ReviewSecond generation liposomal cancer therapeutics: Transition from laboratory to clinic
Graphical abstract
Introduction
Liposomes, uni-lamellar or multi-lamellar spherical vesicles, primarily comprising phospholipids, either from plant or animal source (Torchilin, 2005, Zhang et al., 2008, Zhang and Granick, 2006) were first discovered by A.D. Bangham at the Agricultural Research Council Institute of Animal Physiology at Babraham, Cambridge (Duzgunes and Gregoriadis, 2005) in 1961, when he and his colleagues observed that phospholipids upon dispersion in water spontaneously formed spherical, self-closed vesicles consisting of concentric lipid bilayers (Bangham et al., 1965a). These vesicles initially called ‘smectic mesophases’, were later renamed as ‘liposomes’ (Sessa and Weissman, 1968). The resemblance of the lamellar structure of the vesicles with natural membranes, the capability to discriminate ions (cations diffuse poorly from membranes which are permeable to univalent anions and water) and susceptibility to stabilization or labilization by bioactive molecules similar to biological membranes have rendered liposomes versatile tool in the field of biology, biochemistry and medicine (Bangham et al., 1965a). The ability of the vesicles to swell osmotically, the possibility to vary membrane composition and surface potential and availability of several analytical techniques to study these systems have made liposomes a preferred lipid matrix model of living cells (Bangham et al., 1965b).
With the recognition of the biocompatibility, biodegradability, low toxicity and immunogenicity and the capability to entrap molecules, liposomes have moved a long way from being just another exotic object of biophysical research to becoming a pharmaceutical carrier of choice for numerous practical applications (Black and Gregoriadis, 1976, Gregoriadis, 1976, Juliano and Mccullough, 1980, Neerunjun and Gregoriadis, 1976, Torchilin, 2005).
The size of the liposomes range from 20 nm to more than 1 μm (Samad et al., 2007). Each microscopic vesicle has a hydrophilic core and hydrophobic bilayer which enables the entrapment of both hydrophilic and hydrophobic drugs (Medina et al., 2004, Zhang et al., 2008). These self-assembled lipid vesicles protect the cargo by encapsulating hydrophilic drugs within the aqueous core and hydrophobic drugs within lipid bilayers (Portney and Ozkan, 2006) which leads to the isolation of the drug molecules from the surrounding environment (Zhang and Granick, 2006).
Liposomes are generally classified based on lamellarity of the vesicles and can be distinguished into unilamellar and multilamellar vesicles (Fig. 1). While multilamellar vesicle comprises of several concentric bilayers arranged in an onion peel pattern with aqueous layer between them, unilamellar vesicles contains a single bilayer (Hofheinz et al., 2005, Perezsoler, 1989).
Section snippets
Passive and active targeting
Liposomal formulations of several key active molecules were developed in order to overcome the problems associated with conventional drug therapy such as inefficient bio-distribution throughout the body and lack of specific delivery, by encapsulating the molecules within the vesicles to prevent degradation and passively targeting tissues and organs that have discontinuous endothelium (e.g. liver, spleen and bone marrow) (Immordino et al., 2006).
Passive targeting of tumor by drug-loaded
Conventional liposomes
Liposomes act as reservoirs encapsulating the drug and protecting it from the degradation (Goyal et al., 2005) and reducing the unintended side effects such as cardio- (Forssen and Tokes, 1981), nephro- (Smeesters et al., 1988), neuro- (Park et al., 2008, Rosentha and Kaufman, 1974) or dermal- (Boman et al., 1996) toxicity. Numerous liposomal formulations bearing cancer therapeutics have been approved or are currently undergoing clinical trials (Table 3, Table 4).
Liposomal formulation of
Conclusion
The evolution of new generation pharmaceutical liposomes has marked a new era in drug delivery systems in cancer therapeutics. Liposomes are versatile drug delivery systems which can be designed and modified in order to enhance the effectivity of the therapeutic drug. The wide array of liposomal drug formulations approved and undergoing clinical trials for cancer therapeutics (Table 3) points to the translation of liposomes from an object of research to preferred pharmaceutical carrier for
Acknowledgements
This work was supported by research grants from the Department of Biotechnology (DBT) and Department of Science and Technology (DST), Ministry of Science and Technology, Government of India. KS gratefully acknowledges University Grants Commission, India for awarding her with Senior Research Fellowship.
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