S-Space College of Engineering/Engineering Practice School (공과대학/대학원) Dept. of Material Science and Engineering (재료공학부) Theses (Ph.D. / Sc.D._재료공학부)
Preparation and characterization of the polymeric nanoparticles for cancer diagnosis and therapy
암진단 및 치료를 위한 고분자 나노입자의 제조와 특성화 연구
- 공과대학 재료공학부
- Issue Date
- 서울대학교 대학원
- polymeric nanoparticle; π-conjugated polymer; polysaccharide; PEG; drug delivery system; photoswitching; optical imaging; photodynamic therapy; cancer diagnosis; cancer therapy
- 학위논문 (박사)-- 서울대학교 대학원 : 재료공학부, 2014. 2. 박종래.
- Optical 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.