Thesis (Ph. D.)--Ohio State University, 2006. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2009 Apr 14

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (p. 156-169).

Thesis (Ph. D.)--Drexel University, 2006. / Includes abstract and vita. Includes bibliographical references.

Thesis (Ph. D.)--School of Pharmacy. University of Missouri--Kansas City, 2005. / "A dissertation in pharmaceutical sciences and pharmacology." Advisor: Ashim K. Mitra. Typescript. Vita. Title from "catalog record" of the print edition Description based on contents viewed June 26, 2006. Includes bibliographical references (leaves 174-192). Online version of the print edition.

Thesis (Ph. D.)--University of Texas at Austin, 2004. / Supervisor: Nicholas A. Peppas. Vita. Includes bibliographical references. Also available from UMI.

Thesis (Ph.D. in Pharmaceutical Sciences) -- University of Colorado at Denver and Health Sciences Center, 2005. / Typescript. Includes bibliographical references (leaves 86-92). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

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

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

This thesis describes the preparation and characterization of core-shell noble metal-magnetite hybrid hollow nanocomposites utilizing hierarchical architecture. The hollow magnetite (hFe3O4) nanoparticles were prepared by hydrothermal method, forming the cavity via Oswald ripening. Further surface modifications involved both inorganic and organic coatings, conferring the intracellular drug delivery ability and the catalytic enhancement. In the first part, a series of hierarchical core-shell nanostructures flower-like hFe3O4@AlOOH was synthesized through solvothermal method and sol-gel process. The formation of cavity accessible hFe3O4@γ-AlOOH was achieved using silica-templated solvothermal treatment where the Kirkendall effect was observed. The morphologies of the as-prepared nanocomposites were characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), dynamic light scattering (DLS), thermogravimetric analysis (TGA) and Fourier-transform infrared spectroscopy (FTIR). Then, the nano-encapsulation of platinum drug using hollow magnetite and its derivatives, has been developed with improved loading efficiency via co-solvent system. A dimethylformamide/water co-solvent system was found to be the most efficient system to encapsulate water-insoluble cisplatin. The platinum content was further quantitatively and qualitatively analyzed by inductively coupled plasma mass spectrometry (ICP-MS) and FTIR spectroscopy. The enhancement of loading efficiency could be driven by emulsification due to the diffusion of hydrophobic cisplatin into the hollow cavity of iron oxide nanoparticles. By incorporating water, the loading efficiency of hFe3O4 and hFe3O4@γ-AlOOH increased from 1-2% to 27% and from 6% to 54%, respectively. The grafting of cisplatin on AlOOH nanoflakes might account for the high loading efficiency of flower-like hFe3O4@AlOOH. As a complement to naked hFe3O4, a cell-penetrating poly(disulfide)s (CPD)-decorated hollow iron oxide nanoparticle was synthesized by immobilizing both cysteine and MPTMS as an initiator, followed by in situ polymerization to form hFe3O4-Cys-CPD-CONH2 and hFe3O4-MPS-CPD-CONH2. The