Clinical liposomes

Adjuvants are substances which can modify the immune response of an antigen (139,140). With better understanding of the functions of different arms of the immune system, it is possible to explore the effects of an adjuvant, such that the protective efficacy of a vaccine can be improved. At present, aluminum salt is the only adjuvant approved for use in human vaccines. New adjuvants such as QS-21, 3D-MPL, MF-59, and other liposome preparations are being evaluated. Several of these adjuvants have been in clinical trial, but none have been approved for human use. IL-12 has been proposed as an adjuvant which can specifically promote T-helper 1 ceU response, and can be a very promising adjuvant for future vaccine development. 

DOX, as EPI seems to form fewer amounts of ROS and secondary alcohol metabolite, (ii) encapsulation of anthracyclines in uncoated or pegylated liposomes that ensure a good drug delivery to the tumor but not to the heart, (iii) conjugation of anthracyclines with chemical moieties that are selectively recognized by the tumor cells, (iv) coadministration of dexrazoxane, an iron chelator that diminishes the disturbances of iron metabolism and free radical formation in the heart, and (v) administration of anthracyclines by slow infusion rather than 5-10 min bolus (Table 1). Pharmacological interventions with antioxidants have also been considered, but the available clinical studies do not attest to an efficacy of this strategy. 

A variety of other clinically important infections, such as brucellosis, listeriosis, salmonellosis, and various Mycobacterium infections, are of interest as these are often localized in organs rich in MPS cells. Liposome encapsulation has been demonstrated to improve therapeutic indices of several drugs in a number of infectious models. The natural avidity of macrophages for liposomes can also be exploited in the application of the vesicles as carriers of immunomodulators to activate these cells to an microbicidal, antiviral, or tumoricidal state. These studies were recently reviewed by Emmen and Storm (1987), Popescu et al. (1987), and Alving (1988). In addition to the treatment of "old" infectious diseases, the concept of MPS-directed drug delivery is of considerable interest for the therapy AIDS, possibly enabling control of human immunodeficiency virus replication in human macrophages. 

Because of its clinical importance and the expected benefits of the drug in liposomal form for cancer treatment, all three American "liposome enterprises" (i.e.. Liposome Technology Inc., Erbamont, LyphoMed/Vestar joint ventures, and the Liposome Company, Inc.) are developing a formulation of liposomal doxorubicin. Clinical studies already show promising results as far as the acute toxicity is concerned (less vomiting, nausea, and hair loss) (Gabizon et al., 1989 Treat et al., 1989),... 

For the treatment of lung surfactant deficiency in premature human infants suffering from respiratory distress syndrome, limited clinical trials were performed showing that liposomes in the lung-instilled intratracheally either as an aerosolized mist (Ivey et al., 1977) or as a suspension via an endotracheal tube (Fujiwara et al., 1980)—rapidly improved lung function. No adverse effects were observed as a result of the supplementation with surfactant-like material. It appears, therefore, that liposomes are a suitable system for the delivery of major phospholipid components of endogenous lung surfactant. 

Liposomes have been studied to improve the ocular availability of drugs after application to the eye or after intravitreal injection. Besides, a liposomal eye drop formulation for the treatment of dry eye symptoms was developed and entered the clinical phase II stage (Guo et al., 1988). 

Presently, several clinical trials with liposome-encapsulated agents are under way and more are planned (Zonneveld and Crommelin, 1988 Klausner, 1988). During the last 5 years, key issues related to the pharmaceutical manufacturing of liposomes such as stability, sterilization, upscaling, and reproducibility have been successfully addressed. Although it is generally believed that a proper selection of the bi-layer components can minimize the occurrence of toxic effects due to the use of natural body constituents, the issue of liposome-related toxicity is not a trivial one and should be carefully studied,... 

Thus far no specific articles have been published concerning the tolerance of "pure" liposomes in humans. In all reported clinical... 

For a number of liposome preparations—both injectables and locally administered products—the therapeutic advantages over existing formulations have been proven in animal models clinical trials with liposome preparations are now under way. So far, clinical studies showed no significant toxic effects which could be ascribed to the lipid components of the liposomes used. 

Gabizon A., Sulkes, A., Peretz, T., Druckmann, S., Goren, D., Amselem, S., and Barenholz, Y. (1989). Liposome-associated doxorubicin Preclinical pharmacology and exploratory clinical phase, in Liposomes in the Therapy of Infectious Diseases and Cancer. (G. Lopez-Berestein and I. J. Fidler, eds.), Alan R. 

Weder, H. G., and Zumbuehl, O. (1984). The preparation of variably sized homogeneous liposomes for laboratory, clinical and... 

Virosomes are virus-mimicking systems that contain liposomal bilayer and pH-dependent protein impregnated in the liposomal wall. Virosomes are produced by a detergent dialysis procedure. Many researchers have demonstrated that the virosomes facilitate the leakage of the encapsulated drugs from the endosomes into the cytoplasm. This is, however, complicated technology and, so far, no virosome products are used in the clinical practice. 

An excellent carrier is needed to deliver a sufficient amount of prostaglandins to the diseased site. Liposomes have been studied for a long time as possible drug carriers. However, the clinical use of liposomes has delayed because of some difficulties in mass production, sterilization, stability and safety. Since 1980 we have attempted to use lipid microspheres (lipid emulsions) instead of liposomes as a better carrier for lipophilic drugs (7). 

External stimuli have also been used to further target liposomes. In one such study magnetite particles were incorporated in radiolabeled liposomes and a magnet positioned over the right kidney of a test animal. The liposomes were selectively targeted to that kidney in concentrations that were viewed as significantly high for relevant clinical applications [66],... 

Several liposome-based drugs have been approved for clinical application [64]. One of the clinically approved liposomes is Doxil, a PEGylated liposome containing doxorubicin (DOX), which is used for the treatment of a number of diseases [65]. As shown in this case, in the field of liposome drug development, PEG is widely used to protect the liposome from recognition by opsonins, thereby reducing liposome clearance. 

Kung, V.T., Maxim, P.E., Veltri, R.W., and Martin, F.J. (1985) Antibody-bearing liposomes improve agglutination of latex particles used in clinical diagnostic assays. Biochim. Biophys. Acta 839, 105-109. 

It is of special interest that rheumatoid arthritis is one of the first examples of the extensive antioxidant treatment of human patients. In previous years the most recommended pharmaceutical antioxidant agent has been SOD. In 1986, Wilsman [245] reviewed the results of 10 years of presumably successful clinical experience with CuZnSOD treatment of inflammatory disorders including RA. Niwa et al. [246] recommended the application of liposomal... 

The caloric contribution from propofol infusions can require adjustment of a patient s nutrition regimen. The caloric contribution from amphotericin liposomal and lipid complex formulations is not clinically relevant. 

Di Paolo A (2004) Liposomal anticancer therapy pharmacokinetic and clinical aspects. J. Chemotherap. 16 90-93. 

Gabizon A, Goren D, Cohen R, Barenholz Y (1998) Development of liposomal anthracyclines from basics to clinical applications. Journal of Controlled Release 53 275-279. 

Gabizon A, Barenholz Y. Liposomal anthracyclines— from basics to clinical approval of PEGylated liposomal doxorubicin. In Janoff AS, ed. Liposomes Rational Design. New York Marcel Dekker, 1999 343-362. 

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