International Journal of Pharmaceutics 593 (2021) 120117 Available online 28 November 2020 0378-5173/© 2020 Elsevier B.V. All rights reserved. Review Liposomal doxorubicin as targeted delivery platform: Current trends in surface functionalization Vivek Makwana a, b, c , Jasmine Karanjia d , Thomas Haselhorst e , Shailendra Anoopkumar-Dukie a, b, c , Santosh Rudrawar a, b, c, * a School of Pharmacy and Pharmacology, Griffth University, Gold Coast, QLD 4222, Australia b Menzies Health Institute Queensland, Griffth University, Gold Coast, QLD 4222, Australia c Quality Use of Medicines Network, Griffth University, Gold Coast, QLD 4222, Australia d Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia e Institute for Glycomics, Griffth University, Gold Coast, QLD 4222, Australia A R T I C L E INFO Keywords: Liposomes Doxorubicin Surface functionalization Ligands Targeted drug delivery systems ABSTRACT Liposomal delivery systems have signifcantly enhanced the effcacy and safety of chemotherapeutic agents compared to free (non-liposomal) formulations. Liposomes are vesicles made up of lipophilic bilayer and a hy- drophilic core which provides perfect opportunity for their application as transport vehicle for various thera- peutic and diagnostic agents. Doxorubicin is the most exploited chemotherapeutic agent for evaluation of different liposomal applications, as its physicochemical properties permit high drug entrapment and easy remote loading in pre-formulated liposomes. Pegylated liposomal doxorubicin clinically approved and, on the market, Doxil®, exemplifes the benefts offered upon the surface modifcation of liposome with polyethylene glycol. This unique formulation prolonged the drug residence time in the circulation and increased accumulation of doxo- rubicin in tumor tissue via passive targeting (enhanced permeability and retention effect). However, there is ample scope for further improvement in the effciency of targeting tumors by coupling biological active ligands onto the liposome surface to generate intelligent drug delivery systems. Small biomolecules such as peptides, fraction of antibodies and carbohydrates have the potential to target receptors present on the surface of the malignant cells. Hence, active targeting of malignant cells using functionalised nanocarrier (liposomes encap- sulated with doxorubicin) have been attempted which is reviewed in this article. 1. Introduction The phospholipid vesicles (liposomes) containing chemotherapeutic agent doxorubicin demonstrate a distinct superiority in clinical perfor- mance over free (non-liposomal) doxorubicin, considered as standard care. Unique pharmacokinetic properties offered by liposomal doxoru- bicin resulted in dramatic reduction of cumulative-dose related car- diotoxicity. This improvement in patient daily compliance allowed increasing the accumulated dose and extending treatment duration with doxorubicin. Targeted liposomal doxorubicin involving surface func- tionalization of liposomes with ligands played a key role in overcoming the limitation of doxorubicin liposomal formulations such as selectively targeting specifc cancer cell (eg. endocrine) or organelle (eg. mito- chondria, lysosome). Therefore, there is an increasing demand for tar- geted delivery systems which are able to withhold the molecules inside and transport it to the respective targeted tissue with appreciable safety (Fig. 1). This approach is particularly important for advanced stage cancers where surgical removal is not an option. In the nano- technological advanced era, various platforms such as microspheres (Varde and Pack, 2004), solid lipid nanoparticles (Makwana et al., 2015), dendrimers (Madaan et al., 2014), micelles (Gong et al., 2012), liposomes and polymeric nanoparticles (Shukla and Gupta, 2020; Shukla et al., 2020; Vaidya et al., 2020) are created to achieve targeted de- liveries. Among these carriers, liposomes have many advantages as they can be used for hydrophilic molecules (entrapped in liposomal core), hydrophobic molecules (entrapped in liposomal bilayer) and amphi- philic molecules (lipid-aqueous interface) making them suitable carriers for a wide range of therapeutic applications (Laouini et al., 2012). Li- posomes are also biodegradable, non-toxic and non-immunogenic which make them ideal candidates that can be administered directly into * Corresponding author at: School of Pharmacy and Pharmacology, Griffth University Gold Coast Campus, QLD 4222, Australia. E-mail address: s.rudrawar@griffth.edu.au (S. Rudrawar). Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm https://doi.org/10.1016/j.ijpharm.2020.120117 Received 23 August 2020; Received in revised form 17 November 2020; Accepted 21 November 2020