Delivery to Intracellular Targets by Nanosized Particles - Intracellular Delivery: Fundamentals and Applications - page 80

In the second part of this chapter, two aspects of intracellular drug delivery with
colloidal drug carriers will be discussed in more detail: intracellular delivery to
macrophages and intracellular delivery of nucleic acids.

3 Intracellular Delivery to Macrophages

The accumulation of colloidal drug carriers within phagocytic cells can be exploited
in some drug delivery applications. For example, muramyldipeptide and analogues
which stimulate the antimicrobial and antitumoral activity of macrophages can be
delivered more efficiently as carrier-associated molecules. Muramyldipeptide
(MDP) is a low-molecular-weight, soluble, synthetic compound derived from the
structure of peptidoglycan from mycobacteria. Such compounds would be gener-
ated within macrophages after the ingestion of bacteria; therefore they act on intra-
cellular receptors but, because of their hydrophilicity, they penetrate poorly into the
cells and are eliminated rapidly after i.v. administration. Therefore, muramyl pep-
tides have been associated with both liposomes and nanocapsules. The first studies
using using soluble MDP within liposomes showed activity against pulmonary
(Fidler et al. 1981 ) and liver (Daemen et al. 1990 ) metastases in mice. However, the
low molecular weight and water-solubility means that this compound was poorly
encapsulated and leaked easily from liposomes. In response to this, lipophilic
derivatives such as muramyltripeptide-cholesterol (MTP-Chol; Barratt et al. 1989 )
and muramyltripeptide-phosphatidylethanolamine (MTP-PE; Asano and Kleinerman
1993 ) were developed. These systems promoted increased intracellular penetration
of muramyl peptides into macrophages in vitro. In-vitro studies of nanocapsules
loaded with MTP-Chol indicated that nanocapsules were taken up by phagocytosis
and that a soluble derivative was released in the lysosomes (Seyler et al. 1999 ;
Mehri et al. 1996 ). Thereafter, a number of effector mechanisms are induced in the
macrophages, such as the production of nitric oxide (Morin et al. 1994 ), cytokines
and arachadonic acid derivatives (Seyler et al. 1997 ).
Nanocapsules were also active against hepatic metastases in mice; however, the
treatment was only curative when the tumour burden was low (Barratt et al. 1994 ).
Similar observations were made with liposomes containing MTP-PE (Asano and
Kleinerman 1993 ). Nevertheless, these liposomes have been proposed for the treat-
ment of osteosarcoma (Mori et al. 2008 ).
Similar liposomes were also able to activate macrophages to control bacterial
infections, for example, Klebsiella pneumoniae (Melissen et al. 1994 ). As well as
activating the non specific defence mechanisms of macrophages, muramyl pep-
tides can act as adjuvants facilitate the development of a specific immune response
to an antigen and in this respect as well liposomal encapsulation increases their
efficiency (Turanek et al. 2006 ). The potential of liposomes as immunological
adjuvants (reviewed by Kersten and Crommelin 2003 ) was recognized as early as
1974. Both liposomes and nanoparticles can be used to deliver immunological
adjuvants or antigens or combinations of the two to antigen-presenting cells