Development of Polymerized Phenylboronic Acid-Based Delivery Platform for Cancer Therapy

Abstract

As modern technology continues to advance, factors such as an aging population and changes in lifestyle have led to a continuous increase in cancer. Efforts to overcome cancer are still ongoing. Cancer treatment is carried out through surgery, radiation therapy, Chemotherapy and immunotherapy However, surgery and radiation therapy often come with significant side effects and complications. Moreover, drug treatments can impact both cancerous and healthy tissues and organs, potentially resulting in adverse effects like hair loss, nausea, diarrhea, pneumonia, and in severe cases, the risk of mortality. Immunotherapy, known for having fewer side effects than traditional drug therapy, can still lead to immune-related adverse effects. This includes conditions such as pneumonitis, which arise from the activation of immune cells in healthy tissues. To minimize these side effects and enhance treatment efficacy, attention has turned to nanomedicine based on drug delivery systems. Drug delivery systems have garnered significant attention. Drug delivery systems refer to technologies designed to deliver the desired concentration of drugs to the disease area at a specific time. From early developments like transdermal patches in the 1960s, these systems have progressed to nanoparticles as advanced technology. Nanoparticles leverage unique optical, chemical, and physical properties at the nanoscale, allowing for high tumor accumulation, improved pharmacokinetics, and drug release in response to specific stimuli, among other advantages. Among various nanoparticles, polymer-based nanoparticles offer not only the advantages mentioned earlier but also exhibit high biocompatibility, controllable particle size, the potential for interaction with inorganic particles, and the customization of specific functions through the attachment of particular molecules. In this regard, I focused on the unique properties of a low molecular compound called phenylboronic acid. Phenylboronic acid has the capability to form phenyl boronic ester bonds by binding to specific functional groups like diols, salicylic acid, and dicarbonyl group and can disassociate under acidic conditions. Utilizing these characteristics in polymers has paved the way for creating drug delivery systems based on polymerized phenylboronic acid. This approach can improve the efficacy of current therapeutics and potentially address their existing limitations. Consequently, this research focused on developing a drug delivery system based on polymerized phenylboronic acid, aiming to overcome the shortcomings of current pharmaceuticals. In Chapter I, the importance of drug delivery system for effective cancer treatment is highlighted, with an explanation of polymeric nanoparticle for drug delivery system. Subsequently, polymerized phenlyboronic acid (pPBA)-based nanoparticle and their potential are briefly described. In Chapter II, the development of functional polymer-based antibody complexes to overcome the limitations of antibodies is described. A crucial limitation of the anti-PD- L1 antibody, a form of immune checkpoint inhibitor, is its tendency to bind to PD-L1 in normal tissues. This can result in immune-related adverse events (irAEs) and reduced accumulation in tumor tissues.To overcome this, a strategy was developed to directly link polymers to the antibody's protein structure. However, problems were identified, such as the employment of organic solvents in the binding process and a decrease in the affinity between antibodies and antigens caused by the indiscriminate binding of polymers. Therefore, this study developed antibody complexes by simply mixing antibodies with phenylboronic acid (PBA)-modified hydrophilic polymers (polymerized PBA, pPBA). The reversible binding between PBA and antibodies was responsive to the low acidity characteristic of tumor tissue, allowing the released antibodies to bind to PD-L1 in tumor tissue, contributing to anticancer therapy. Furthermore, due to the size of the antibody complex and the polymer protective shell, increased tumor accumulation, inhibition of antibody degradation by enzymes in the bloodstream, and extended circulation time were demonstrated. In summary, functional polymer-based antibody complexes with PBA have the potential as therapeutic agents, showing possibilities such as simple manufacturing, maintenance of antibody functionality through reversible binding, high tumor accumulation, and enhanced anticancer effects. They also hold promise for various antibodies with sugar proteins. In Chapter III, the development of functional polymer-based iron oxide nano complexes for overcoming the limitations of iron-based ferroptosis therapy is described. Ferroptosis is a form of cell death that hinges on the Fenton reaction, necessitating high concentrations of iron(II) ions within cells. Yet, the existence of ferritin, which sequesters iron ions, along with the unique intracellular reduction system in cancer cells, has impeded the effectiveness of therapies based on iron particle-induced ferroptosis. To address this, the functionality of ferritinophagy, which degrades ferritin, and sulfasalazine, which collapses the reduction system, were examined. By considering the potential binding of salicylic acid and PBA, this study aimed to develop iron oxide nano complexes carrying sulfasalazine. In this study, Polymerized phenylboronic acid was attached to the surface of ultrasmall iron oxide nanoparticles, accompanied by the modification of hydrophilic polymers. Then, iron oxide nano complexes carrying sulfasalazine were developed. The reversible binding between sulfasalazine and PBA was responsive to the low acidity of lysosomes in cancer cells, causing the release of sulfasalazine to degrade ferritin and collapse the reduction system, thereby enhancing the Fenton reaction of iron ions for a more potent anticancer effect. Furthermore, due to the hydrophobic drug-loading functionality of iron oxide complexes, the suppression of hemolysis in the bloodstream and enhanced ferroptosis-based anticancer therapy through simultaneous delivery of iron oxide and sulfasalazine were demonstrated. In conclusion, the ferroptosis-enhancing effect of iron oxide nano complexes, aided by ferritinophagy, overcomes the limitations of conventional iron particles, offering a new ferroptosis treatment method. In conclusion, the polymerized phenylboronic acid-based drug delivery platform, aimed at overcoming the limitations of existing drugs, has been successfully developed. In Chapter II, effective treatments with high tumor accumulation of antibody carriers based on simple manufacturing techniques were demonstrated. In Chapter III, the improved endocytosis-based anticancer effects of iron oxide complexes capable of simultaneous drug and iron delivery were elucidated. The materials and approaches used in this functional polymer-based drug delivery platform demonstrate significant scalability and potential for application not only in cancer treatment but also in addressing a range of other diseases.