Design of ‘smart’ molecular systems programmed for the delivery of anticancer drugs
In recent years, the design of novel antitumor agents allowing the destruction of malignant cells while sparing healthy tissues has become one of the major challenges in medicinal chemistry. Within this framework, our research group is specialized in the design of ‘smart’ molecular systems programmed to allow: (1) the transport in the body of potent anticancer agents in an innocuous manner toward safe tissues, (2) the efficient recognition
Our research group is specialized in the design of ‘smart’ programmed molecular systems
of malignant specificities located either at the surface of cancer cells or in the tumor microenvironment and (3) the controlled release of the parent drug exclusively at the tumor site. To achieve such a complex task in an autonomous manner, these drug delivery systems are composed of four distinct units including a potent anticancer drug, an enzymatic trigger and a targeting moiety articulated around a self-immolative linker. The originality of this technology relies on the structure of the central linker that includes three different chemical functionalities suitable for the successive introduction of each part of the device. This allows the on-demand synthesis of a wide variety of drug-trigger-targeting device combinations and therefore the custom design of the most appropriate assembly for the treatment of a given malignancy, based on its unique tumor-associated specificities.
- An Example of our ‘smart’ drug delivery systems programmed for the selective recognition of tumor-associated receptors
This targeting assembly is programmed to be selectively activated by the b-galactosidase present in lysosomal compartment of cancer cells expressing the folate receptor. Thus, recognition of the membrane receptor by the targeting ligand (step 1) triggers the receptor-mediated endocytosis of the whole device (step 2) that is followed by the intracellular enzyme-catalyzed mechanism of drug release (step 3). Since b-galactosidase is present in lysosomes of both healthy and malignant cells, this highly specific internalization process allows the prodrug activation to occur exclusively inside receptor-positive tumor cells thereby avoiding unselective drug release in non-malignant tissues. However, as the prodrug activation is catalytic, the b-galactosidase confined in the targeted cells triggers the liberation of sufficient drug quantities to induce the death of both receptor-positive and surrounding receptor-negative tumor cells (step 4).
- An Example of our programmed molecular systems designed to target the specificities of the tumor microenvironment
This compound includes a glucuronide trigger, the potent doxorubicin and a self-immolative linker bearing a poly(ethylene glycol) side chain ended by a maleimide functional group. After intravenous administration (step 1), the in situ binding of the drug delivery system to the thiol at the cysteine 34 position of plasmatic albumin via Michael addition produces the corresponding macromolecular drug carrier (step 2). Once in targeted tumor tissues, b-glucuronidase-catalysed cleavage of the glycosidic bond triggers the release of doxorubicin in a stringently controlled fashion, thereby restoring its cytotoxicity (step 3).
Design of mechanically interlocked molecular systems programmed to operate autonomously in biological environments
Over the past two decades, the design of functional interlocked molecules programmed to perform specific tasks in response to an external stimulus has received considerable attention. In particular, much effort has been devoted to control the dynamic behavior of mechanically interlocked architectures with the ultimate goal to develop molecular motors and machines for nanotechnological applications. In contrast, the biological properties of functional interlocked molecules have remained largely overlooked. Therefore, we have been interested by the development of mechanically interlocked molecular systems programmed to operate autonomously in biological environments.
- A Mechanically Interlocked Molecular System Programmed for the Delivery of an Anticancer Drug
We recently developed an enzyme-sensitive -rotaxane designed to release a potent anticancer drug within tumor cells. The molecular device includes a protective ring that prevents the premature liberation of the drug in plasma. However, once located inside cancer cells the -rotaxane leads to the release of the drug through the controlled disassembly of the mechanically interlocked components, in response to a determined sequence of two distinct enzymatic activations.
Figure 1. A) The principle of the intracellular drug delivery with functional interlocked system 1. When in the blood stream, rotaxane 1 does not release the drug due to the presence of the protective ring that prevents hydrolysis of the esterase-sensitive moiety. Once inside cancer cells, the process of drug release is initiated by the activation of the galactoside trigger by intracellular b-galactosidase (step A). This is followed by a spontaneous sequence of reactions that leads to opening of the protective ring and the concomitant disassembly of the interlocked architecture (steps B and C). As a result the ester linkage of the thread becomes accessible to intracellular esterases that induce the liberation of the active drug (step D). B) Structure of rotaxane 1 and the paclitaxel release mechanism.
- A rotaxane-based propeptide
In collaboration with Prof. David A. Leigh and Dr. V. Aucagne, we designed a rotaxane in which a macrocycle protects an extended pentapeptide thread from degradation by different types of peptidases and the cocktail of enzymes present in human plasma. The glycosidase-catalyzed cleavage of the carbohydrate unit in a stopper of the rotaxane triggers the release of the bioactive parent peptide through a self-immolative mechanism.