This thesis describes the synthesis of amphiphilic block copolymer based on polyether in micelle formation and its drug delivery applications. Despite the growing interest of amphiphilic block copolymers for the application of micelle as an ideal drug delivery carrier, there still remain some challenges to overcome simultaneously such as stability, degradability and even loading efficiency of the micelle. We also demonstrated that the effect of structural difference of cyclic- and non-cyclic unit in the ability of micelles as a drug delivery carrier.
Considering the wide range of suitability and functionalities of TGE monomers and its copolymers, we envisioned that it may offer a number of opportunities to meet some drug delivery carrier requirements and expand the usefulness of block copolymers in the development of nanocarriers.
Introduction of Thesis
Introduction of polyglycerol
Due to these properties, PG can be synthesized in diverse architecture from linear to hyperbranched with various compositions, resulting in the useful design and application (Figure 1.1).10–12 Therefore, many efforts have been made to synthesize and apply PG as an alternative. fit. to PEG. Hyperbranched polyglycerol (hbPG) can be synthesized by anionic ring-opening polymerization with glycidol, which is latent AB2 monomer. Functionalized polyglycerol can be synthesized using a functionalized initiator, epoxide monomers or post-polymerization modifications (Figure 1.3).
Especially, new epoxide functional monomers have been actively developed to synthesize functional PG from various groups.
Introduction of polymeric micelle as a drug delivery carrier
Block copolymer micelles can be divided depending on the intermolecular forces, which drive the separation of the core block from the water. The preparation protocol, such as solvents, dialysis procedures and thermal treatment, will influence the micellization, size and shape of micelles. Thus, the choice of the method to prepare the micelles can be an alternative to control the size and shape of the micelles.
This state manipulation can be used to improve micelle drug loading efficiency and size. After intravenous injection, the environment of the micelles has changed significantly, such as dilutions, pH and salt changes, or the micelles may encounter many proteins and cells. Kinetic stability explains how the system changes over time and how quickly the micelles can disintegrate.
After intravenous administration, the concentration immediately becomes low and dissociation of the micelles can begin. In addition, kinetic stability can ensure that the encapsulated drug can be stored in the micelles after injection. The two micelles temporarily come together, the core of the micelles comes into contact and the chains can exchange.
Micelle morphologies such as spheres, rods, bilayers, inverse rods, and large spheres were controlled (Figure 1.9).60. The incorporation of titratable groups into the polymer can control the formation of micelles because the solubility of the polymer can change upon protonation. In addition to the above examples, there are many properties that can be used in targeted drug delivery.
The light sensitivity of micelles is also attractive for controlling the release of loaded therapeutic agents.
The Power of the Ring: pH-Responsive Hydrophobic Epoxide Monomer for
Introduction
The self-assembly of amphiphilic molecules has generated considerable interest due to their potentially wide-ranging applications from detergents, templates, and catalysts to drug delivery. 1–3 Polymeric amphiphiles, such as amphiphilic block copolymers, have attracted particular attention due to the high physical and chemical flexibility in each block from the corresponding monomer, which in turn allows tuning the stability and functionality of the resulting self-assembled nanostructures. Among these, self-assembled polymeric micelles in aqueous solutions have been exploited as ideal carriers for drug delivery, some of which have been successfully advanced in clinical settings, such as Pluronics, Paclical, and Genexol-PM.4,5. In addition to the important stabilizing role of the hydrophilic block, the self-assembly of polymeric micelles depends on the choice of the hydrophobic block.
In particular, the properties of the hydrophobic blocks determine the stability, degradability and loading efficiency of the formed micelles. For example, polymeric micelles often undergo dynamic dissolution at high dilution and exposure to changes in pH and salt concentration after systemic injection into the bloodstream.6 Accordingly, active research has been conducted to adjust many synthetic parameters that affect micelle stability, including crystallinity. ,7,8 stereoregularity,9 molecular weight and substituents10–13 on the hydrophobic block. Together with the development of micelles that respond to external stimuli such as pH, light, redox and temperature,14–20 they investigated the control of the release profile of the internal payload by introducing new structures in the hydrophobic block.21–25 Thus, we can conclude that the hydrophobic block in amphiphilic block copolymers plays a key role in modulating the critical parameters of polymeric micelles.
