Tuftsin-bearing liposomes in treatment of macrophage-based infections
Introduction
The search for improved ways of administering drugs to patients to achieve maximum efficacy with minimal side effects has been one of the most ‘sought-after’ dreams of clinicians for years. However, in actual practice, application of drugs in therapeutic and preventive medicine is marred by their indiscriminate action and inability to reach only the areas in need of treatment. In spite of the enormous advances made in molecular biology and pharmacology over the last two decades, development of new, more selective drugs is still a very expensive, time consuming and often uncertain process. While the drugs are available to combat a wide range of genetic, malignant, and infectious diseases, their efficacy is often compromised by their inability to reach the intended site at an appropriate concentration. Consequently, much attention has been focussed on an alternative approach, namely the use of drug delivery systems, which are expected to optimise the action of the drugs already in existence by transporting or facilitating their release where they are needed.
Successful homing of drugs to the target depends on the design of the carrier as little can be done to influence the target and its surroundings. In a typical drug targeting sequel, the carrier-drug unit would preserve its integrity, avoid interception by normal cells, penetrate interposing membranes, selectively recognise and associate with the target before the drug is released in the target area. Selective drug delivery to specific foci in the body have two vital benefits. First, it ensures optimal interaction of the drug with the site(s) of its action at the right rate and frequency. Secondly, on reducing the drug dose as well as by increasing the target specificity, the potential for any side effects is greatly diminished.
A large number of macromolecular, cellular, and synthetic carriers have been explored with the aim of perfecting drug delivery systems which would localise drugs to the desired sites in vivo, thus minimising the side effects [1], [2], [3]. Amongst these, liposomes bearing cell-specific recognition molecules (e.g., antibody, lectin, glycolipid etc.) on their surface have received wide attention as vehicles for site-specific delivery of drugs and enzymes in vivo [4], [5], [6], [7]. Liposomes, soon after their discovery in the mid sixties, have been studied extensively, and employed in virtually every aspect of biotechnology including gene delivery. Liposomes are best suited as carriers for drugs and enzymes as they are formed from naturally occurring phospholipids and therefore possess low inherent toxicity, immunogenicity, and high drug to carrier ratio [1], [8].
Despite their resemblance to the cell surface, ‘conventional’ liposomes, when administered in vivo, rapidly accumulate in the MPS [9], [10], [11], [12]. The major sites of their accumulation are Kupffer cells of the liver and the resident macrophages of the spleen. About 70 to 80% of intravenously injected liposomes are concentrated into the Kupffer cells of the liver, 5 to 8% into macrophages in the spleen, and even fewer into phagocytic cells in bone marrow [8], [13], [14]. The rate and the site of the uptake of the liposomes by the MPS are influenced by the injected dose, blood flow, local tissue damage, and interaction of liposomes with the serum proteins [13], [15]. The interaction of serum proteins with the particles depends on the physicochemical properties of the particles, i.e. charge, size, hydrophobicity, and fluidity of the particle surface [13], [15]. This tendency of the liposomes to localise in MPS can be turned into an advantage in the treatment of a variety of infections in two ways: (1) As the MPS cells play an important role in non-specific host defence against infections in general, liposomes can be used to activate them by encapsulating in them, thus enhancing non-specific resistance to infections caused by various micro-organisms [11], [12]. (2) Liposomal encapsulation of antiparasitic and antimicrobial agents can result in enhancement of their therapeutic efficacy against intracellular infections involving the MPS [9], [10], [11], [12]. This must potentially be achieved by grafting on the liposome surface the ligands, e.g. tuftsin, that not only bind specifically to the MPS cells but also stimulate them non-specifically against infections.
In the early 1980s, our research group embarked on a project of drug delivery in macrophages. Over the years we have successfully used tuftsin-bearing liposomes [16], [17], [18], [19], [20], [21], [22], [23] in our laboratory as carriers for immunomodulator/drug homing to macrophages. In this review we present the overview of the tuftsin-bearing liposomes and their usefulness in the treatment of macrophase-based infections.
Section snippets
Tuftsin-bearing liposomes
Tuftsin is a natural macrophage activator tetrapeptide (Thr–Lys–Pro–Arg) which is a part of the Fc-portion of the heavy chain of the leukophilic immunoglobulin G (residues 289–292). The tetrapeptide is released physiologically as the free peptide fragment after enzymatic cleavage [24]. Two enzymes are responsible for the production of tuftsin from leucokinin; tuftsin-endocarboxypeptidase, a specific enzyme, cleaves the heavy chain at the Arg–Glu bond between residues 292 and 293, and the
Malaria
Malaria is still considered the most prevalent and devastating disease world wide which affects about 300–500 million people and claims 1.5–2.7 million human lives. Furthermore, one-third of the world human population lives in areas which are infested with the disease [36]. Numerous efforts have been made towards the development of effective vaccines against malaria as an effective vaccine may elicit a protective immune response in individuals of diverse genetic makeup and could complement
Leishmaniasis
Leishmaniasis is caused by the hemoflagellate protozoan and represents four major clinical syndromes; visceral, cutaneous, mucocutaneous, and diffuse cutaneous leishmaniasis. It is estimated that world wide more than 12 million people are infected and approximately 350 million are at risk. The most devastating clinical form, visceral leishmaniasis (kala azar), is caused by Leishmania donovani which causes disseminated disease, characterised by fever, hepatosplennomegaly, anemia, leukopenia and
Fungal infections
Fungal infections continue to be a major problem in management of immunocompromised patients. The presence of any fungal disease in humans commonly implies that the host defence systems have been compromised due to some reason. Thus, the fungal infections often represent the opportunistic infections which are the major cause of morbidity in immunocompromised/deficient human subjects. The clinical effects of the fungal disease in the immunocompromised host vary widely according to the nature of
Tuberculosis
Tuberculosis is a single most infection which results in the largest number of deaths world-wide; nearly 3 million people are killed every year [80]. The association of tuberculosis with HIV infection has significantly exacerbated the situation in developed and developing nations [81]. HIV infection is the highest risk factor identified so far for latent tuberculosis infection to progress to an active disease. This infection also increases the risk to new tuberculosis infection that will
Acknowledgements
We thank Drs. R.K. Jain, A. Puri, A. Singhal, A. Agarwal, M. Owais, P.Y. Guru, S. Chandra and N.B. Singh for their contribution in the work.
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2022, BiomaterialsCitation Excerpt :Tuftsin-modified liposomes (Tuft-Lip) have been shown not only to be more easily absorbed by macrophages than liposomes but also to enhance macrophage activation to increase their natural killing activity [106,107]. Therefore, Tuft-Lip can be used as immunomodulators and nanocarriers targeting macrophages, which have significant improved effects against tuberculosis, malaria, leishmaniasis, and fungal infections [108]. For example, rifampicin-loaded Tuft-Lip drastically reduced the loading of M. tuberculosis in the lungs of infected mice by greater than 2000 times compared to free rifampicin [65].