morphologies were characterized by TEM/energy-dispersive X-ray spectroscopy (TEM/EDX) and the compositions of the as-prepared iron oxide nanocomposites were characterized by TGA, FTIR and X-ray photoelectron spectroscopy (XPS) and ICP-MS. The CPD coating not only serve as a protective layer, but also prevent the encapsulated cisplatin from a premature release. The hFe3O4-MPS-CPD-CONH2 exhibit promising features for the intracellular delivery of cisplatin, demonstrating a glutathione (GSH)-responsive drug release. Comparing with other hFe3O4 nanoparticles, an enhancement of cellular uptake of hFe3O4-MPS-CPD-CONH2 could be observed by optical microscope, showing rapid accumulation of the hFe3O4-MPS-CPD-CONH2 nanocomposites in the primary human renal proximal tubular epithelial cells (HRPTEpiCs) cell in 2 h. At 24 h, hFe3O4 (F), hFe3O4-MPS (FS) and hFe3O4-MPS-CPD-CONH2 (FSC) together with cisplatin treatment did not cause any significant cytotoxicity to the cells when the particle concentration is less than 10 µg/mL. Interestingly, FSCC showed a certain extent of toxicity with increasing Fe and Pt concentration along with the treated time. It may suggest that the hFe3O4-MPS-CPD-CONH2 nanoparticle, as a cisplatin carrier, could enhance the drug efficiency by increasing cellular uptake of the nanoparticles in HRPTEpiCs together with the boosted cytotoxicity. Based on these data, cisplatin- hFe3O4-MPS-CPD-CONH2 (FSCC) treatments with the concentration less than 20 µg/mL and duration no more than 24 h could maintain around 70% of the cell viability of the HRPTEpiCs. The hypothesis, at which CPD serves as an efficient carrier for intracellular cisplatin delivery, could be confirmed by both microscopic images and the cell viability test. In the second part, a series of Au/Fe3O4 hybrid nanocomposites was prepared to investigate their catalytic efficiencies using 4-nitrophenol reduction as a model system. The flower-like hFe3O4@γ-AlOOH@SiO2-NH2@Au was prepared by using protonated ammonium on hFe3O4@γ-AlOOH@SiO2-NH2 to entangle gold nanoparticles (AuNPs) via electrostatic attraction. In comparison to numerous of catalytic studies, the turnover frequency (TOF) of hFe3O4@γ-AlOOH@SiO2-NH2@Au shows a superior conversion rate up to 7.57 min-1 (4-nitrophenol per Au per min) for the 4-nitrophenol using sodium borohydride as a reductant. A rapid conversion of 4-nitrohpenol was observed using flower like composites that converted the 4-nitrophenol within 2 min. Our result suggests that silica residue hinders the reduction rate of the 4-nitrophenol. A significant deviation from pseudo first order was observed for densely AuNPs-functionalized nanoflower system, hFe3O4@γ-AlOOH@SiO2-NH2@Au2X, which is different from most of the 4-nitrophenol reductions reported in literature. The hFe3O4@γ-AlOOH@SiO2-NH2@Au also demonstrates catalytic activity when heated up to 800 °C before reduction. The recyclability was examined using magnetically recycled hFe3O4@γ-AlOOH@SiO2-NH2@Au, which showed insignificant decrease in the catalytic efficiency. To prove the concept, platinum nanoparticles (PtNPs) immobilized hFe3O4@γ-AlOOH@SiO2-NH2@Pt and hFe3O4@γ-AlOOH@SiO2-NH2@Pt/Au were also prepared via electrostatic attraction to verify the feasibility of endowing modular functionality via post modification.

