Alteration in the Temperature-Dependent Content Release Property of Thermosensitive Liposomes in Plasma

Abstract

Liposomes have been proposed as carriers for the delivery of molecules to cells. They have been shown to enhance the efficacy of encapsulated drugs, prolonging the circulation time and reducing side effects. Moreover, the targeting of liposomes to desirable sites has been attempted. 1,2) In addition, a number of attempts have been made to develop functional liposomes, which can regulate the release of drugs responding to various stimuli, such as pH, [3][4][5][6] light 7,8) and temperature. 9-15)The liposomes injected into blood would be opsonized by serum components, and rapidly taken up by the reticuloendothelial system (RES) including the liver and spleen. [16][17][18][19][20] This is a major problem for researchers, because it is a significant disadvantage for the delivery of drugs to non-RES tissues. Moreover, some serum components have a destabilizing effect upon lipid vesicles and thereby cause leakage of liposomal contents. For example, high-density lipoprotein (HDL) is known to cause the disintegration of liposomes. 21,22) Yatvin et al. and Weinstein et al. reported an unique approach to controlling the release of drugs using temperaturesensitive liposomes in conjunction with local hyperthermia.9-11) The barrier efficiency of the membrane abruptly decreases near the gel-to-liquid crystalline phase transition temperature (T m ) of the phospholipid membrane. The temperature-sensitive liposomes have been designed to release a drug in response to local hyperthermia, during which a tumor was heated at temperatures of 41 to 45°C. Other strategies have been used for the production of temperature-sensitive liposomes. One example is the use of polymers, which are attached to the liposome to exhibit temperature-sensitivity and cause release of the internal content above a certain temperature. 14,15) In the development of the liposome, pharmaceutical scientists have been confronted with two difficulties. The first is how to prolong circulation time. Recently, the liposome surface has been modified with GM1 ganglioside 23) and polyoxyethylene derivatives, 24,25) which have some ability to escape the RES. The second is the problem regarding the stability of liposomes in systemic circulation after injection. In general, it is favorable for a drug delivery system (DDS) to have liposomes that are stable in the blood circulation, especially for chemotherapy and gene therapy. In addition, when trying to develop stimulus-sensitive liposomes, one should consider the influence of the serum components on the function of liposomes. Liu and Huang have observed that DOPEbased pH-sensitive liposomes lost their pH-sensitivity in the presence of serum. 26)Anionic lipids are frequently used in preparing liposomes for drug delivery. In the fluid state, negatively charged liposomes composed of phosphatidylglycerol (PG) interacted with serum components and caused an increase in the leakage of the encapsulated drug. 27) Therefore, it is necessary to investigate the effects of serum components on the temperature-dependent release propert...

Proteins and cholesterol lipid vesicles are mediators of drug release from thermosensitive liposomes

“…It is known that serum increases the permeability of TSL membranes as well as the release rate for encapsulated compounds [4,5,13,14]. Objective of the present study was to identify serum components responsible for mediating the drug release from current TSL formulations.…”

“…It is well known that presence of serum is an essential prerequisite to increase the drug release rate from TSL [4,5,13,14]. Since TSL are mainly located in the bloodstream after application it is crucial to identify the impact of individual serum components on vesicle integrity.…”

“…Albumin (HSA) and immunoglobulin type G (IgG) are the major protein components in human blood (up to 88% of total protein). Both proteins interact with liposomes and increase drug leakage [14,[20][21][22]. But also proteins from the complement system gained reasonable clinical interest, since they might yield to serious hypersensitivity reactions in patients upon intravenous (i.v.)…”

Intravenous magnetic nanoparticle cancer hyperthermia

“…[13][14][15][16][17] For example, MNPs have been trapped either in the core or in between the lipid bilayer of thermosensitive liposomes and, on AMF heating, shown to release encapsulated drugs. 13,[18][19][20] A chain of three 20 nm MNPs were attached to loaded liposomes and shown to release doxorubicin and exhibit mouse tumor control over 17 days using an unusually low 10 kHz field applied for 3 hours at a time. 21 When positively charged cisplatin ionically bound to phosphate-starch coated MNPs was heated, it was shown to release the drug and kill cells.…”

Improving Efficiency of Adriamycin Crossing Blood Brain Barrier by Combination of Thermosensitive Liposomes and Hyperthermia

“…Therefore thermosensitive liposomes combined with hyperthermia, which was heated up to 41-45°C with infrared light, a hot-water bath, supersonic wave, radio frequency and microwaves, can realize specific site targeting. 10) On one hand, hyperthermia can enhance tumor blood flow and microvascular permeability. On the other hand, thermosensitive liposomes have an enhanced permeation and retention effect for tumor vasculature combined with hyperthermia treatment.…”