@PhdThesis{diss_mods_00025320,
  author = 	{W{\"o}ll, Steffen},
  title = 	{Chemoenzymatic surface modification of liposomal drug carriers},
  year = 	{2019},
  publisher = 	{Christian-Albrechts-Universit{\"a}t zu Kiel},
  address = 	{Kiel},
  keywords = 	{Liposomes; Sortase-A; Drug Delivery; Nanotechnology; Liposomen; Nanotechnologie},
  abstract = 	{Drugs are encapsulated in nano-sized liposomes to refine their pharmacokinetic, pharmacodynamic or physico-chemical behavior upon administration. Immunoliposomes utilize targeting ligands conjugated to their surface to specifically target the encapsulated drug to the disease affected tissue. The conjugation reaction combining the carrier and ligand is a critical manufacturing step since it is a possible source of product heterogeneities. In this work, Sortase A transpeptidase was investigated as chemoenzymatic tool providing a site specific anchoring of ligands on liposomes. 
Pentaglycine motifs serving as Sortase-A acceptor motifs were integrated into various liposomal formulations. Liposome manufacturing via a solvent injection process and subsequent tangential flow filtration was characterized regarding liposome size, polydispersity and lipid composition. Sortase-A catalyzed the conjugation of  LPETG-modified antibodies to the liposomal surface. The reaction kinetics and efficiency were examined under aspects of liposomal surface properties, temperature, enzyme and substrate concentration. Additionally, Sortase-A depletion procedures from the reaction bulk and alternative manufacturing strategies (post-insertion) were characterized.
Conjugation of CD11b{\textlnot} specific antibodies led to a targeting of liposomes to human and murine myeloid cells in vitro. For the first time, sortagged liposomes specifically delivered model fluorophores to murine splenic myeloid cells in vivo. Additionally, epidermal growth factor receptor targeted liposomes loaded with doxorubicin exhibited a specifically higher cytotoxicity on a breast cancer cell line compared to their non targeted counterparts. 
In this thesis, it became obvious that Sortase A transpeptidation is a suitable technology to anchor targeting ligands on liposomes. The obtained results contribute to the elucidation of site-selective conjugation strategies utilized for the design of targeted nanotherapeutics.},
  url = 	{https://macau.uni-kiel.de/receive/diss_mods_00025320},
  file = 	{:https://macau.uni-kiel.de/servlets/MCRFileNodeServlet/dissertation_derivate_00008293/Dissertation_Steffen_Woell.pdf:PDF},
  language = 	{en}
}