Development of Drug-Polymer Conjugated Delivery Vehicles Functionalized with Stimuli-Responsive Drug Release for Cancer Therapy

Abstract

According to the development of advanced technologies including biotechnology, cancer treatments have been developed over decades, but a lot of people around the world still suffer from cancer, and cancer is still the leading cause of death worldwide. Since the discovery of anticancer drugs from natural products and beginning to be used in humans, various therapeutic agents have been discovered to treat cancer, and there have been many problems with various side effects. When the drugs are injected into the body, it affects not only cancer tissues but also other normal tissues, resulting in dizziness, hair loss, and even death. To solve the issues, a field called drug delivery system has been established. Drug delivery systems have been actively studied to effectively deliver drugs to the desired site to reduce side effects and increase drug efficacy, and numerous drug delivery systems have been suggested. In particular, according to the development of nanotechnology, nanomedicine utilizing a nanometer-sized material has been presented and has received a lot of attention due to the unique properties of nanomedicine. Nanomedicine can be applied to various diseases including cancer, providing high therapeutic effects, and it is still a research area with potential for development. Among nanomedicine, drug delivery carriers based on polymers have been attracting attention because of the greatest advantage of being able to precisely control physicochemical properties. However, there has been a problem that the polymeric delivery carrier becomes unstable and collapses in the process of delivery to the diseased site after systemic administration into the body. Therefore, a more stable and functional drug delivery system has been required to effectively treat cancer without side effects, and this study suggests the potential for high therapeutic effect by utilizing the advantages of drug-polymer conjugated delivery vehicles through the chemical bond between polymers and drugs, and then presents the possibility of scalable manufacturing for successful clinical translation. In Chapter I, current strategies in the delivery system for cancer therapy and polymeric delivery carrier as nanomedicine are described. Then, the potential of a drug-polymer conjugated delivery vehicle to solve problems of common polymeric delivery carriers was presented. In Chapter II, a prodrug-mediated polymer architecture as combinational drug and gene co-delivery carrier was demonstrated. Most of the previous cisplatin and siRNA co-delivery vehicles were focused on loading the two by utilizing hydrophobic interaction and charge interaction, respectively. Herein, a novel functional co-delivery carrier based on chemical bond was designed to minimize influence among therapeutic agents during the process of drug loading, and prevent leakage of the cargo during the process of drug delivery. The axial reaction site of Pt(IV), which is a prodrug form of cisplatin [Pt(II)], could be used for the conjugation of two molecules. Thus, low-molecular-weight polyethylenimines were conjugated utilizing the axial reaction site of Pt(IV), and polyethylene glycol (PEG) was subsequently conjugated to synthesize the prodrug-mediated polymer architecture (Pt-PA-PEG). The nanocomplex was formulated by charge interaction between the Pt-PA-PEG and siRNA. The nanocomplex showed reducing environment-sensitive dissociation of polymer architecture and the simultaneous release of active Pt(II) drug, resulting in faster gene release as well as higher drug efficacy. Despite simple prodrug-mediated polymer architecture, the Pt-PA-PEG with siRNA nanocomplex exhibited a significantly effective anti-cancer effect in vitro and in vivo. An enhanced therapeutic effect of nanocomplex can be explained by tumor targeting via EPR effect, improved drug and siRNA release in the intracellular reducing environment at the same time. Taken together, overall results remarkably present the potential of therapeutic effect of Pt-PA-PEG as a stable drug-polymer conjugated co-delivery carrier. In Chapter III, a facile strategy to enable solubilizing and loading of drugs utilizing coordinate interaction between drug and polymerized phenylboronic acid (PBA) was presented. To date, numerous polymeric carriers have been developed for effective drug delivery. Generally, those carriers have employed a self-assembly strategy based on hydrophobic interactions to load hydrophobic drugs. However, hydrophobic interactions for drug loading are insufficient for high drug loading, colloidal stability, and stimuli-responsive drug release. Thus, reversible bond between 1,3-dicarbonyl of curcumin (CUR), which is a natural product-derived drug, and PBA depending on pH was discovered, and hydrophilic polymer conjugated with PBA (pPBA) was synthesized to solubilize and load CUR via the coordinate interaction. The formation of nano-construct enabled high drug loading (up to 79.2%), uniform size, and colloidal stability, forming a hydrophobic core and hydrophilic shell. Moreover, pH-responsive drug release was achieved, which could enhance the anti-cancer effect. As a further study, it was confirmed that the strategy utilizing coordinate interaction could be applied to other drugs with 1,3-dicarbonyl (e.g., doxorubicin). Taken together, successful incorporation of the coordinate interaction into drug loading suggests a lot of potential for the stable and functional drug-polymer conjugated delivery carrier to enable high drug loading for facile and effective anticancer therapy. In Chapter IV, scalable manufacture of uniform and homogenous polymeric carriers was demonstrated. Nanomedicine-based drug delivery systems have led to many advances in translational research for decades. However, conventional bulk mixing methods, commonly used for the preparation of nanomedicine, have impeded successful clinical translations of nanomedicines due to the limited ability of scalable production of nanomedicines with high uniformity. Thus, nanomedicine was formulated through rapid convective mixing of two aqueous solutions of a hydrophilic polymer and an anti-cancer drug, doxorubicin (DOX), in the swirling microvortex reactor, which is a microfluidic chip device. Compared to conventional bulk-mixed nanomedicine, the microvortex-synthesized nanomedicine exhibited narrower size distributions and then enhanced anti-cancer effect in vitro and in vivo. High-speed on-chip nanomedicine synthesis will provide a potential for a scalable manufacturing platform for reliable clinical translations of nanomedicines. In conclusion, the functional drug-polymer conjugated delivery vehicles were successfully developed and exhibited excellent therapeutic effect in both the pro-drug mediated carrier as drug and gene co-delivery platform in Chapter II, and 1,3-dicarbonyl/PBA interaction-based delivery vehicle for chemo- and immunotherapy in Chapter III. Furthermore, scalable manufacture of the polymeric carrier was successfully presented in Chapter IV. This suggested the potential of effective cancer therapy via the drug-polymer conjugated delivery vehicle and its successful clinical translation.