), 10 mM) with complete disappearance of particles in less than 2 hour. Numerous therapeutics that are highly effective toward cancer cells have been developed; however, many cannot be administered to patients due to poor solubility in water and pH dependent properties. We have successfully encapsulated 7-ethyl-10-hydroxycampothecin (SN-38) into Co-alb NPs with encapsulation efficiency as high as 94% and loading capacities greater than 30%. We employed an emulsion-solvent evaporation method to incorporate SN-38 into Co-alb (SN38 Co-Alb NPs). Release of the drug from SN38 Co-Alb NPs was determined for particles incubated in PBS or PBS-GSH. SN38 Co-Alb NPs were exceptionally stable under physiological condition (PBS pH 7.4), but exhibited sustained release of SN-38 over time in the presence of GSH. Uptake and toxicity of the particles were also investigated in a gastric carcinoma cell line (SNU-5) where high degrees of macropinocytic uptake were observed. The particles displayed significant toxicity making them a prime candidate for further testing in animal models.