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Approved for public release; distribution is unlimited / Maintaining the Fleet Readiness Plan (FRP) construct of six aircraft carriers available within 30 days, plus two additional carriers available within 90 days is a difficult task. Maintenance requirements on carriers alone make satisfying the FRP a challenging scheduling problem. We develop a carrier maintenance scheduling model with a goal to meet, as best as possible, the FRP requirements over a ten-year period, while obeying simple maintenance facility constraints. This model allows us to anticipate gaps in coverage and also quantitatively assess the benefit, or burden, of re-sizing the fleet. We conclude that by increasing the average cycle time for a Carrier Strike Group (CSG) to 27 months we can meet the FRP requirements continuously after an initial maintenance adjustment period of 62 months. / Lieutenant, United States Navy

Student Number : 9903022H MSc Dissertation School of Chemistry Faculty of Science / Cancer is characterised by the unconstrained growth of cancerous cells, which damages the healthy cells and ultimately the tissue of the host. Chemotherapy forms an essential component in the treatment of this disease, however most anti-tumour drugs suffer from various deficiencies, e.g. increased toxicity, reduced serum half life and poor water solubility. The focus of this project was to address some of these deficiencies by conjugating selected drugs to a water-soluble polymeric carrier. Selected water-soluble biodegradable carriers were synthesized. Copolyaspartamides, polyamidoamines and polyamides were obtained by condensation polymerisation, Michéal–type addition polymerisation and ester amine base-catalysed polymerisation. The nascent water soluble polymers were used to conjugate platinum, ferrocene and tetramethylmelamine derivative, respectively. The percentage drug in each polymer drug conjugate was determined by considering the mass of the drug in the conjugate as a percentage of the total mass of the drug-polymer conjugate. Platinum was linked to the carrier via polymer attached amine, carboxyl and hydroxyl ligands. Platinum content of the conjugates ranged from 7 to 11 % by mass. The ferrocenylation agent, 4-ferrocenylbutanoic acid, and the tetramethylmelamine derivative, 3-(4,6-bis(N,N-dimethylamino)-1,3,5-triazacyclohexatrien-2-yl) propanoic acid was polymer-bound by amidation reactions. Iron content of the ferrocence conjugated ranged from 2 to 12 % by mass. While the drug content based on tetramethylmelamine in the 3-(4,6-bis[N,N-dimethylamino]-1,3,5-triazacyclohexatrien-2-yl) propanoic acid polymer conjugate ranged from 8.4 to 8.6 % by mass. There was a preliminary attempt to coconjugate both, 4-ferrocenylbutanoic acid and 3-(4,6-bis[N,N-dimethylamino]-1,3,5- triazacyclohexatrien-2-yl) propanoic acid to the same polymer. This co-conjugate contained 2.9 % iron and 3.4 % tetramethylmelamine by mass.

