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Preparation and characterization of the polymeric nanoparticles for cancer diagnosis and therapy : 암진단 및 치료를 위한 고분자 나노입자의 제조와 특성화 연구

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dc.contributor.advisor박종래-
dc.contributor.author정근수-
dc.date.accessioned2017-07-13T05:40:31Z-
dc.date.available2017-07-13T05:40:31Z-
dc.date.issued2014-02-
dc.identifier.other000000018126-
dc.identifier.urihttps://hdl.handle.net/10371/117940-
dc.description학위논문 (박사)-- 서울대학교 대학원 : 재료공학부, 2014. 2. 박종래.-
dc.description.abstractOptical imaging and photodynamic therapy (PDT) are emerging modalities for cancer diagnosis and therapy. Polymeric nanoparticles (PNPs) have been extensively used as bioimaging probes or PDT drug carriers since PNPs in vivo utility was well-demonstrated in nanoscopic size-motivated tumor targeting efficiency, and as excellent biocompatibility. However, the clinical use of PNPs is limited by some inherent obstacles in both optical imaging and PDT. In particular, the high resolution of PNP-mediated optical imaging can be hindered by photon-limiting interferences such as scattering, absorption, and autofluorescence occurring in biological tissues. PNPs aimed to deliver the PDT drugs are mainly used for small-animal studies and are not generally transferred into the clinic because of the immunogenic response from the body and the inconvenience of further medication for clinical purposes. Therefore, a new type of PNPs is required to develop practical diagnostic/therapeutic agents.
In this thesis, two different types of PNPs are suggested as alternatives to high performance diagnostic/therapeutic agents for a clinic. The first type is photoswitchable PNPs based on the nanocomposite of π-conjugated polymer and photochromophore, which provides high resolution of bioimaging through bistable photoswitching of near-infared (NIR) fluorescence. The second type is PNPs of sugar-based polymers and their amphiphilic derivatives, providing high tumor targeting efficiency and high therapeutic efficacy by taking the virtues of its nanosopic size, biocompatibility, antifouling property, and loading capability of hydrophobic drugs. The aims of this study are to introduce the essential requirements of PNPs through a theoretical approach, design a new type of PNPs of π-conjugated polymer or sugar-based polymer as diagnostic/therapeutic agents, and analyze the biological performance of each PNP used in cancer diagnosis and therapy.
Part I provides a general introduction of PNP-based cancer diagnostic/therapeutic agents regarding the essential requirements for a new type of PNPs. Optical imaging is summarized with an imaging mechanism, multiple performance parameters, and inherent obstacles. Photodynamic therapy is also summarized with a photo-triggered therapy mechanism and performance parameters. The main challenges and issues of the PNPs for the advanced optical imaging/photodynamic therapy are indicated by the state of the art analysis. Throughout the analysis, the aim and scope of this research contains a theoretical study and preparation, and characterization of new PNPs as the diagnostic/therapeutic agents are introduced.
Part II discusses a new type of photoswitchable PNPs based on binary nanocomposite of π-conjugated polymer and photochromophore. The composite PNPs showed bright fluorescence in the NIR region and its high-contrast photoswitching through the efficient intraparticle fluorescence energy transfer (FRET) as well as tiny colloidal size PNPs for in vivo delivery. Consequently, the composite PNPs can allow the dynamic signal to be distinguished from the static autofluorescence of biological tissues to improve the capability of signal identification. By taking the merit of photoswitching, the composite PNPs can be suggested as a new strategy to overcome the inherent limitation of optical imaging.
Part III presents synthesis and biological use of new sugar-based polymers, poly(oxyethylene galactaramide)s (PEGAs), in order to take the combined merits of PEG and polysaccharides such as biocompatibility, antifouling property, and pendant functional groups. PEGAs with hydrogen bond-mediated self-assembly into PNPs and PEGA nanoassemblies (PEGA PNPs) exhibited high tumor targeting efficiency from the virtues of the size-motivated EPR effect and the antifouling effect. PEGA PNPs hold great potential for practical biomedical applications including optical imaging, which is worthy of further exploitation for payload carriage and immunogenicity evaluation.
Part IV discusses amphiphilic derivatives of PEGAs synthesized through conjugation of bile/fatty acids to validate the in vivo utility of PEGAs for clinical use, and especially, PDT. PEGA amphiphilies were designed as sugar-based polymeric biosurfactants (SPBs), and self-assembled into PNPs that have a hydrophobic core and a hydrophilic/antifouling exterior. PNPs of PEGA amphiphile exhibited stable loading capability of hydrophobic drugs (or dyes) and the attractive features of PEGAs. Consequently, hydrophobic dyes (rubrene or IR780 iodide)-entrapped PNPs showed high in vitro/vivo tumor selectivity with tumor cells and tumor-bearing mice. Furthermore, the hydrophobic PDT drug (pyropheophorbide-a, PPa)-entrapped PNPs exhibited high efficacy of in vivo PDT with tumor-bearing mice. The improved biological performances are summarized in Part V and clearly show the potentials of new PNPs as alternatives for an advanced cancer diagnostic/therapeutic agents.		-
dc.description.tableofcontentsPart I Basic research on polymeric nanoparticles for cancer diagnosis and therapy

