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암특이적 약물 전달을 위한 PEG가 도입된 자극감응형 나노입자
- Alternative Title
- Nguyen Dai Hai
- Author(s)
- Dai Hai Nguyen
- Alternative Author(s)
- Nguyen Dai Hai
- Advisor
- 박기동
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2013-08
- Language
- eng
- Alternative Abstract
- Cancer is one of the leading causes of death worldwide and chemotherapy is a major therapeutic approach for the treatment which may be used alone or combined with other forms of therapy. However, conventional chemotherapy has the potential to harm healthy cells in addition to tumor cells. Using targeted nanoparticles to deliver chemotherapeutic agents in cancer therapy offers many advantages to improve drug delivery and to overcome many problems associated with conventional chemotherapy. This work covers the general areas of responsive nanocarriers and encompassed methods of fabricating nanocarrier-based drug delivery systems for controlled and targeted therapeutic application. Chapter 1 provides general information of cancer and cancer treatment strategies. The recently cancer treatment based on nanocarrier were introduced. In addition, the special features as well as requirements of nanoparticles for targeted drug delivery were presented. This chapter describes overall objectives of this study with the current status of stimuli-responsive self-assembled nanocarriers for cancer chemotherapy. In chapter 2, self-assembled nanogels based on reducible heparin-Pluronic copolymer was developed for intracellular protein delivery. Heparin was conjugated with cystamine and the terminal hydroxyl groups of Pluronic were activated with the VS group, followed by coupling of VS groups of Pluronic with cystamine of heparin. The chemical structure, heparin content and VS group content of the resulting product were determined by 1H NMR, FT-IR, toluidine blue assay and Ellman's method. The HP conjugate showed a critical micelle concentration of approximately 129.35 mg L−1, a spherical shape and the mean diameter of 115.7 nm, which were measured by AFM and DLS. The release test demonstrated that HP nanogels were rapidly degraded when treated with glutathione. Cytotoxicity results showed a higher viability of drug-free HP nanogel than that of drug-loaded one. Cyclo(Arg–Gly–Asp–D-Phe–Cys) (cRGDfC) peptide was efficiently conjugated to VS groups of HP nanogels and exhibited higher cellular uptake than unmodified nanogels. In chapter 3, stimuli–responsive Pluronic micelles is developed for targeting cancer chemotherapy. In particularly, the role of crosslinking disulfide bond and hydrazone bond in arrangement of environmental stimuli including redox and pH were discussed. Specifically, acrylic acid was grafted onto PPO blocks of Pluronic by dispersion/emulsion polymerization and used to introduce thiol groups as well as hydrazine groups. DOX was conjugated to the hydrazone groups to achieve the pH-triggered release. The micelles were crosslinked by the formation of disulfide bonds due to the presence of thiol groups on the polymer backbones. The physico-chemical properties of the micelles were characterized. In vitro release studies were performed to investigate pH-dependent release of DOX from the Pluronic micelles. FA was conjugated to the Pluronic polymer for targeting cancer cell. FA conjugated micelles were compared with the micelles without FA using confocal laser scanning microscopy (CLSM) and flow cytometry. The Pluronic micelles functionalized with FA targeting ligand on the surface showed the enhanced cellular uptake. In chapter 4, self-assembled magnetic nanoparticles (SAMNs) were fabricated from β-cyclodextrins functionalized superparamagnetic iron oxide (SPIO@CD), paclitaxel (PTX), adamantylamine-poly(ethylene glycol)-vinyl sulfone (ADA-PEG-VS), and c(RGDfC) peptide for integrated cancer cell-targeted drug delivery. In this approach, PTX and ADA-PEG-VS enabled the host-guest inclusion with SPIO@CD to form PEG-ADA:SPIO@CD:PTX SAMNs. Furthermore, cyclo(Arg-Gly-Asp-d-Phe-Cys) (c(RGDfC)) peptide, a targeting ligand, could conjugate onto the VS groups of the PEG arms of SAMNs. The architecture of SAMNs were characterized FT-IR, TEM, and thermo gravimetric analysis (TGA), which confirmed that PEG, CD have been effectively functionalized on the surface of SPIO nanoparticles. SAMNs were enabling to be controlled over the sizes, surface chemistry, payloads of supramolecular nanoparticle vector. The sizes, drug entrapment efficiency (DEE), drug loading efficiency (DLE), and SIPO encapsulation of SAMNs could turn by changing its components. In vitro PTX release profile from SAMNs was highly ADA response. Cumulative releases of PTX from SAMNs were 44.1% and 9.6% with and without ADA treatment after 120 h. Most importantly, the analyses of vibration sample magnetometer (VSM) verified that the magnetic property of SAMNs was increased under the external magnetic field. c(RGDfC)-conjugated SPIO nanocarriers exhibited a higher level of cellular uptake than unmodified ones in vitro according to flow cytometry and confocal laser scanning microscopy (CLSM).
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- Graduate School of Ajou University > Department of Molecular Science and Technology > 3. Theses(Master)
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