ABC運輸蛋白的過度表達是多重抗藥性（MDR）的重要機制之一，癌細胞會同時對結構上無關的抗癌藥物產生抗藥性。避免癌細胞的多重抗藥性有不同方法，其中用聚合物納米載體來攜帶易受多重抗藥性影響的抗癌藥物近年來獲得了很大的關注。本研究的目標在使用一個相對新穎的納米開發技術，被稱為瞬時納米沉澱（FNP），去開發一種運載著易受多重抗藥性影響的抗癌藥物的聚合物納米粒子系統。為此，我們使用專門設計的四流多進旋渦混合器（MIVM），把阿黴素（DOX），一種屬於蒽環類的抗癌藥物，亦同時作為P糖蛋白（P-gp）底物的藥物，包進在二嵌段共聚物內。 / 目的：本研究的目的是:（一）通過MIVM，利用瞬時納米沉澱去配製運載DOX的聚合物納米粒子；（二）辨别和優化納米粒子的大小，物理性能和運載DOX聚合物納米粒子的體外釋放速率；（三）檢查納米粒子的表面元素和化學組成;(四）評估優化納米粒子在抗藥性癌症細胞模型的抗腫瘤能力和抵抗多重抗藥性的能力。 / 方法：不同藥物（DOX)對聚合物比例的瞬時納米沉澱是通過在四流MIVM中混合溶在有機溶液二甲基甲酰胺（DMF)或二甲基酮（ACT)的鹽酸阿黴素(DOX.HC1)或阿黴素游離鹼（DOX.FB)和兩親性二嵌段共聚物[聚乙二醇-聚乳酸；分子量2000-10000]和反抗溶劑（含有氫氧化鈉為DOX.HCl或純淨水DOX+FB)來製備的。納米混懸劑的平均粒徑和粒度分佈會通過動態光散射粒度分析法去檢測，表面電荷會通過界達電位測量去檢測。阿黴素的包封率和載藥量會用紫外/可見光譜儀在波長為480 nm時測定。粒子形態將會用原子力顯微鏡（AFM)來去檢測，粒子表面的組合物將會用X-射線光電子能譜（XPS)來去檢測DOX聚合物納米粒子在不同pH值的的體外釋放會通過紫外/可見光譜儀去檢測。DOX聚合物納米粒子的體外細胞毒性會利用橫若丹明B比色法檢定，藥物積累和反轉運會利用流式細胞儀分析來測定。 / 結果：在適當優化鹽酸阿黴素（DOX.HC1)或阿黴素游離鹼（DOX.FB)的聚合物的比例後，我們成功製備了平均粒徑小於100 nm的DOX聚合物納米粒子(DOX.NP)與使用在有機溶液中DOX.HC1和水相的氫氧化鈉中和法相比，通過在有機溶液中的DOX.FB和純水作為反溶劑來製備的DOX.NP表現出類似的平均粒子大小（小於100 nm)，但顯示出更高的藥物包封率（48 %， 而不是中和法的25 %)。用DOX.FB製備的DOX.NP的載藥量可達14 %DOX.NP表現出pH依賴性的藥物釋放曲線，和在酸性pH值時更强的累積釋放率。X-射線光電子能譜顯示沒有阿黴素出現在納米粒子的表面上P-gp過度表達的LCC6抗藥性乳腺癌细胞的細胞毒性作用顯示了 DOX.NP和DOX.HC1在缓衝溶液中的差異並不顯著。相對DOX.HC1，流式細胞儀分析確定了 DOX.NP明顯增加了細胞攝取DOX的能力。此外，在外排後，DOX.NP在細胞內DOX的濃度顯示出了更長的保留時間。 / 結論：一種通過在多進旋過混合器（MIVM)進行反溶劑沉澱，用於配製具有可控的粒子大小運載DOX的聚合物納米粒子的快速，方便，和可重複性的方法已經被開發。配製的納米粒子顯示出pH值依賴性持續的藥物釋放曲線和更強的癌細胞攝取DOX能力。 / Over-expression of ATP-binding cassette (ABC) is one of the most important mechanisms responsible for multidrug resistance (MDR), in which tumor cells exhibit simultaneous resistance to structurally unrelated anticancer drugs. Various approaches have been attempted to circumvent MDR in cancer cells, among which polymeric nanocarrier for delivery of MDR-sensitive anticancer drugs has received considerable attention in recent years. The present project was aimed at developing a polymeric nanoparticle system using a relatively novel nanoparticle technology termed flash nanoprecipitation (FNP) for delivery of MDR-susceptible chemotherapeutic agents. To this end, doxorubicin (DOX), an anthracycline anticancer agent and a P-gp substrate, was incorporated into an amphiphilic diblock copolymer using a specially designed four-stream multi-inlet vortex mixer (MIVM). / PURPOSES: The objectives of the present study are: (a) to formulate DOX-loaded polymeric nanoparticles by FNP using an MIVM; (b) to characterize and optimize the particle size, physical properties and in vitro DOX release rate of the formulated nanoparticles; (c) to examine the surface elemental and chemical compositions of the formulated nanoparticles; (d) to evaluate the anti-tumor activity of the optimized nanoparticles and their ability to combat MDR in resistant cancer cell line models. / METHODS: FNP of DOX was effected in a four-stream MIVM by mixing organic solutions of doxorubicin hydrochloride (DOX.HCl) or doxorubicin free base (DOX.FB) and an amphiphilic diblock copolymer [polyethylene glycol-polylactic acid (PEG-PLA); MW2k-10 ki]n dimethylformamide (DMF) or acetone (ACT) at different drug-to-polymer ratios with an antisolvent (water containing sodium hydroxide for DOX.HCl or pure water for DOX.FB). The resulting nanosuspensions were characterized for mean particle size and size distribution by dynamic light scattering particle size analysis; surface charges by zeta potential measurements; drug encapsulation efficiency and drug loading by UV/visible spectroscopy at 480 nm; particle morphology by atomic force microscopy (AFM); and surface composition by x-ray