Chapter 1 Introduction......................................................................................2
1.1 General introduction to polymeric nanoparticles for cancer diagnosis and therapy..............................................................................................................................2
1.1.1 Polymeric nanoparticles for cancer diagnosis.................................................4
1.1.1.1 Optical imaging....................................................................................6
1.1.1.2 Magnetic resonance (MR) imaging......................................................9
1.1.1.3 Ultrasound (US) imaging.....................................................................9
1.1.1.4 Nuclear imaging.................................................................................11
1.1.2 Polymeric nanoparticles for cancer therapy..................................................12
1.1.2.1 Chemotherapy....................................................................................13
1.1.2.2 Gene therapy.......................................................................................15
1.1.2.3 Photodynamic therapy (PDT)............................................................17
1.2 Conventional polymeric nanoparticles for cancer diagnosis and therapy................19
1.2.1 Natural polymer based nanoparticles............................................................19
1.2.2 Synthetic polymer based nanoparticles.........................................................22
1.3 Main challenges and issues related to polymeric nanoparticles for cancer diagnosis and therapy.....................................................................................................................23
1.3.1 Polymeric nanoparticles for tumor targeting and delivery............................23
1.3.1.1 Angiogenesis in cancer.......................................................................23
1.3.1.2 Passive tumor targeting......................................................................24
1.3.1.3 Active tumor targeting........................................................................25
1.3.2 Cancer diagnosis: Optical imaging...............................................................27
1.3.1.1 Conventional approaches for polymeric imaging probes..................27
1.3.1.2 Novel approaches for high resolution imaging..................................30
1.3.3 Cancer therapy: Photodynamic therapy........................................................32
1.3.2.1 Conventional approaches for polymeric drug carriers.......................32
1.3.2.2 Novel approaches for high therapeutic efficacy.................................34
1.4 Aim and scope of this research................................................................................37
1.4.1 Preparation and characterization of π-conjugated polymer nanoparticles as photoswitchable nanoprobes for high resolution imaging.....................................37
1.4.2 Preparation and characterization of sugar-based polymeric nanocarriers for cancer diagnosis and therapy..................................................................................38
1.5 References................................................................................................................39




Part II π-Conjugated polymer nanoparticles for high resolution bioimaging

Chapter 2 π-Conjugated polymer/photochromophore binary nanococktails: bistable photoswitching of near-infrared fluorescence for in vivo imaging..............................................................................................................46
2.1 Introduction..............................................................................................................46
2.2 Experimental............................................................................................................49
2.2.1 Materials and instrumentation.......................................................................49
2.2.2 Preparation of nanococktails (NCs)..............................................................49
2.2.3 Photoswitching experiment...........................................................................52
2.2.4 In vitro photoswitching in an in vivo-mimicking model...............................52
2.2.5 In vivo/ex vivo photoswitching......................................................................52
2.2.6 In vivo toxicity study.....................................................................................62
2.3 Results and discussion.............................................................................................54
2.3.1 Preparation of nanococktails (NCs) as photoswitchable nanoprobes...........54
2.3.2 Photoswitching behavior of NCs..................................................................57
2.3.3 In vitro photoswitching of NCs in an in vivo-mimicking model...................67
2.3.4 In vivo photoswitching of NCs in a mouse model........................................69
2.4 Conclusions..............................................................................................................80
2.5 References................................................................................................................81
Part III Sugar-based polymeric nanoparticles for cancer diagnosis

