Cationic liposomal system

Borgatti M., Breda L., Cortesi R., Nastruzzi C., Romanelli A., Saviano M., Bianchi N., Mischiatic C, Gambari R. Cationic liposomes as delivery systems for double-stranded PNA-DNA chimeras exhibiting decoy activity against NF-kB transcription factors. Biochem. Pharmacol. 2002 64 609-616. 

In this respect, an interesting approach to reduce degradation and possible toxicity problems related to nucleic acid use in vivo is offered by their encapsulation in or association to microcarrier systems, such as neutral or cationic liposome and polymeric microparticles [41 14],... 

Miller, A.D., The problem with cationic liposome/micelle-based non-viral vector systems for gene therapy, Current Medicinal Chemistry, 2003, 10, 1195-1211. 

Formation of a complex between DNA and polycationic compounds appears to be the initial and quite possibly a critical parameter for nonviral gene delivery. Several synthetic vector systems, which are generally cationic in nature, including poly(lysines), cationic liposomes or various types of block copolymers and recently dendrimers, have been shown to self-assemble with plasmid DNA [13-15] [16]. Specific physicochemical properties manifested by these DNA complexes depend on the type of cationic agent used however, interesting patterns for such interactions are beginning to evolve [17, 18]. Under certain conditions, the interaction of DNA with polyvalent cations results in... 

Several vectors have been used in an attempt to deliver the cf gene to the airway epithelial cells of sufferers. The most notable systems include adenoviruses and cationic liposomes. Vector delivery to the target cells can be achieved directly by aerosol technology. Delivery of cftr cDNA to airway epithelial cells (and subsequent gene expression) has been demonstrated with the use of both vector types. However, in order to be of therapeutic benefit, it is essential that 5-10% of the target cell population receive and express the cftr gene. This level of integration has not been... 

The therapeutic efficacy of either systemic or local pulmonary delivery of the IFN-y gene was evaluated in a murine allergen-induced airway hyperresponsiveness (AHR) model (Dow et al. 1999) and it was found that a high efficiency of gene transfer could be achieved. Intratracheal administered cationic liposomes were prepared from a mixture of l,2-diacylglycero-3-ethylphosphocholine (EDMPC) and cholesterol. Intravenous injections were prepared from l,2-dioleyl-3-trimethylammo-ninm propane (DOTAP) and cholesterol and compared with pulmonary administered... 

There is a wide variety of vectors used to deliver DNA or oligonucleotides into mammalian cells, either in vitro or in vivo. The most common vector systems are based on viral [retroviruses (9, 10), adeno-associated virus (AAV) (11), adenovirus (12, 13), herpes simplex virus (HSV) (14)] andnonviral [cationic liposomes (15,16), polymers and receptor-mediated polylysine-DNA] complexes (17). Other viral vectors that are currently under development are based on lentiviruses (18), human cytomegalovirus (CMV) (19), Epstein-Barr virus (EBV) (20), poxviruses (21), negative-strand RNA viruses (influenza virus), alphaviruses and herpesvirus saimiri (22). Also a hybrid adenoviral/retroviral vector has successfully been used for in vivo gene transduction (23). A simplified schematic representation of basic human gene therapy methods is described in Figure 13.1. 

Nonviral vector systems are usually either composed of a plasmid based expression cassette alone ( naked DNA), or are prepared with a synthetic amphipathic DNA-complexing agent (84, 88). Gene delivery systems based on nonviral vectors mainly comprise cationic liposomes, DNA-polymer-protein complexes, and mechanic administration of naked DNA. An idealized/optimized multifunctional nonviral gene delivery system is depicted in Figure 13.4. 

Cullis, P.R., Chonn, A. (1998). Recent advances in liposome technologies and their applications for systemic gene delivery. Adv. Drug Deliv. Rev., 30(1-3), 73-83. Audouy, S.A., de LeiJ, L.F., Hoekstra, D., Molema, G. (2002). In vivo characteristics of cationic liposomes as delivery vectors for gene therapy. Pharm. Res., 19(11), 1599-1605. 

Sakurai, F., Nishioka, T., Saito, H., Baba, T., Okuda, A., Matsumoto, O., Taga, T., Yamashita, F., Takakura, Y. and Hashida, M. (2001) Interaction between DNA-cationic liposome complexes and erythrocytes in an important factor in systemic gene transfer via the intravenous route in mice the role of the neutral helper lipid. Gene Then, 8, 677-686. 

Liu, D. (1997) Cationic liposome-mediated gene delivery via systemic administration. J. Liposome Res., 7,187-205. 

For example, the use of a conically shaped lipid, dioleoylphos-phatidylethanolamine (DOPE), in cationic liposomes helps the destabilization of the cellular membranes, leading to a more efficient delivery of plasmid DNA in cell culture.84 The structural diversity of the lipidic colloids offers great flexibility in their applications as drug delivery and drug targeting systems. 

As a means to overcome these problems, alternative nonviral DNA carrier systems have been developed [3], and of those cationic liposomes have been the most widely used and characterized [4], A number of such liposomal systems have... 

A current theme in plasmid-based delivery approaches is to mimic Nature s methods for nucleic acid delivery. To date, the best system to emulate Nature has been viral vectors. Briefly, most viral vectors escape immune surveillance, interact with cell membranes (e. g., receptor), internalize (via endocytosis), escape from endosomes, migrate to the nuclear envelope, enter the nucleus, and finally take over cellular functions. Plasmid-based systems (cationic liposomes and cationic polymers) can mimic portions of these events. This chapter will explore the barriers facing gene delivery vectors, with an emphasis of the pharmacokinetic behavior of these systems. In order to understand the in-vivo barrier, a brief review of physiology will be provided. 

An alternative method for introducing a plasmid DNA vector is to use liposomes. As they are composed of aqueous vesicles surrounded by a phospholipid bilayer, liposomes allow encapsulation and transportation of many substances, both hydrophilic and lipophilic, along with the plasmid. Liposomes also allow molecules such as antibodies, proteins, and sugars to be incorporated into their surface, to target them to specific sites. Due to the structural versatility shown by these systems, the chances of effective transfection may be increased by changes in the lipid composition, which may alter the superficial charge or the vesicle size (Bramwell and Perrie, 2005). Cationic liposomes have wide applications in gene transfection. 

For the neutral form of 13 bases, again a very poor correlation between partitioning into octanol and liposomes was observed. The range found for the partition coefficients was 2.0 to 6.0 in octanol and +1.0 to < 5.0 in the liposomal system (-2 is the observable minimum according to the authors). Poor correlations were also found for the cationic forms of the bases (r2 = 0.49). Generally, the differences (log Poct.-log Psuv) for the neutral forms are smaller than the differences observed for the charged species. 

However, if a drug is dissolved in oil and emulsified with surfactants, the first term of the numerator in Equation (5.196) becomes negligible because the drugs in an oil droplet remain in the oil phase until coalescence occurs whereas micelles constantly change in a micellar system. Figure 5.38 shows the stabilization of indomethacin in the presence of cationic liposome at pH 9.37 (carbonic buffer) and 40°C. 

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