Drug Delivery Systems
The niche in which the Leishmania lives presents challenges to drug delivery, as the drug has to achieve antiparasitic levels in multiple sites and the specific area targeted depends on the species of Leishmania. For example in VL a drug must target parasites within macrophages in the spleen, liver and bone marrow, whereas in CL the drug must reach parasites in the cutaneous lesion(s). On top of this, antileishmanial drugs must cross multiple membranes in order to reach the parasite and act upon it. Once at the site of infection, any drug must first permeate the infected macrophage membrane before crossing the membrane of the PV and finally cross the plasma membrane of the parasite (Figure 1). Studies using live imaging of immunolabeled parasites and lysotracker dyes have shown the dynamic nature of PV.[3] These studies showed that the increase in size of L. amazonensis PVs was associated with a decrease in acidic vesicles within infected macrophages. A drug-loaded carrier could be taken up by phagocytosis and the resulting membrane-bound vesicle could fuse with a PV and aid in delivery to parasites within the macrophage or the drug could diffuse into the PV from the cytoplasm and enter parasites after the carrier has been degraded within a PV. Technical developments will aid in characterizing delivery to the parasites within the PV but successful drug delivery is generally based on a reduction in parasite burdens within infected macrophages. Most analytical methods for drugs are based on high-performance liquid chromatography and assessment of delivery to the parasite would require isolation of amastigotes, which may cause drug loss, and an assay method of a suitable sensitivity level to detect the drug present. In most in vivo studies traditional pharmacokinetic parameters (e.g., distribution phase half-life, elimination phase half-life, area under the plasma concentration–time curve, volume of distribution, total body clearance) and drug levels at the targeted site are used to assess delivery. For example, antimonial drugs given by the intravenous route are only present in the blood for a short period of time as they have a short half life (absorption phase mean half-life of 0.85 h) and a rapid clearance (elimination mean half-life of 2.02 h),[20] which would limit their uptake by the host cells and explain why multiple dosing is required for parasiticidal levels to reach the Leishmania parasites. Recent reviews discuss the problems associated with delivery of drugs using different routes of administration,[21–23] the problems associated with drug delivery to specific sites or organelles within the body[24,25] and drug deposition and uptake at these sites.[26,27] A drug delivery system can improve delivery by directing more of the drug dose to tissues and away from the systemic circulation. Once the drug formulation has accessed cells at the site of uptake then the release rate for the drug and its inherent physicochemical properties will influence its release into surrounding tissues.[27,28] Most drug delivery systems act as drug depots giving more time for the drug to concentrate within the targeted cells. Macrophages, which are found in high concentrations in a number of locations in the body, for example, liver, lungs and spleen play an important role in enhancing tissue uptake of particulate nanoformulations. Macrophages phagocytose particles from their immediate vicinity as part of their innate immune response and as a consequence act as a local drug depot. This means that the drug is directed directly to the Leishmania parasite in infected macrophages.[29–31] Borborema et al. demonstrated the advantages of this type of approach using a liposomal formulation of meglumine antimoniate They showed that using the carrier system reduced the IC50 value value against the intracellular amastigote stage of L. major compared with the drug solution, from 93 to 10.5 µM. Moreover, they also showed and that infected macrophages were more efficient than uninfected macrophages at taking up the liposomes.[31] A drug delivery system can facilitate a reduction in the total drug dose and/or number of doses required, which is particularly important for a potentially toxic drug. This can be important for a drug that causes nephrotoxicity such as AMB. This beneficial feature for drug delivery systems has been clearly demonstrated by the higher efficacy and lower toxicity of lipid formulations of AMB compared with AMB solution.[32] However these lipid formulations are prohibitively expensive for widespread use in endemic countries. This problem is being addressed by a WHO initiative, which facilitated the donation of 445,000 vials of AMBisome for the treatment of VL.
Figure 1.
Route a drug must take to access intracellular Leishmania amastigotes within macrophages. A drug enters the body by the route administered and has to reach the sites where infected macrophages reside and as a consequence have to cross multiple membranes to enter the parasite.
N: nucleus of the cell.
Repurposing drugs originally designed for other clinical conditions may give new antileishmanial treatments.[33] The feasibility of this approach has already been shown by AMB, originally developed for the treatment of fungal infections, and MILT, which was originally in development for the treatment of cancer. Repurposing clinically approved drugs for treatment of leishmaniasis is an attractive approach as the majority of the required toxicity testing has already been completed, although additional testing would be required if a different mode of administration is used. Endemic countries often have traditional medicines that have been used for the treatment of leishmianiasis, and development of novel drugs from plant products has been investigated.[34]
Nanomedicine. 2014;9(10):1531-1544. © 2014 Future Medicine Ltd.