Chapter 3 Poly(oxyethylene sugaramide)s: unprecedented multihydroxyl building blocks for tumor-homing nanoassembly.........................................85
3.1 Introduction..............................................................................................................85
3.2 Experimental............................................................................................................89
3.2.1 Materials and instrumentation.......................................................................89
3.2.2 Synthesis of dimethyl galactarate (DMGA)..................................................90
3.2.3 Synthesis of poly(oxyethylene galactaramide)s (PEGAs)............................90
3.2.4 Conjugation of dyes to PEGA2 and mPEG-amine.......................................92
3.2.5 Conjugation of folic acid (FA) to PEGA2.....................................................93
3.2.6 Cellular Uptake Behavior of PEGA2 Nanoparticles: Cellular fluorescence imaging...................................................................................................................94
3.2.7 Cell attachment onto the surface of 96-well plate.........................................94
3.2.8 In vivo/ex vivo near-infrared fluorescence imaging......................................95
3.3 Results and discussion.............................................................................................96
3.3.1 Synthesis of poly(oxyethylene galactaramide)s (PEGAs) as hydrogen bondable building blocks.......................................................................................96
3.3.2 Colloidal behavior of PEGA nanoassembly in water..................................101
3.3.3 In vitro antifouling characteristics of PEGA nanoassembly........................106
3.3.4 In vivo antifouling characteristics and tumor homing behaviour of PEGA nanoassembly........................................................................................................112
3.4 Conclusions............................................................................................................119
3.5 References..............................................................................................................120

Part IV Sugar-based polymeric nanoparticles for cancer therapy

Chapter 4 Amphiphilic derivatives of poly(oxythylene sugaramide)s: Sugar-based polymeric biosurfactants as drug carriers with high tumor-homing efficiency........................................................................................... 124
4.1 Introduction............................................................................................................124
4.2 Experimental..........................................................................................................127
4.2.1 Materials and instrumentation.....................................................................127
4.2.2 Synthesis of sugar-based polymeric biosurfactants (SPBs): bile/fatty acid (BA/FA) conjugated PEGA2 ................................................................................127
4.2.3 Determination of critical micelle concentration (CMC) of SPBs...............131
4.2.4 Fluorescence labeling of SPBs....................................................................131
4.2.5 Preparation of hydrophobic dye (or drug)-loaded SPB nanoparticles (NPs).....................................................................................................................131
4.2.6 In vitro fluorescence imaging with tumor cells...........................................132
4.2.7 In vivo fluorescence imaging with tumor-bearing mice..............................132
4.2.8 Photo-induced toxicity evaluation with apoptosis imaging with tumor cells.......................................................................................................................133
4.2.9 Photodynamic therapy with tumor-bearing mice........................................133
4.3 Results and discussion ...........................................................................................135
4.3.1 Synthesis of SPBs.......................................................................................135
4.3. Self-assembly of SPBs into NPs...................................................................140
4.3.3 Intracellular delivery of hydrophobic dye-loaded SPB NPs.......................142
4.3.4 In/ex vivo biodistribution of hydrophobic dye-loaded SPB NPs in tumor-bearing mice.........................................................................................................144
4.3.5 Preparation of pyropheophorbide-a (PPa)-loaded SPB NPs as a nano photosensitizer......................................................................................................150
4.3.6 Photo-induced toxicity of PPa-loaded SPB NPs against tumor cells..........157
4.3.7 Photodynamic therapy of PPa-loaded SPB NPs with tumor-bearing mice ......................................................................................................................161
4.4 Conclusions............................................................................................................164
4.5 References..............................................................................................................165

Part V Conclusions

Chapter 5 Conclusive remarks and the outlook ..........................................169		-
dc.formatapplication/pdf-
dc.format.extent9073604 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 대학원-
dc.subjectpolymeric nanoparticle-
dc.subjectπ-conjugated polymer-
dc.subjectpolysaccharide-
dc.subjectPEG-
dc.subjectdrug delivery system-
dc.subjectphotoswitching-
dc.subjectoptical imaging-
dc.subjectphotodynamic therapy-
dc.subjectcancer diagnosis-
dc.subjectcancer therapy-
dc.subject.ddc620-
dc.titlePreparation and characterization of the polymeric nanoparticles for cancer diagnosis and therapy-
dc.title.alternative암진단 및 치료를 위한 고분자 나노입자의 제조와 특성화 연구-
dc.typeThesis-
dc.contributor.AlternativeAuthorKeunsoo Jeong-
dc.description.degreeDoctor-
dc.citation.pagesxxiv, 173-
dc.contributor.affiliation공과대학 재료공학부-
dc.date.awarded2014-02-
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