Design and Evaluation of Enzyme-Powered Nanobots for Crossing Biological Barriers and Treating Cancer
[eng] The field of nanomedicine has garnered increasing clinical interest over the past few decades, leading to the approval of numerous products, particularly in oncology. This is due to their ability to encapsulate and deliver drugs directly to target sites, reducing required dosages and side effe...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/220673 |
| Acceso en línea: | https://hdl.handle.net/2445/220673 http://hdl.handle.net/10803/694310 |
| Access Level: | acceso abierto |
| Palabra clave: | Nanomedicina Oncologia Nanomedicine Oncology |
| Sumario: | [eng] The field of nanomedicine has garnered increasing clinical interest over the past few decades, leading to the approval of numerous products, particularly in oncology. This is due to their ability to encapsulate and deliver drugs directly to target sites, reducing required dosages and side effects while protecting the drugs from degradation. However, nanoparticle-based drug delivery systems have not significantly surpassed traditional treatments in terms of bioavailability, with only 0.0014% of injected doses being taken up by cancer cells, even with active targeting strategies. This inefficiency can be attributed to the various physical and biological barriers that nanoparticles must overcome, such as the extracellular matrix or the mucus barrier, which impede effective drug delivery. Therefore, this thesis aims to develop enzyme-powered nanobots as carriers of therapeutic agents capable of overcoming these barriers to enhance cancer treatment efficacy. In the first project, we established a bladder cancer murine model and administered urease-powered nanobots propelled with urea. These nanobots were able to penetrate the extracellular matrix and exhibit enhanced tumor accumulation compared to passive conditions. Moreover, treatment with a single administration of nanobots carrying radioiodine as a therapeutic agent resulted in a remarkable reduction in tumor size. The mucus barrier also poses a significant obstacle to efficient treatment delivery. In our second project, we developed catalase-powered nanobots capable of penetrating it. These nanobots are powered by H2O2, which serves not only as fuel but also as a mucolytic agent. Using an in vitro mucus-secreting model, we demonstrated a 60% reduction in mucus integrity after treatment with H2O2-propelled nanobots. Similar results were observed in ex vivo mouse colons, where intestinal mucus content decreased by 65% post-treatment. Barrier-crossing studies showed that only actively moving nanobots could significantly overcome the mucus layer. Building on this knowledge, our third project focused on pseudomyxoma peritonei, a mucinous carcinoma characterized by cancer cells growing embedded in mucus. To improve the delivery of the standard-of-care drug, we loaded it into the nanobots and used them as an all-in-one self-propelled mucolytic drug delivery system. We treated pseudomyxoma peritonei tumors ex vivo and confirmed that the drug alone cannot overcome the thick mucus to reach the cancer cells. However, treatment efficacy was significantly enhanced in terms of reduced tumor cell viability when using drug-loaded nanobots powered by H2O2, as the degradation of mucus combined with the movement of the nanobots facilitates drug delivery. Overall, this thesis highlights the potential of enzyme-powered nanobots as a versatile platform for cancer treatment. The advancements presented herein could lead to more effective therapeutic strategies, addressing significant barriers in current treatments and ultimately improving patient outcomes in oncology. |
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