For biomedical applications of micelles, poly(ethylene glycol) (PEG) is most often used as a hydrophilic block to ensure stability in water due to its high solubility, biocompatibility, low immunogenicity, and stealth effect.26,27 As a alternative to PEG, its polyether analog, polyglycerol (PG) has attracted attention due to its biocompatibility and other advantages over PEG, such as controllable structure, functional group, and easy synthesis.28–34 To date, monomers of different epoxies have been developed with physico-chemical tuners. properties and functionalities. Here, we report the design and synthesis of a new epoxide monomer, tetrahydropyranyl glycidyl ether (TGE) and a series of its homopolymers (PTGE) and amphiphilic polymers, poly(ethylene glycol)-block-poly(tetrahydropyranyl glycidyl ether) (PEG) -b-PTGE), using the TGE block as a pH-responsive hydrophobic block (Figure 2.1 and Table 2.1). The molecular design of TGE meets all the required design principles and addresses the challenges encountered in drug delivery systems to achieve highly tunable polymeric micelles with high stability, loading capacity, convenient release and degradability.
Unlike its acyclic analog, 1-ethoxyethyl glycidyl ether (EEGE), reported in the literature,40-45 the TGE monomer with a cyclic pendant group provides superior stability, high loading capacity, and controllable degradation in polymeric micelles. The superior biocompatibility combined with the high biological stability of our system is expected to lead to the development of a versatile platform for smart drug delivery systems.
Experimental Section
Results and Discussion
Moreover, the GPC results of PTGE homopolymers showed monomodal distribution and narrow polydispersity index (Mw/Mn using polystyrene as a standard in THF (Table 2.1 and Figure 2.13). To confirm the presence of the initiator and the successful incorporation of TGE into PTGE homopolymn MALDI-ToF spectrometry was performed. The I3/I1 ratio is plotted as a function of the respective polymer concentrations (Figure 2.4; see Figure 2.18 for collected spectra).
The CMC values of PEG-b-PTGE decreased with increasing the number of hydrophobic blocks. It is worth noting that the CMC values for PEG-b-PTGE are about 10 times lower than those of the PEG-b-PEEGE copolymers. The core size of the micelles of PEG-b-PTGE decreased with increasing length of the hydrophobic PTGE block.
Encouraged by the FRET data on their encapsulation stability, we further investigated the stability of the prepared micelles inside cells. After incubation for 6 hours, one could even observe some noticeable differences between the micelles of the T series. After lowering the pH, the intensity of the fluorescence excitation band shifted and decreased with time (Figure 2.27).
The change in the excitation band is shown in Figure 2.8, which shows the ratio of fluorescence intensity at 339 and 332 nm (I3/I1) as a function of time. E3 micelles with a longer hydrophobic block showed rapid release of encapsulated pyrene compared to E2 micelles, but the release kinetics were still faster than those of the T-series micelles (Figure 2.8g). The structures of the EEGE monomer and the PEG-b-PEEGE block copolymer are presented for comparison.
The spacing between the signals corresponds to the mass of the TGE monomer (158.09 g/mol) in the homopolymer.
Conclusion
제가 학업을 마칠 때까지 항상 응원해주신 분들께 감사의 말씀을 전하고 싶습니다. 실험적인 지도로 올바른 길을 갈 수 있도록 많은 응원과 격려 부탁드립니다. 그리고 바쁜 일정에도 불구하고 석사학위 심사를 맡아주시고 많은 친절한 말씀을 해주신 권태혁 교수님, 유자형 교수님에게도 감사드립니다.
연구실에서 기쁨과 어려움을 함께 나누었던 KBS 식구들에게 감사의 말씀을 전하고 싶습니다. 선배님들 덕분에 많이 배우고 성장할 수 있었습니다. 항상 웃으면서 에너지를 주고, 적극적이고 배우려고 하는 그런 사람이 되고 싶어요.
그리고 각자의 길을 걷고 있는 졸업생 선배님들께도 감사의 말씀을 전하고 싶습니다. 조언을 해준 은용이, 항상 친절하게 대해준 태민이, 고분자 합성과 미셀 연구를 가르쳐준 병호에게 감사 인사를 전하고 싶습니다. 무엇보다 석사과정을 함께 마친 동기들에게 감사드립니다.
이러한 동기들 덕분에 비록 제가 아주 어리고 미성숙했음에도 불구하고 석사 과정을 성공적으로 마칠 수 있었습니다. 다시 한번 제가 학위를 마칠 수 있도록 도와주신 많은 분들께 감사의 말씀을 전하고 싶습니다.
