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Date of Award
Dissertation - Pacific Access Restricted
Doctor of Philosophy (Ph.D.)
Pharmaceutical and Chemical Sciences
First Committee Member
Second Committee Member
Third Committee Member
Fourth Committee Member
Novel terpolymers of leucine (L), aspartic acid (D), and valine (V) were developed as targeting drug delivery carriers that specifically interact with the α 4 β 1 integrin, which is over-expressed in human malignant melanoma cells. As such, copolymerization and terpolymerization of leucine-N-carboxyanhydride (NCA), β-benzyl-aspartate-NCA, and valine-NCA, in dioxane, initiated with triethylamine, were investigated to determine the random nature of the terpolymer composition, for potential application as a targeting drug delivery carrier. The reactivity ratio of each monomer was determined by using Fineman-Ross, Kelen-Tüdös, and nonlinear least-squares curve fitting methods. The product of the estimated reactivity ratios from the monomers in the binary copolymerizations indicated that random polymers were predominantly formed. Based on the reactivity ratios determined from the binary copolymers, Alfrey-Goldfinger equations were used to estimate the composition of the terpolymers. There was no statistical difference between the actual monomer compositions and the calculated compositions of the terpolymers, which validate the randomness of the terpolymers. Therefore, the poly (Leucine-Aspartate-Valine) synthesized in this study is primarily a random terpolymer. The probability of the appearance of LDV sequences occurring within the random polymers were assessed by analyzing the influence of tacticity on the 13 C NMR signals of LDV terpolymers, a statistical method based on the terminal terpolymerization model, and the Poisson distribution, with the highest probability (∼13%) of LDV occurring in a random terpolymer of LDV to be approximately 8 to 9 triad units. Poly (LDV) polymers were shown to exhibit strong binding affinity for A-375 human malignant melanoma cells. The effectiveness of poly (LDV) to target malignant melanoma was evaluated and it showed that 21.3 ± 2.10% of melanoma cells adhered to poly (LDV) films compared to 39.0 ± 3.90% with the positive control fibronectin, whereas binding to HTB-129 human breast carcinoma cells and NHEK normal human keratinocytes were not significant. Poly (LDV)-doxorubicin conjugates displayed excellent selectivity and cytotoxicity in the delivery of doxorubicin. It was shown that the poly (LDV)doxorubicin conjugates exhibited cytotoxicity toward human malignant melanoma cells, but were less toxic than free doxorubicin. In addition, poly (LDV)-doxorubicin conjugates displayed a substantial reduction in toxicity per mole of doxorubicin against normal human keratinocyte cells when compared to free doxorubicin. Fluorescence microscopy showed poly (LDV)-FITC conjugates bound to the A-375 cells and were internalized within 30 minutes. Scatchard plots of poly (LDV)-doxorubicin conjugates were generated, which determined the association constants and established that there is one class of binding sites. It was shown that poly (LDV) could be internalized in a target specific manner by human malignant melanoma cells, which is dependent on the number of LDV targeting moieties in the polymer. These results established that poly (LDV) could be used as a drug delivery carrier that specifically targets the α 4 β 1 integrin.
0493966501 , 9780493966502
Wamsley, Andrea Kay. (2002). Poly(amino acid) as a targeting drug delivery carrier. University of the Pacific, Dissertation - Pacific Access Restricted. https://scholarlycommons.pacific.edu/uop_etds/2726
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