The use of chemotherapeutical drugs is the most extended approach for cancer treatment due to their power to destroy cancer cells. However, most chemotherapists have the counterpart of an inherent toxicity for the rest of the body. The therapeutic strategies based on Bioorthogonal Chemistry aim to substantially reducing or even eliminating the undesired side effects of powerful pharmaceuticals by the bioorthogonal activation of the non-toxic prodrugs at the action place. The most extended technology for this purpose is based on the implantation at the action place of micro-devices consisting in micro-particles made of an artificial biocompatible polymer containing palladium or gold nanoparticles. Next, a bioorthogonal prodrug is introduced in the body not causing any effect until it reaches the bioorthogonal devices, where the metal nanoparticles catalyze the uncaging of the prodrug into the drug exclusively where the implants are. Although the therapeutic potential of focal bioorthogonally-controlled chemotherapy is vast, there are some issues associated to the catalytical devices that need to be addressed before translating this technology to the clinic. The matrix, although biocompatible, is not biodegradable, which prevents removal of the implant after therapy. Additionally, the direct contact between the metal’s surface and the proteins from the biological milieu, causes the nanoparticles’ coating reducing their catalytical capacity progressively. The research program of BOOMCHEMBAGS originated to fill this gap in the state-of-the-art by developing biocompatible and biodegradable devices designed to protect the surface of bioorthogonal catalyst based on metallic nanoparticles from direct contact with proteins from the biological milieu. To achieve this overall objective, the following specific objectives were planned:
O1. To develop biocompatible devices to contain catalytically-active Pd nanoparticles (PdNPs) protected from the direct contact with proteins and at the same time, reachable for small molecule substrate.
O2. To validate the functional properties of the Pd-devices under physiological conditions.
O3. To develop new prodrug/s to be bioorthogonally activated by the Pd-devices.
O4. To validate the new therapeutic strategy in biological experiments.
The work carried out during the implantation of BOOMCHEMBAGS project resulted in the successful achievement of the objectives proposed and more. A novel therapeutic strategy has been developed based on the activation of bioorthogonal prodrugs by catalytic devices made of the entrapment of PdNPs within microporous crystals made of natural occurring biopolymers (PdNPs@BpolCrystals). The devices allow the flow of small molecules such as prodrugs and drugs, but restrain the penetration of big molecules such as serum proteins. In this way, prodrugs can reach the PdNPs entrapped in the crystals, undergo the bioorthogonal uncaging reaction, and then, the drug is released exerting its actions. At the same time, the nanoparticles are fully isolated from the surrounding proteins, so their catalytic performance is maintained after several catalytic cycles. The unprecedented characteristics of the devices developed, solve the most crucial unmet requirements of previous metal-nanoparticles-based bioorthogonal devices. Additionally, beyond the original objectives, it was observed that the rate of the reaction catalysed by the new devices can be notably accelerated by irradiating them with harmless near infrared (NIR) radiation. This kind of radiation is known to be able to penetrate biological tissue triggering processes within the body by remote action. Together, the development of the new catalytic devices and prodrugs activable by them achieved in BOOMCHEMBAGS, bring this kind of therapeutic strategies closer to becoming a real treatment for patients treated with otherwise toxic drugs and will mean a great advance in the improvement of their quality of life.
