Synthetic molecular nanodevices for selective peptide-based therapy
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During this thesis we tried to design, synthesise and analyse some novel devices for the selective delivery of peptides. These systems are based on the enzyme-activated anticancer prodrugs developed by Prof. Gesson in Poitiers and the peptide rotaxanes developed by Prof. Leigh in Edinburgh. The innovative rotaxanes we constructed are devised to protect and selectively release a peptide in response to an enzyme-specific stimulus for the targeted therapy of cancer. In Chapter 1 we tried to expose the main synthetic strategies aimed at improving the stability and permeation features of biologically active peptides. We examined some prodrug approaches and particularly the tumour-activated prodrugs (TAPs), largely investigated for use in anticancer chemotherapy. TAPs are generally three-part molecules composed of trigger, spacer and effector units. We also presented the original methodology developed by Prof. Leigh, namely the hydrogen bond-directed assembly of peptide rotaxanes, to protect a peptide thread from external environment. Finally we presented our project which consists of a combination of the peptide prodrug and rotaxane approaches. Therefore, based on the knowledge of both research groups we tried in Chapter 2 to develop some model systems in order to study the influence of the rotaxane architecture upon prodrug molecules. The first step towards such rotaxane-based peptide prodrugs relied on the efficient design of a spacer which has to be bulky enough to work as a stopper for the macrocycle. Much of the work presented in this chapter is based on the design and synthesis of such self-immolative units. We then explored the response of our model rotaxanes under the action of the activating enzyme. After this detailed study, in Chapter 3 we applied our concept to the biologically active peptide Met-enkephalin. In this chapter we presented a comparison between a rotaxane prodrug of Met-enkephalin and its non-interlocked derivative. Thus both compounds were successfully synthesised and evaluated to release the free peptide after enzymatic activation. The protective effect of encapsulating the peptide within a rotaxane assembly was also studied in human plasma and with different proteases. Finally, in Chapter 4, we introduced the construction of a rotaxane-based molecular machine programmed to synthesise a short peptide unit from the amino acids carried on its thread. We synthesised with success a one-station model rotaxane to study the catalyst effect of the macrocycle. Unfortunately this model machine proved not to work and current research is still ongoing to achieve such a synthetic device.