Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 785

Later, AmB was attached to poly(HPMA)-polymer through a degradable
GlyPheLeuGly linker (Nicoletti et al. 2009 ). The copolymers had an IC 50 of
0.03 mg/ml against L. donovani amastigotes in murine peritoneal exudate mac-
rophages and in murine bone marrow-derived macrophages and an IC 50 0.57 mg/ml
against L. donovani in differentiated THP-1 cells. This activity was comparable
with free AmB (IC 50 : 0.03-0.07 mg/ml and 0.24-0.42 mg/ml against L. donovani
amastigotes in mice derived macrophages and amastigotes in THP-1 cells, respec-
tively) and Fungizone (IC 50 : 0.04-0.07 mg/ml against amastigotes in mice derived
macrophages). Conjugates also showed potent in vivo activity with ca. 50% inhibi-
tion of parasite burden at 1 mg/kg body weight upon i.v. administration. Recently,
the poly(HPMA)-AmB copolymer was conjugated with alendronic acid (Nicoletti
et al. 2010 ). However, no advantage of the combinatorial conjugates was observed
as compared to single-drug poly(HPMA)-AmB conjugates. Furthermore, there was
no significant activity for the poly(HPMA)-alendronic acid conjugate within the
concentration range tested.
A single attempt of using less invasive treatments administered by oral via
employed nanosuspensiones made of AmB in an aqueous solution of Tween 80,
Pluronics F68 and sodium cholate, but only reduced 29% the liver parasite load on
experimental visceral leishmaniasis (Kayser et al. 2003 ).

7.2.2 Cutaneous Leishmaniasis

Intravenously administered liposomal Sb v (New and Chance 1980 ; New et al. 1981 )
and AmBisome (Yardley and Croft 1997 ) were more effective than free drugs.
However, when administered by i.p. or s.c. vias liposomal treatments failed against
experimental cutaneous leishmaniasis ( L. major ).
The success of treatment for early stages of cutaneous leishmaniasis depends on
how physically accessible the infected macrophages in the stratum spinosum are to
the drug delivery system. Circulating nanoparticles can became close to the stratum
spinosum only from local extravasation. The higher IC 50 values (25 mg/kg) for
cutaneous leishmaniasis than for visceral leishmaniasis (0.3 mg/kg) of i.v.
AmBisome reflect the difficulty for particulate material to target the infected cells
(Yardley and Croft 2000 ). Although clinical applications of i.v. AmBisome against
cutaneous leishmaniasis have been reported, up to date there are no available data
on optimum dosage regimen and extention of treatment (del Rosal Rabes et al.
2010 ; Wortmann et al. 2010 ). Succesful short term treatments (5 days at 3 mg/kg/day
plus a reinforcement dose at the tenth day) (total dose: 18 mg/kg) in adults have
been reported (Rapp et al. 2003 ; Solomon et al. 2007 ). Other authors recommend
total doses of 40 mg/kg (Brown et al. 2005 ). However, the need for i.v. administra-
tion together with its high cost may limit the use of AmBisome.
AmB loaded in apolipoprotein-stabilised phospholipids bilayer disk complexes,
completely cleared parasites, with no lesions remaining on experimental cutaneous
leishmaniasis upon i.p. administration (Nelson et al. 2006 ). Apolipoproteins modi-
fied by acetylation, oxidization and others serve as ligands for class A scavenger