Linkers for bioconjugation
Cancer is a heterogeneous disease that represents one of the principal causes of mortality in developed countries. Due to the social and economic implications of this pathology, tremendous efforts have been making over the past decades to improve available therapeutic options to tackle this illness....
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/399915 |
| Acceso en línea: | http://hdl.handle.net/10803/399915 |
| Access Level: | acceso abierto |
| Palabra clave: | Biomolècules Biomoléculas Biomolecules Bioquímica Biochemistry Materials biomèdics Materiales biomédicos Biomedical materials Ciències Experimentals i Matemàtiques 547 |
| Sumario: | Cancer is a heterogeneous disease that represents one of the principal causes of mortality in developed countries. Due to the social and economic implications of this pathology, tremendous efforts have been making over the past decades to improve available therapeutic options to tackle this illness. Although a large number of potent chemotherapeutic agents have been identified and successfully used in clinical practice, the development of new anticancer chemotherapeutic drugs with higher antitumor efficacy and less toxicity remains as a research challenge. Current advances in the mechanistic understanding of the molecular drivers of malignancy have led to many anticancer drugs, which are targeted directly at the cancerous cells and not the neighbouring healthy cells. Thus, in order to enhance the efficacy of existing anticancer agents, several drug delivery approaches have been developed. Appropriately, ADCs strategy consists on bind determinate cell-killing drug to a monoclonal antibody (mAb) through a specific linker. Due to their high-binding specificity for tumor-specific antigens, mAb can be used as vehicles to target cell- killing payloads to tumor cells. Accordingly, two kinds of linkers are suitable to attach the payload to the antibody. On one hand, non-cleavable linkers afford and stable binding between the drug and the antibody, and alternatively, the drug could be released in the proximity or even inside of affected cells using cleavable linkers. Based on the potential of ADCs as prodrugs, our main goal is develop linkers, which could promote the drug release close to the affected tumor cells. Taking into account that connection between the antibody and the cytotoxic agent has significant effects on the selectivity, pharmacokinetics and therapeutic index of the ADC an efficient binding is needed. Therefore, the properties of a successful linker can be split up into different modules that have been combined to form an effective bridge between the cytotoxic payload and the carrier antibody. In the present thesis, we focus on the development of new linkers for bioconjugation and more specifically for Antibody–Drug conjugates (ADCs). With this purpose in mind, a conscious design of the linkers for ADCs has to be done. In the present thesis, different cleavable (Chapter 1) and non-cleavable (Chapter 2) linkers are studied and it will be explained in detail along the thesis. As a consequence, the design has to be focused on linkers stables in systemic circulation. Additionally, cleavable linkers should be unstable in tumor cells environment, such as high concentration of glutathione, highest acidic concentration, and enzymatic cleavage, among others as above-mentioned. These conditions should allow, chemically or enzymatically, the release of the drug from the carrier (antibody- linker). On one hand, the systems studied in chapter I involve N-alkylated dialkylglycines and the tetrahydropyran moiety as cleavable Linkers. On the other hand in chapter II, the mesitylene ring and perfluoroarylated compounds were studied as non-cleavable linkers for bioconjugation. The present thesis include and extensive study regarding both cleavable and non-cleavable linker. Particularly, the preparation and chemical modification of the handles in order to test and optimize the bioconjugation step. Also an interesting study was carried out in order to determine how the bioconjugation step affect to the macromolecular entities. Specifically we focus on the conjugation to antibodies and how the covalent binding of the studied linkers affect to the antigen- antibody bind affinity. |
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