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Nanotechnology approaches for improved vasoactive intestinal peptide based-drug delivery systems

AuthorsKlippstein, Rebecca
AdvisorPozo, David
Issue Date2013
PublisherCSIC-JA-UPO-USE - Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER)
Universidad de Sevilla
AbstractThe specific purpose of this project is to study the feasibility as a proof of concept of different nanotechnology approaches in order to improve the drug delivery of the neuropeptide vasoactive intestinal peptide (VIP). Two main questions have been addressed using VIP engineered NPs: 1. VIP functionalized gold NPs. In this case, VIP could act as a drug/diagnostic molecule for theranostic applications. 2. VIP functionalised liposomes as a targeting agent to transport drugs to a specific tissue site. The rationale behind the first part of this study is to substantially increase the half-life of VIP in biological fluids to be employed in therapeutics. VIP-based drug design is hampered by the instability of the peptide and has limited bioavailability. For this reason VIP was functionalized to gold nanoparticles to investigate a potential protection from protease degradation and the mechanisms involved in this process. Remarkably, although it has been hypothesized that surface functionalization of proteins and bioactive peptides on noble metallic nanoclusters might protect from protease degradation, so far there are no formal proofs in this sense. Our aim is to prove that coating gold NPs with the neuropeptide VIP impairs the hydrolytic activity of extracellular proteases, leading to VIP-mediated functional responses after harsh conditions resembling the extracellular circulating proteases milieu. We used several experimental approaches combining physical and chemical characterization to determine size, dispersion and homogeneity of VIP AuNPs by AFM/TEM/DLS analysis as well as additional biochemical quantification of VIP-elicited cellular responses mediated by specific VIP receptors. Our study places the concept of surface functionalization in the broader perspective of proteins escaping from extracellular proteases, which could represent a major driven force and an added value to steer the research in the field of engineering NPs. In the second part of this study, VIP was used as a directing agent of a drug-loaded liposome to prostate cancer cells, and was compared with a non-targeted liposome in order to evaluate its therapeutic efficacy. The specific delivery of anticancer drugs to prostate cancer cells has important implications for diagnosis and therapy. Biomarkers that differentiate cancerous tissues from normal tissues can be used as targets for this purpose and one of these attractive molecular targets is VIP receptors which are overexpressed in human prostate cancer compared to normal prostate tissue. For this reason VIP liposomes have been synthesized to exploit VIP receptors to actively target carriers to PCa and therefore improve its therapy. The use of liposomes is recognized as a promising strategy for improving the delivery of anticancer drugs to tumours, leading to a reduction in drug toxicity and improving the therapeutic outcomes. Furthermore, VIP liposomes were used to encapsulate doxorubicin (an anticancer anthracycline antibiotic) to prostate cancer cells. The aim of this study was to assess the potential of VIP as a ligand for prostate cancer targeting by liposomal nanocarriers and evaluate the efficacy of the treatment. Moreover, we wanted to investigate the effect of a peptide coupling method on the cellular uptake, cytotoxicity and apoptosis of doxorubicin liposomal formulations. In addition, in vivo experiments were addressed in a preclinical setting in order to evaluate the VIP active driven targeting to the prostate cancer cells by liposomes.
Appears in Collections:(CABIMER) Tesis
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