In vitro, in vivo, and in silico investigations of polymer and lipid based nanocarriers for drug and gene delivery
Year: 2013
Type: dissertation
Abstract: Nanomedicine research has expanded rapidly in the last decades. Several nanoparticle formulations are accepted in clinical use, e.g. for the treatment of cancer, infections and eye diseases, and also for diagnostics. Nanoparticle mediated drug delivery has many potential advantages over the free drug, such as better pharmacokinetic profile, lowered toxicity, and its possible use for cell-specific targeting and intracellular drug release. Therapeutic genes can also be packed into nanocarriers to protect them from enzymatic degradation and to mediate their cellular entry. Nonetheless, even though nanoparticles have so many advantages, there are many extracellular and intracellular barriers to overcome before achieving successful drug or gene delivery. The focus of this research work was to examine the formation and physico-chemical and biological features of lipid and polymer based nanoparticles for drug and gene delivery. First, the effect of the polymeric gene carrier composition and structure on DNA condensation efficacy and transgene expression was examined. The linear architecture and flexibility of poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA)-based block co-polymers clearly enhanced DNA condensation and transfection efficiency. In addition, by conjugating a membrane active protein, hydrophobin (HFBI) to DNA-binding cationic dendrons, the transfection efficacy was increased compared to plain dendron. However, cationic polymer-DNA complexes are prone to disruption by polyanions such as glycosaminoglycans (GAG) in the extracellular space. We coated poly(ethyleneimine) PEI/DNA complexes with anionic lipid mixture. The coating was able to protect the contents against GAGs, and it could respond to the change of endosomal pH and release the cargo inside the cells. In addition, two classes of liposomal cancer cell targeting approaches were evaluated in physicochemical studies and in cancer cell models in vitro and in mice. A promising activated endothelium targeting peptide (AETP) failed to target the liposomes to the cells. Molecular modeling revealed that hydrophobic AETP was hidden in the polyethylene glycol (PEG) shield of the liposomal surface thus it was not accessible for the target receptors. The last study describes applicability of pre-targeting and local intraperitoneal administration of epithelial growth factor receptor (EGFR)-targeted liposomes for drug targeting to tumors located in peritoneal cavity. In conclusion, the composition and architecture of nanocarriers have a crucial impact on DNA condensation, stability of the complexes and transfection efficacy. In liposomal cancer drug targeting, PEG shield may hinder the targeting efficiency of small molecular peptides. Intraperitoneal administration of liposomal drugs seems to be promising route for targeting to tumors located in the peritoneal cavity.
Source: Työväentutkimus Vuosikirja
Author: Julia Lehtinen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1520199507