Tetraether lipid Liposomes for the Preparation of Novel Liposomal Drug Carriers
Liposomes currently have a broad spectrum of medical applications, especially in diagnostics and therapy. Stability of the liposomal drug carriers is one of the most important limitations, which concerns fast elimination of vesicles in the human body. Therefore in this thesis, very stable tetraether...
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|Liposomes currently have a broad spectrum of medical applications, especially in diagnostics and therapy. Stability of the liposomal drug carriers is one of the most important limitations, which concerns fast elimination of vesicles in the human body. Therefore in this thesis, very stable tetraether lipid liposomes were prepared and characterized. The study consists of the investigation of stability properties of tetraether lipid liposomes, the lectin conjugation onto the liposomal membrane, tyrosine kinase inhibitor encapsulation and characterization of these liposomes. These investigations were structured in five chapters:
Chapter 1 introduced the tetraether lipid liposomes, their extraction and preparation methods, stability properties and pharmaceutical applications. In this context, modification and application of the tetraether lipid liposomes as drug delivery systems were also discussed. This chapter focused on the application of liposomes in the field of cancer therapy as anti-angiogenic drug carriers.
Chapter 2 describes the tetraether lipid liposomes which were tailored with an archaeal lipid, Glycerol Dialkyl Nonitol Tetraether (GDNT), isolated from the thermoacidophilic archaeon Sulfolobus acidocaldarius. Investigations of thermal stability, stability during autoclavation and pH stability were carried out. Furthermore, morphological images were presented. In this chapter a special lipid was isolated and purified for the preparation of liposomal vesicles. Liposomes tailored with GDNT showed high stability in various pH and temperature conditions. The results showed that the GDNT liposomes are even stable after autoclavation. The second chapter was presented in the form of a protocol.
Chapter 3 describes stability properties of tetraether lipid liposomes under conditions simulating the pulmonary system and gastrointestinal tract. The tetraether lipids were isolated from the thermoacidophilic archaeon Thermoplasma acidophilum. In contrast to the liposome formulations presented in Chapter 2, these liposomes were prepared with total tetraether lipids instead of a specific type of tetraether lipid. In addition to studies of pH stress and stability during autoclavation, the stability properties of these liposomes were investigated in fetal calf serum and lung surfactant conditions. The TEL content of the liposomes provides extreme stability to the liposomes which is very promising for drug delivery and targeting systems. The results of this work are considered as a preliminary study to elucidate the optimal ratio of tetraether lipid and conventional lipid for the following studies.
Chapter 4 deals with lectin-carbohydrate interactions. The model lectin Concanavalin A (ConA) extracted from the Jack-bean Canavalia ensiformis was used to modify tetraether lipid liposomes. ConA binds to sugar domains localized on inflamed tissues or tumors. The ConA modified TEL liposomes provide an effective targeting mechanism to the inflamed area or tumors. The polymeric form of the sugar mannose, ―mannan‖, was used for the surface modification of a bio-chip. This bio-chip simulated the carbohydrate residues on the cell surface. The binding properties of ConA- modified liposomes onto the mannan coated chip surface were investigated with Reflectometric Interference Spectroscopic (RIfS) measurements which were performed with a BIAffinity device and subsequently with Atomic Force Microscopy (AFM). These measurements provide full information about the binding characteristics of ConA onto the mannan surface. In this regard, ConA can be considered as a useful model for the investigation of specific biomarkers. In the future, ligand conjugated TEL liposomes may serve as efficient carriers for specific drug targeting.
Chapter 5 presents an anti-angiogenic effect of a tyrosine kinase inhibitor entrapped in tetraether lipid liposomes to protect the drug and to decrease the adverse effects on the organism. The anti-angiogenic effect was determined by investigation of blood vessels on a chorioallantoic membrane (CAM) model, especially because of its dense capillary network and eligibility of continuous screening of the implant. Besides in ovo investigations, anti-angiogenic effects of the tyrosine kinase inhibitor ―imatinib‖ entrapped tetraether liposomes were elucidated with cell viability and Western blot assays. According to the comparative results of application between imatinib solution and imatinib encapsulated tetraether lipid liposomes, tetraether lipid liposomes were considered to be promising carriers for tyrosine kinase inhibitors due to the high anti-angiogenesis efficiency with much lower drug concentration. This approach yields to decrease the undesirable side effects of the drug and reduces the amount of drug necessary for an efficient therapy.