photoelectron spectroscopy (XPS). In vitro DOX release from the nanoparticles was measured at different pHs by UV/visible spectroscopy. In vitro cytotoxicity was evaluated by Sulforhodamine B colorimetric assay, and drug accumulation and efflux were determined by flow cytometric analysis. / RESULTS: DOX-loaded polymeric nanoparticles (DOX.NP) with mean particle size below 100 nm were obtained after appropriate optimization of the DOX.HCl or DOX.FB to polymer ratio. Compared with the neutralization method using DOX.HCl in the organic phase and sodium hydroxide in the aqueous phase, DOX.NP prepared with DOX.FB in the organic phase and pure water as antisolvent exhibited a similar mean particle size (< 100 nm) but a significantly higher drug encapsulation efficiency (48% as opposed to 25% for the neutralization method). Drug loading of DOX.NP prepared with DOX.FB could reach up to 14%. DOX.NP exhibited a pH-dependent drug release profile with a much higher cumulative release rate at acidic pHs. XPS revealed that no DOX was present on the nanoparticle surface. The cytotoxic effect on P-gp over-expressing LCC6/MDR cell line revealed insignificant differences between DOX.NP and DOX.HCl in buffered aqueous media. DOX.NP exhibited a marked increase in DOX cellular uptake relative to free DOX, as determined by flow cytometric analysis. Furthermore, DOX.NP showed a significant retention of intracellular concentration of DOX after efflux. / CONCLUSION: A rapid, convenient, and reproducible method for generating DOX-loaded polymeric nanoparticles with controllable particle size through antisolvent precipitation in a multi-inlet vortex mixer has been developed. The formulated nanoparticles displayed a pH-dependent sustained drug release profile and an enhanced DOX uptake into cancer cells. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Tam, Yu Tong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 119-130). / Abstracts also in Chinese. / ABSTRACT --- p.i / 摘要 --- p.iv / ACKNOWLEDGEMENTS --- p.vi / TABLE OF CONTENTS --- p.vii / LIST OF FIGURES --- p.x / LIST OF TABLES --- p.xiii / ABBREVIATIONS --- p.xv / Chapter CHAPTER 1. --- Introduction --- p.1 / Chapter 1.1 --- Rationale of the Study --- p.2 / Chapter 1.2 --- Doxorubicin --- p.3 / Chapter 1.2.1 --- Origin --- p.3 / Chapter 1.2.2 --- Physico-chemical properties --- p.6 / Chapter 1.2.3 --- Mechanism of Action --- p.7 / Chapter 1.2.4 --- Multidrug Resistance in Cancer --- p.7 / Chapter 1.2.4.1 --- Mechanisms of Multidrug Resistance --- p.8 / Chapter 1.3 --- Nanoparticles for Cancer Therapy --- p.9 / Chapter 1.3.1 --- Properties of Nanoparticles --- p.9 / Chapter 1.3.1.1 --- Small Particle Size --- p.10 / Chapter 1.3.1.2 --- High Payload Density --- p.11 / Chapter 1.3.1.3 --- Flexible Modification of Surface Properties --- p.11 / Chapter 1.3.2 --- Targeted Cancer Therapy --- p.12 / Chapter 1.3.2.1 --- Passive Tumor Targeting --- p.13 / Chapter 1.3.2.2 --- Active Tumor Targeting --- p.14 / Chapter 1.3.3 --- Reversal of Multidrug Resistance --- p.15 / Chapter 1.3.3.1 --- Endocytosis of Nanoparticles --- p.16 / Chapter 1.3.4 --- Nanoparticle Approaches to Anti-cancer Drug Delivery --- p.17 / Chapter 1.3.4.1 --- Liposomes --- p.18 / Chapter 1.3.4.2 --- Polymeric Nanoparticles --- p.18 / Chapter 1.4 --- Fabrication of Nanoparticles --- p.19 / Chapter 1.5 --- Aims and Scope of the Present Study --- p.21 / Chapter CHAPTER 2. --- Materials & Methods --- p.23 / Chapter 2.1 --- Materials --- p.24 / Chapter 2.1.1 --- Chemicals --- p.24 / Chapter 2.1.2 --- Materials for Cell Culture --- p.25 / Chapter 2.2 --- Methods --- p.26 / Chapter 2.2.1 --- Preparation of Doxorubicin Nanoparticles by Flash Nanoprecipitation --- p.26 / Chapter 2.2.1.1 --- Acid-Base Neutralization during Mixing --- p.26 / Chapter 2.2.1.2 --- Preparation of Doxorubicin Free Base before Mixing --- p.29 / Chapter 2.2.1.2.1 --- Doxorubicin Free Base Preparation --- p.29 / Chapter 2.2.2 --- Determination of Particle Size and Zeta Potential --- p.30 / Chapter 2.2.3 --- Co-stabilizers and Particle Stability --- p.30 / Chapter 2.2.4 --- Chemical Stability of Doxorubicin --- p.31 / Chapter 2.2.5 --- Determination of Encapsulation Efficiency --- p.31 / Chapter 2.2.5.1 --- Calibration Curve of Doxorubicin --- p.33 / Chapter 2.2.5.2 --- Dialysis --- p.33 / Chapter 2.2.5.3 --- Ultrafiltration --- p.35 / Chapter 2.2.6 --- Determination of Drug Loading --- p.35 / Chapter 2.2.6.1 --- Freeze Drying --- p.36 / Chapter 2.2.7 --- Morphological Examination --- p.36 / Chapter 2.2.7.1 --- X-ray Photoelectron Spectroscopy --- p.36 / Chapter 2.2.7.2 --- Atomic Force Microscopy --- p.36 / Chapter 2.2.8 --- In vitro release study --- p.37 / Chapter 2.2.8.1 --- Experimental Protocols --- p.37 / Chapter 2.2.8.2 --- Calculation of Cumulative Drug Release --- p.37 / Chapter 2.2.9 --- In vitro cytotoxicity study --- p.38 / Chapter 2.2.9.1 --- Sulforhodamine B Colorimetric Assay --- p.38 / Chapter 2.2.10 --- Cellular Uptake study --- p.39 / Chapter 2.2.10.1 --- Drug Accumulation Assay --- p.39 / Chapter 2.2.10.1 --- Drug Efflux Assay --- p.39 / Chapter 2.2.11 --- Analytical techniques --- p.40 / Chapter 2.2.11.1 --- UV/Vis Analysis --- p.40 / Chapter 2.2.11.2 --- HPLC Analysis --- p.40 / Chapter 2.2.12 --- Statistical analysis --- p.41 / Chapter CHAPTER 3. --- Results & Discussions --- p.42 / Chapter 3.1 --- Preparation of Doxorubicin Nanoparticles by Flash Nanoprecipitation --- p.43 / Chapter 3.1.1 --- Acid-Base Neutralization during Mixing --- p.44 / Chapter 3.1.1.1 --- Influence of Drug Concentration --- p.44 / Chapter 3.1.1.2 --- Influence of Alkaline Medium --- p.48 / Chapter 3.1.1.3 --- Influence of Drug-to-Polymer Ratios --- p.53 / Chapter 3.1.1.4 --- Particle Stability --- p.54 / Chapter 3.1.1.5 --- Co-stabilizers Tests on Stability --- p.55 / Chapter 3.1.1.5.1 --- Effect of PEG-PLA Co-polymers --- p.55 / Chapter 3.1.1.5.2 --- Effect of Co-stabilizers --- p.56 / Chapter 3.1.2 --- Preparation of Doxorubicin Free Base before Mixing --- p.62 / Chapter 3.1.2.1 --- Influence of Solvent System --- p.62 / Chapter 3.1.2.2 --- Influence of Drug-to-Polymer Ratios --- p.65 / Chapter 3.1.2.3 --- Drug Loading --- p.65 / Chapter 3.1.2.4 --- Particle Stability --- p.68 / Chapter 3.1.2.4.1 --- Concentrated Particle Stability --- p.73 / Chapter 3.2 --- Stability Studies on Doxorubicin Nanoparticle at Physiological and Cancer Cell pHs --- p.75 / Chapter 3.2.1 --- Chemical Stability --- p.75 / Chapter 3.2.2 --- Physical Stability --- p.77 / Chapter 3.3 --- In vitro Release Study --- p.79 / Chapter 3.4 --- Morphological Examination --- p.86 / Chapter 3.4.1 --- Zeta Potential --- p.92 / Chapter 3.5 --- In vitro Cellular Study --- p.93 / Chapter 3.5.1 --- Cellular Uptake Study --- p.93 / Chapter 3.5.1.1 --- Drug Accumulation and Drug Efflux --- p.93 / Chapter 3.5.2 --- Cytotoxicity of Blank Nanoparticles --- p.98 / Chapter 3.5.3 --- Cytotoxicity of DOX loaded Nanoparticles --- p.100 / Chapter CHAPTER 4. --- Conclusions --- p.106 / APPENDIX --- p.109 / REFERENCES --- p.118