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.