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dc.contributor.authorYu, Yun
dc.date.accessioned2016-04-05T19:12:35Z
dc.date.available2016-04-05T19:12:35Z
dc.date.issued2013
dc.identifier.isbn9781303476112
dc.identifier.other1459756710
dc.identifier.urihttp://hdl.handle.net/10477/50458
dc.description.abstractPolymer-drug conjugate, also known as macromolecular prodrug, is a type of polymeric nanomedicine in which drugs are covalently bonded to polymers. This dissertation focuses on the development of four types of novel biodegradable polymer-drug conjugates for anticancer drug delivery. A novel biodegradable brush polymer-drug conjugate (BPDC) with paclitaxel (PTXL) as the divalent agent to bridge between the degradable polylactide (PLA)-based backbone and hydrophilic poly(ethylene glycol) (PEG) side chains, was prepared by the copper-catalyzed azide-alkyne cycloaddition reaction of alkyne-functionalized polylactide (PLA) with azide-functionalized PTXL-PEG conjugate. After multi-step synthesis of alkyne-functionalized lactide monomer, the alkyne-functionalized PLA was prepared by ring-opening polymerization (ROP) of the functional lactide with L-lactide. The azide-functionalized PTXL-PEG conjugate was also prepared by multi-step organic synthesis. The well-controlled chemical structures of the BPDC and its precursors were verified by proton nuclear magnetic resonance ( 1 H NMR) and gel permeation chromatography (GPC) characterizations. Dynamic light scattering (DLS) analysis indicated that BPDC molecules assembled in water to form nanoparticles with sizes of 8-40 nm. Multiple hydrolysis reactions under the experimental conditions were observed, which resulted in the release of PTXL moieties and the cleavage of PLA-based backbone. To improve the drug release profile of the above BPDC, another biodegradable BPDC was synthesized through azide-alkyne click reaction of alkyne-functionalized polylactide (PLA) with azide-functionalized paclitaxel (PTXL) and poly(ethylene glycol) (PEG). Well-controlled structures of the resulting BPDC and its precursors were verified by 1 H NMR and GPC characterizations. Both DLS analysis and transmission electron microscopy (TEM) imaging indicated that the BPDC had a nanoscopic size around 10-30 nm. Drug release behavior of BPDC was monitored by high performance liquid chromatography (HPLC) indicating 50 % of drug moiety was effectively released within 24 h. The significant hydrolytic degradability of the PLA backbone of the BPDC was confirmed by GPC analysis of its incubated solution. As illustrated by cytotoxicity and cell uptake study, BPDC exhibited high therapeutic efficacy toward MCF-7 cancer cells. To further demonstrate the versatility of such BPDC template, a novel brush polymer-drug conjugate (BPDC) consisting of biodegradable scaffold and pH-responsive drug conjugation was prepared. The biodegradable scaffold, PLA- graft -aldehyde/PEG (PLA- g -ALD/PEG), was synthesized via copper-catalyzed azide-alkyne click reaction. Then BPDC was obtained by conjugating doxorubicin (DOX) with the scaffold through acid-liable Schiff base linkages. Well-controlled structures of the resulting BPDC and its precursors were verified by 1 H NMR and GPC characterizations. As revealed by DLS and TEM, the BPDC had well-defined nanostructure with size of 10-30 nm. Due to the Schiff base conjugation linkage in BPDC, acid-liable drug release behavior of the NPs was observed. Both cytotoxicity and cell internalization study of BPDC in MCF-7 breast cancer cells indicated its great potential application as an anticancer nanomedicine. Finally, biodegradable nanoparticles (NPs) mainly consisting of hydrophobic polymer-drug conjugate, PLA- g -DOX, were prepared for anticancer drug delivery via nanoprecipitation. PLA- g -DOX conjugate was synthesized by azide-alkyne click reaction to transform alkyne-functioanlized PLA into PLA-g-aldehyde (PLA-g-ALD), followed by DOX conjugation to form acid-sensitive Schiff base linkage between drug moieties and polymer scaffold. PLA- g -DOX was further used to prepare NPs with precisely controlled drug loading by nanoprecipitaiton in the presence of a PEGylated surfactant. The effects of organic solvent, PLA- g -DOX concentration and PLA- g -DOX/surfactant mass ratio on size and size distribution of NPs were systematically examined based on DLS and TEM analysis. Due to the Schiff base conjugation linkage in PLA- g -DOX, acid-liable drug release behavior of the NPs was observed. Cytotoxicity and cell uptake studies of the NPs towards MCF-7 breast cancer cells indicated their promising potential applications as anti-cancer nanomedicines.
dc.languageEnglish
dc.sourceDissertations & Theses @ SUNY Buffalo,ProQuest Dissertations & Theses Global
dc.subjectPure sciences
dc.subjectApplied sciences
dc.subjectBiodegradable polymers
dc.subjectClick chemistry
dc.subjectDoxorubicin
dc.subjectDrug delivery
dc.subjectFunctional polylactide
dc.subjectPaclitaxel
dc.subjectPolymer-drug conjugates
dc.titleBiodegradable Polymer-Drug Conjugates for Anticancer Drug Delivery
dc.typeDissertation/Thesis


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