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Delivery of complex molecules such as peptides, proteins, oligonucleotides and plasmids is an intensively studied subject, which has attracted considerable medical and pharmaceutical interest. Encapsulation of these molecules with biodegradable polymers represents one way of overcoming various problems associated with the conventional delivery of macromolecules, for example instability and short biological half-life. The use of carriers made of hydrophilic polysaccharides such as chitosan, has been pursued as a promising alternative for improving the transport of biologically active macromolecules across biological surfaces. The development of nanoparticles as a delivery system also has major advantages of achieving possible drug protection, controlled release and drug targeting by either a passive or an active means. The aim of this study was to develop a simple and effective method to formulate biodegradable nanoparticles for the delivery of a model protein-bovine serum albumin (BSA) and an angiogenesis inhibitor, arginine-rich hexapeptide (ARE peptide). Major factors which determine nanoparticle formation and loading of the protein and the peptide as well as the underlying mechanisms controlling their incorporation and release characteristics were investigated. The preparation technique, based on the complex coacervation process, is extremely mild and involves the mixture of two aqueous solutions (chitosan and dextran sulfate) at room temperature. The formation of nanoparticles is dependent on the concentrations of chitosan (CS) and dextran sulfate (DS); particles with size, of 257 to 494nm can be obtained with 0.1%w/v solutions of CS and DS. Zeta potential of nanoparicles can be modulated conveniently from -34.3mV to +52.7mV by varying the composition of the two ionic polymers. / Both bovine BSA and the ARH peptide were successfully incorporated into CS-based nanoparticles, mainly via an electrostatic interaction, with entrapment efficiency up to 100% and 75.9% for the protein and peptide respectively. Incorporation of both the protein and peptide into nanoparticles resulted in an increase in size suggesting their close association with the nanoparticle matrix material. The difference in sign and magnitude of zeta potential of empty and macromolecules-loaded nanoparticles supports the hypothesis that protein and peptide association with nanoparticles can be modulated by their ionic interaction with the oppositely charged ionic polymer (DS) in the nanoparticles. The release of BSA from the nanoparticles was very slow in water compared to that in l0mM phosphate buffer pH 7.4; whereas, ARH peptide showed extremely low level of release in water at the low ratio of DS but at the high ratio of DS, its release was in biphasic fashion, with an initial burst effect followed by an almost constant but very slow release up to 7 days in both water and 1 OmM phosphate buffer (pH 7.4). It was found that, unlike ARH peptide, the percentage of BSA released was relatively slower for the nanoparticles with a high ratio of DS. It is speculated that this difference in the release behaviour of BSA and ARH peptide, could be due to the effect of molecular size of the compounds and their interaction with the polymer matrix of the nanoparticle. The results of this study suggest that these novel CS/DS nanoparticulate system, prepared by a very mild ionic crosslinking technique, have potential to be a suitable carrier for the entrapment and controlled release of peptides and proteins.

Thesis (M. Phil.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Graduation date: 1994

Thesis (Ph. D.)--Ohio State University, 2006. / Full text release at OhioLINK's ETD Center delayed at author's request

Signal Transducer and Activator of Transcription 3 (STAT3), a common oncogenic mediator, is constitutively activated in many types of human cancers and plays a critical role in tumor growth and cancer immune evasion. The focus of this dissertation is the delivery of STAT3 inhibitor cucurbitacins to tumors using polymeric nano-carriers for the inhibition of tumor growth and modulation of tumor-induced immunosuppression. The anticancer and immunomodulatory activity of STAT3 inhibitor JSI-124 (cucurbitacin I) was studied in mice carrying B16 tumor. The results showed that JSI-124 + CpG or 7-acyl lipid A combination therapy modulated immunosuppression in tumor environment and generated superior anti-tumor effects compared to monotherapy. In further studies, a sensitive and reproducible liquid chromatography-mass spectroscopy (LC-MS) method was developed and validated for quantitative analysis of STAT3 inhibitor cucurbitacins in vitro and in biological samples. Moreover, nano-delivery systems based on poly(ethylene oxide)-block-poly(-caprolactone) (PEO-b-PCL) micelles and its analogues containing physically encapsulated cucurbitacin and poly(D,L -lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing chemically conjugated JSI-124 for the delivery of STAT3 inhibitor to tumor and dendritic cells (DCs) were developed and characterized. Polymeric micelles of different PCL based core structure were able to significantly increase the water solubility of STAT3 inhibitor cucurbitacins, and slow the rate of drug release by a diffusion dependent mechanism. The chemical structure of the micellar core was found to control the release rate of cucurbitacin from the micelles. PLGA NPs containing conjugated JSI-124, on the other hand, demonstrated a degradation dependent drug release profile over a 1-month period. Both nanoparticulate formulations exhibited potent anticancer and STAT3 inhibitory activity against B16 cancer. Moreover PLGA-JSI-124 NPs suppressed STAT3 activation in immunosuppressed p-STAT3highDCs and significantly improved their function in stimulating T cell proliferation in vitro. These findings show that JSI-124 esters of PLGA NPs can potentially provide a useful platform for JSI-124 delivery to tumor and its targeted delivery to DCs. The results of this research not only proved the principle of STAT3 inhibition in tumors as an efficient intervention for enhancing the therapeutic efficacy of TLR ligand-based cancer immunotherapy, but led to development of nano-delivery systems with potential application in cancer chemo-and immunotherapy. / Pharmaceutical Sciences