Drug Targeting Organ-Specific Strategies

114 4 Cell Specific Delivery of Anti-Inflammatory Drugs to Hepatic Cells
but is not related to the immunogenicity of the conjugate [93]. These studies may indicate
that in addition to the pro-fibrotic actions of KCs, these cells are also endowed with anti-fibrotic
capacities that are downregulated by dexamethasone.
Dexa has also been incorporated into several particle-type carriers, although most of them
were not designed for the specific targeting of KCs or SECs. Yokoyama and Watanabe incorporated
Dexa-21-palmitate into lipid microspheres for targeting inflammatory cells and
macrophages in the treatment of rheumatoid arthritis [188]. They demonstrated high uptake
of lipid-incorporated Dexa by macrophages, up to five times higher anti-inflammatory activity
of lipid-incorporated Dexa as opposed to free Dexa and a significantly higher rate of improvement
in patients with rheumatoid arthritis treated with encapsulated Dexa. Magnani
et al. used Dexa-21-phosphate encapsulated in human erythrocytes for this same purpose
[189]. They also showed high concentrations of corticosteroids in macrophages and effective
inhibition of the respiratory burst of stimulated macrophages by encapsulated Dexa , which
was not found for free Dexa. Recently, we incorporated Dexa disodium phosphate into liposomes
especially designed for KC targeting [190]. These liposomes are currently used to
study their effects on the development of fibrosis in rats subjected to bile duct ligation.
4.10 Selective Drug Delivery for the Treatment of Other
Hepatic Disorders
Drug targeting preparations have been given to patients with various infectious diseases. For
the treatment of Leishmaniasis, liposomes as well as mannosylated HSA have been used to
deliver antiparasitic drugs, such as methotrexate, amphotericin B, doxorubicin and muramyl
dipeptide to KCs [97,98,191–193]. These conjugates all inhibited the growth of Leishmania
parasites in Kupffer cells as well as in splenic macrophages in mice infected with this parasite.
Liposomal amphotericin B was also tested in immunocompetent patients with visceral Leishmaniasis
and was proven to be an effective treatment. Side-effects typical for amphotericin B
(hypokalaemia, nephrotoxicity) occurred significantly less frequently after treatment with
the liposomal formulation as compared to the convential formulation of the drug [98].
Drug targeting preparations based on lactosylated HSA have been used for the treatment
of chronic viral hepatitis, because these viruses reside in hepatocytes. Fiume et al. coupled
several anti-viral nucleoside analogues to this carrier for the treatment of hepatitis [194,195].
The conjugate of adenine arabinoside monophosphate and lactosylated HSA (araAMPlacHSA)
has been studied in animals as well as in humans [1,196]. From the clinical trials it
was concluded that use of this conjugate allowed more prolonged treatment of chronic hepatitis
B than free araAMP, because of the lack of side-effects after chronic application of the
conjugate, which enhanced its chemotherapeutical index. To date, however, no follow-up has
been published.
The treatment of tumours in the liver with drug targeting preparations is hampered by the
lack of tumour specifity of most preparations. Liposomes incorporating the immunomodulator
muramyl tripeptide phosphatidylethanolamine have been used as an ‘aspecific’ approach
to increasing the number of tumouricidal macrophages in the liver in order to prevent the development
of metastases [99]. To date, the greatest tumour cell specificity has been obtained