Novel gene delivery systems for brain targeting

Disorders of the central nervous system such as brain tumours, Alzheimer's disease, Parkinson's disease, Huntington's disease and others lead to a worst decline in the quality of life of patients. The possibility of using gene therapy for the treatment of these disorders is hindered due to the presence of blood-brain barrier and due to the lack of safe and efficacious gene delivery systems that can cross this barrier and express exogenous genes in global areas of the CNS. Various receptors such as transferrin receptors, lactoferrin receptors and low-density lipoprotein receptor-related proteins 1 & 2 are widely expressed on the blood-brain barrier for the transport of endogenous molecules. These endogenous transport systems could be exploited for transport of molecules across the blood-brain barrier. In this thesis, we demonstrated the synthesis and characterization of transferrin-, lactoferrin-, lactoferricin-, Angiopep-2-bearing diaminobutyric polypropylenimine (DAB) dendrimers and evaluated their brain targeting efficiencies in vitro and in vivo. Transferrin- and lactoferrin- bearing DAB dendriplexes led to a 2-fold and 6.4-fold increase in gene expression in the brain respectively, as compared to unconjugated DAB dendriplex after intravenous administration in mice, while decreasing the gene expression in other major organs of the body. Lactoferricin-bearing dendriplex did not show any gene expression in the brain after intravenous administration, whereas unexpected results requiring further investigation were obtained after intravenous administration of Angiopep-2-bearing dendriplex.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral-pg

Grantor dc:publisher.institution

University of Strathclyde

Year dc:date.issued

2015

Author dc:creator

• Somani, Sukrut

DOI

10.48730/gcmd-3x32

Identifier

T14110

Author Identifier

201279228

OAI identifier oai:identifier

oai:strathclyde:k35694439