Disseny de vesícules extracel·lulars selectivament vectoritzades amb glicolípids cap a les cèl·lules dendrítiques

Author

Guixeras Carreras, Jordi

Abstract

Current cancer therapies have reached a plateau because new drugs that follow the traditional treatment pathway still have severe systemic toxicity. Moreover, they are not able to cause higher cancer cell mortality due to the acquired resistances that tumours generate towards chemotherapy drugs. As an alternative, several studies have proposed immunotherapy, which involves activating the immune system selectively, so that it recognises tumours as threats to be killed and can thus fight these cancer cells. Of the different types of immunotherapies, therapeutic vaccines aim to awaken the patient's immune system. They are based on the administration of a tumour antigen once the disease has already appeared, with the intention of activating an immune response, especially of the cytotoxic lymphocytes that are responsible for eliminating tumour cells. Encoding antigens with nucleic acids is advantageous because of the self-adjuvant property of the genetic material and the ease of exchanging the encoded antigen without significantly changing the formulation. However, nucleic acids are very labile molecules and unable to penetrate cells. Therefore, they need a vector that protects them and transports them specifically to the target cells, the antigen presenting cells. Thus, the aim of the present work is to develop new nano-vectors based on lipid systems that encapsulate the antigenic genetic material and are selectively vectorised towards the antigen presenting cells. Of the various existing vectors, extracellular vesicles, nanosystems naturally released by all human cells that already contain genetic material and have intercellular communication functions through gene material and proteins transference, have been chosen and compared with liposomes as artificial lipid systems.
In this work, it has been designed a new type of vectorization of extracellular vesicles, using cholesterol- and mannose-based glycolipids, which are expected to integrate into their lipid membrane and expose mannoses on the surface, so extracellular vesicles can be selectively targeted to antigen presenting cells. Two synthetic routes have been developed to obtain two glycolipids, which differ in the presence or absence of a linker between the two units. Then, the methodology of incorporation of these glycolipids into the vesicles has been established and their integration has been confirmed by confocal microscopy. Finally, their functionality has been studied by cell uptake assays, demonstrating a cell uptake efficiency of more than 50% when the glycolipids have been added to the extracellular vesicles. In conclusion, this work confirms that extracellular vesicles selectively targeted to antigen presenting cells are promising nanosystems to become the nucleic acid-based therapeutic vaccines of the near future.

Director

Fornaguera i Puigvert, Cristina
Faijes Simona, Magda

Degree

IQS SE - Master’s Degree in Industrial Engineering

Date

2022-07-06