Doctoral Themes

New multitarget hybrid drugs for Alzheimer's disease therapy: free drug and controlled delivery using nanocarriers

Supervisors

Silvia Chaves, silvia.chaves@tecnico.ulisboa.pt

Maria Teresa Viciosa Plaza, teresaviciosa@tecnico.ulisboa.pt

Registration Institution

Instituto Superior Técnico, Universidade de Lisboa

Project description

With increasing human life expectancy, the number of patients with severe age-dependent neurodegenerative Alzheimer ́s disease (AD) is growing dramatically. AD has few available symptomatic drugs, and the rate of failure in drug development is high due to poor understanding of the disease complexity. The recognized complex multi-etiology of AD has led to the recent development of multi-target unimolecular drug candidates. Another challenge in AD is the permeability of the drugs at the blood-brain barrier (BBB). Here, the use of drug nanocarriers can increase BBB permeability, due to the possibility of surface multi-functionalization, small size, and very high surface-to-volume ratio.

In this project, new multi-target hybrids (based on FDA drugs) will be designed, synthesized and evaluated in terms of physico-chemical (antioxidant activity, metal chelation) and biological properties (enzyme inhibition, Aβ aggregation, cell viability, neuroprotective effect). The best candidate drugs will be encapsulated in novel nanocarriers constituted by a core of mesoporous silica nanoparticles (MSN) and a shell of poly(D,L-lactide-co-glycolide) (PLGA). This biodegradable copolymer will be synthesized by ring opening polymerization using a grafting-from approach on MSNs containing a dye anchored to their structure for optical tracing. Mobility of the encapsulated drugs and the polymer chains will be studied by calorimetric and dielectric techniques, and correlated with the PLGA degradation kinetics, in order to obtain structure- property relations which will guide the design of the nanocarriers for optimization of drug release kinetics. The best drug-nanocarrier systems will be tested in vivo using mice models of the disease during an internship at Cukurova University.

Keywords

Alzheimer's disease; Multi-target drugs; Hybrid nanoparticles; Controlled delivery; Smart systems

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