Development of self-assembling protein-only nanoparticles for targeted therapies
- Autores: Naroa Serna
- Directores de la Tesis: Neus Ferrer Miralles (dir. tes.), Ugutz Unzueta Elorza (dir. tes.), Antonio Villaverde Corrales (dir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2018
- Idioma: español
- Tribunal Calificador de la Tesis: Grzegorz Wegrzyn (presid.), Esther Julián Gómez (secret.), Joaquin Seras Franzoso (voc.)
- Programa de doctorado: Programa Oficial de Doctorado en Biotecnología
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- Resumen
Innovative medicines urgently demand novel cell-targeted functional vehicles for the controlled delivery of conventional and novel drugs, desirably within the nanoscale. Nanostructured materials show high tissue and cell penetrability that make them very appealing in medicine, while escaping both renal clearance and aggregation in lung when sizing between 6 nm and 100 nm. The architecture of such vehicle-drug conjugates should be tight enough to allow stable systemic circulation and delivery into target tissues, thus minimizing the potential toxicity/side-effects of the cargo due to generic exposition of healthy organs. Importantly, the vehicle itself must be non-immunogenic and non-toxic. In fact, toxicity of the materials currently under exploration for nanoparticle fabrication is a major matter of concern. Carbon nanotubes, dendrimers, different types of polymers, ceramics and metals, despite possessing appealing physicochemical properties exhibit adverse effects concerning cytotoxicity and accumulation in the body and in the environment. All these materials need to be functionalized upon fabrication to associate with the cargo drug and to acquire receptor-based targeting properties.
Alternatively, proteins are fully biocompatible and functional biomaterials suitable for scaled-up bioproduction, and about 400 protein therapeutics have been approved for used in humans by the FDA and EMA, proving the industrial feasibility of biological production for human therapies. Proteins can be conveniently modified by conventional genetic engineering to recruit desired functions such as cell receptor binding, internalization, endosomal escape, nuclear delivery, self-assembling and cross-molecular interactions for drug loading.
In this context, we have previously developed a methodological platform to generate self-organizing, protein-only building blocks based on modular schemes, which once self-assembled as nanoparticles of around 20 nm, mimic the viral functions relevant to architectonic stability, proper biodistribution, cell targeting and cell internalization. We have previously demonstrated that these nanoparticles show selective biodistribution and accumulation into the tumor upon intravenous administration in vivo.
In this thesis, on one hand, we have deeply studied this self-assembly platform and developed an engineering principle that allows obtaining nanoparticles of a defined size. In addition, we have analyzed whether the nanoparticulate presentation of multifunctional proteins favours their delivery through the blood-brain barrier for their possible application in neurological diseases.
On the other hand, we have selected different cytotoxic protein domains (BAKBH3, PUMA, GWH1…) and generated stable nanoparticles with the capacity to accumulate in the target cells and that also, show intrinsic cytotoxic activities for their application in cancer and infectious diseases. In summary, the generation of fully functional, non immunogenic, vehicle-free protein-only nanoparticles escaping renal filtration and showing cytotoxic activity is a totally new concept in Nanomedicine that is expected to have a deep social, scientific and methodological impact in emerging medicines of cancer and potentially, of other relevant human diseases.
