Investigation of branched and linear polymers as oral delivery systems of antimalarial drugs

• Autores: Elisabet Martí Coma Cros
• Directores de la Tesis: Xavier Fernández Busquets (dir. tes.), Santiago Imperial Ródenas (tut. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2019
• Idioma: español
• Tribunal Calificador de la Tesis: María Antonia Busquets Viñas (presid.), Maria Carmen Fernandez Becerra (secret.), Paula Alexandra de Carvalho Gomes (voc.)
• Programa de doctorado: Programa de Doctorado en Biotecnología por la Universidad de Barcelona
• Materias:
  • Química
    • Química analítica
      • Análisis de polímeros
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• Resumen

  • Malaria is an infectious disease that affects nearly half of the population in 90 countries around the world. In 2017 it was estimated that there were 219 million cases and 435,000 deaths disproportionately distributed worldwide. Indeed, 92 % of malaria cases and 93 % of malaria deaths occur in Africa, while the remainder of the cases are distributed among South East-Asia, Eastern Mediterranean, Western Pacific, and the Americas. Vast global efforts and large economic investments have been made worldwide to reduce, control and eliminate malaria, resulting in a great reduction of the incidence in the last 20 years. Nevertheless, malaria remains a global public health issue. Malaria in humans is caused by an intracellular protest which has an extremely complicated live cycle that occurs within two hosts, the human and the Anopheles vector. The parasite is Plasmodium, and there are five species namely P. ovale, P. malariae, P. knowlesi, P. vivax and P. falciparum, the latter being responsible for the majority of the morbidity and mortality of this disease. Malaria is a treatable disease, however antimalarial drugs must cross at least three sequential membranes (EPM, PVM and PPM) in order to enter the intracellular parasite, reach appropriate therapeutic concentrations; reason why they required drug delivery systems (DDSs). Actually, nano-DDSs have shown to have a positive effect on disease treatment providing solutions to solubility, pharmacokinetics, target selectivity, and/or protection against degradation, resulting in an increase in drug half-life. The aim of this thesis was to characterize different polymeric nanocarrier, branched (DHP-bMPA and HDLDBC-bGMPA) and linear (AGMA1, ISA1, ISA23 and ARGO7), as oral drug delivery systems. Results obtained performing in vitro experiments demonstrated that PAAs and dendrimers have low unspecific toxicity, no hemolitic activity, specific pRBCs targeting and drug encapsulation capacity. Furthermore, PAAs displayed slow degradation, affinity to parasite proteins, which could explain the preferential binding to pRBCs, and intake by macrophages, indicating PAAs potential to treat other intracellular parasitic disease like Leishmania. Additionally, dendrimers that form spontaneous micellar carrier, and bind to merozoites, showed an intake by HUVEC cells in different location, which could be further investigated to treat as well other disease. On the other hand, encapsulated drugs with the two types of polymers showed optimal in vivo capacity to inhibit Plasmodium growth after i.v and oral administration. Moreover, when PAA-FITC where given to female mosquitoes fluorescence was observed in the midgut and in the insect’s tissues. In conclusion, the date showed in this thesis work presented the branched and linear polymers investigated as a versatile platform for the encapsulation of orally administrated antimalarial drugs, for direct administration of antimalarials to mosquitos, and potential carriers for the treatment of other parasitic diseases.