Development of polymeric drug delivery vehicles for targeted cancer therapy

The aim of my Ph. D. thesis is to generalize a method for targeted anti-cancer drug delivery. Hydrophilic polymer-drug conjugates involve complicated synthesis; drug-encapsulated polymeric nanoparticles limit the loading capability of payloads. This thesis introduces the concept of nanoconjugates to overcome difficulties in synthesis and formulation. Drugs with hydroxyl group are able to initiate polyester synthesis in a regio- and chemo- selective way, with the mediation of ligand-tunable Zinc catalyst. Herein, three anti-cancer drugs are presented to demonstrate the high efficiency and selectivity in the method (Chapter 2-4). The obtained particles are stable in salt solution, releasing drugs over weeks in controlled manner. With the conjugation of aptamer, particles are capable to target prostate cancer cells in vitro. These results open the gateway to evaluate the in vivo efficacy of nanoconjugates for target cancer therapy (Chapter 5). Mechanism study of the polymerization leads to the discovery of chemosite selective synthesis of prodrugs with acrylate functional groups. Functional copolymer-drug conjugates will expand the scope of nanoconjugates (Chapter 6). Liposome-aptamer targeting drug delivery vehicle is well studied to achieve reversible cell-specific delivery of non-hydoxyl drugs e.g. cisplatin (Chapter 7). New monomers and polymerization mechanisms are explored for polyester in order to synthesize nanoconjugates with variety on properties (Chapter 8). Initial efforts to apply this type of prodrugs will be focused on the preparation of hydrogels for stem cell research (Chapter 9).

The effects of PVP(FE(III)) catalyst and polymer molecular weight on gene delivery via biodegradable crosslinked polyethylenimine

Human gene therapy has faced many setbacks due to the immunogenicity and oncogenity of viruses. Safe and efficient alternative gene delivery vehicles are needed to implement gene therapy in clinical practice. Polymeric vectors are an attractive option due to their availability, simple chemistry, and low toxicity and immunogenicity. Our group has previously reported biodegradable polyethylenimines (PEI) that show high transfection efficiency and low toxicity by cross-linking 800 Da PEI with diacrylate cross-linkers using Michael addition. However, the synthesis was difficult to control, inconsistent, and resulted in polymers with a narrow range of molecular weights. In the present work, we utilized a heterogenous PVP(Fe(III)) catalyst to provide a more controllable PEI crosslinking reaction and wider range of biodegradable PEIs. The biodegradable PEIs reported here have molecular weights ranging from 1.2 kDa to 48 kDa, are nontoxic in MDA-MB-231 cells, and show low toxicity in HeLa cells. At their respective optimal polymer:DNA ratios, these biodegradable PEIs demonstrated about 2-5-fold higher transfection efficiency and 2-7-fold higher cellular uptake, compared unmodified 25 kDa PEI. The biodegradable PEIs show similar DNA condensation properties as unmodified PEI but more readily unpackage DNA, based on ethidium bromide exclusion and heparan sulfate competitive displacement assays, which could contribute to their improved transfection efficiency. Overall, the synthesis reported here provides a more robust, controlled reaction to produce cross-linked biodegradable PEIs that show enhanced gene delivery, low toxicity, and high cellular uptake and can potentially be used for future in vivo studies.

Self-sealing of thermal fatigue and mechanical damage in fiber-reinforced composite materials

Fiber reinforced composite tanks provide a promising method of storage for liquid oxygen and hydrogen for aerospace applications. The inherent thermal fatigue of these vessels leads to the formation of microcracks, which allow gas phase leakage across the tank walls. In this dissertation, self-healing functionality is imparted to a structural composite to effectively seal microcracks induced by both mechanical and thermal loading cycles. Two different microencapsulated healing chemistries are investigated in woven glass fiber/epoxy and uni-weave carbon fiber/epoxy composites. Self-healing of mechanically induced damage was first studied in a room temperature cured plain weave E-glass/epoxy composite with encapsulated dicyclopentadiene (DCPD) monomer and wax protected Grubbs' catalyst healing components. A controlled amount of microcracking was introduced through cyclic indentation of opposing surfaces of the composite. The resulting damage zone was proportional to the indentation load. Healing was assessed through the use of a pressure cell apparatus to detect nitrogen flow through the thickness direction of the damaged composite. Successful healing resulted in a perfect seal, with no measurable gas flow. The effect of DCPD microcapsule size (51 um and 18 um) and concentration (0 - 12.2 wt%) on the self-sealing ability was investigated. Composite specimens with 6.5 wt% 51 um capsules sealed 67% of the time, compared to 13% for the control panels without healing components. A thermally stable, dual microcapsule healing chemistry comprised of silanol terminated poly(dimethyl siloxane) plus a crosslinking agent and a tin catalyst was employed to allow higher composite processing temperatures. The microcapsules were incorporated into a satin weave E-glass fiber/epoxy composite processed at 120C to yield a glass transition temperature of 127C. Self-sealing ability after mechanical damage was assessed for different microcapsule sizes (25 um and 42 um) and concentrations (0 - 11 vol%). Incorporating 9 vol% 42 um capsules or 11 vol% 25 um capsules into the composite matrix leads to 100% of the samples sealing. The effect of microcapsule concentration on the short beam strength, storage modulus, and glass transition temperature of the composite specimens was also investigated. The thermally stable tin catalyzed poly(dimethyl siloxane) healing chemistry was then integrated into a [0/90]s uniweave carbon fiber/epoxy composite. Thermal cycling (-196C to 35C) of these specimens lead to the formation of microcracks, over time, formed a percolating crack network from one side of the composite to the other, resulting in a gas permeable specimen. Crack damage accumulation and sample permeability was monitored with number of cycles for both self-healing and traditional non-healing composites. Crack accumulation occurred at a similar rate for all sample types tested. A 63% increase in lifetime extension was achieved for the self-healing specimens over traditional non-healing composites.