6.2. Targeted drug delivery to macrophages
For an effective therapeutic intervention, either melatonin or accessory therapeutic agents should be delivered specifically to macrophages in the atherosclerotic lesions to avoid off-target effects on other tissues. However, it is noteworthy that melatonin off-target effects are beneficial and caution should be directed towards other therapeutics (Reiter, Tan, Paredes & Fuentes-Broto, 2010). Targeted drug delivery refers to the specific delivery of a therapeutic agent or a combination of agents using various carriers (basically nano-scale carriers) such as nanoparticles, liposomes, niosomes, carbon nanotubes, and dendrimers to a certain cell or tissue. Targeted drug delivery to the macrophages in the atherosclerotic lesions seems to optimize the efficacy of therapeutic agents enwrapped in drug-delivery systems (Fig. 2) (Jain, Mishra & Mehra, 2013).
The basis of targeted drug delivery is to decorate drug carriers with ligands that can specifically recognize the target (cell or tissue of interest). For example, macrophages express high levels of sugar-binding receptors such as mannose receptors on their surface. Therefore, decorating drug-delivery systems with ligands to bind mannose receptors can create a targeted drug-delivery system for specific delivery of the therapeutic agents to macrophages (Ezekowitz et al., 1991; Taylor, Bezouska & Drickamer, 1992).
In line with this, functionalization of liposomes with mannosyl ligand (mannosylated liposomes) specifically targets rat alveolar macrophages and elicits increased uptake of liposomes both in vivo andin vitro (Chono, Tanino, Seki & Morimoto, 2007). Functionalization of gelatin nanoparticles with mannose ligands successfully delivers amphotericin B to macrophages to ameliorate visceral leishmaniasis (Nahar, Dubey, Mishra, Mishra, Dube & Jain, 2010). Mannosylated SLNs (Nimje et al., 2009), and mannose-engineered polyethylene glycol/PLGA show similar results (Tomoda & Makino, 2007). Also, encapsulating therapeutic agents in chitosan microparticles has shown enormous success in the specific delivery of the agents to macrophages (Kunjachan, Gupta, Dwivedi, Dube & Chourasia, 2011).
In addition to mannose receptors, other macrophage cell surface molecules could be a specific target, against which new ligands can be designed on drug carriers. We propose that further experiments should be carried out to find out the cell surface molecules that are specifically expressed/overexpressed in activated macrophages in the atherosclerotic regions. Discovering such molecules would enable us to deliver melatonin and other accessory agents to macrophages that specifically reside in atherosclerotic regions.