Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 761

therefore, not surprising that oral inhalation therapy is considered not only as the
preferred mode of administration of drugs to the lungs (regional drug delivery), but
also as a potential pathway to the blood stream (Patton and Byron 2007 ). However,
many challenges in formulation development (Rogueda 2005 ) and little under-
standing of the interactions between the therapeutic molecules and the respiratory
surfaces have significantly constrained advances in pulmonary drug delivery strate-
gies (Sakagami 2006 ).
Alveolar macrophages remove inhaled particulate matter from the air spaces and
red blood cells from the septum by phagocytosis and endocytosis, kill intracellular
infecting bacteria, produce pro-inflammatory cytokines, migrate to local lymphoid
tissue, and presentate antigen and activate T cells. In contrast to antigen presenting
cells from lymphoid tissue, the lung alveolar macrophages and dentritic cells are
biased towards an immunosuppressive response, and need strong inflammatory
inducing signals via toll like receptors, complement, or Fc receptors to overcome
this . Alveolar macrophages are found in the connective tissue of the septum and in
the air space of the alveoli, lying on the surface of the alveolar cells type II and type
I, immersed within alveolar fluid which is covered by a surfactant layer. However,
compared to Kupffer cells (macrophages lining the endotelial liver vasculature)
alveolar macrophages are not readily accessible for liposomes or other nanoparti-
cles in systemic circulation. Because of this, the inhalatory via is the only way of
administration that enables a direct contact between particulate drug carriers and
alveolar macrophages.
There are two objectives of targeting alveolar macrophages using inhaled
therapies. First, such targeting can deliver extremely large amounts of the anti-
mycobacterial drugs to the macrophage cytosol, even potentially sufficient to over-
come drug resistance. Second, uptake of particles by macrophages has the potential
to activate infected macrophages. A recent paper on RIF-loaded PLGA micropar-
ticles reported that infected macrophages possess an enhanced phagocytic activity
with respect to uninfected cells. This is a very interesting finding since it demon-
strates that phagocytic activity, during infection, is not only maintained but even
increased (Hirota et al. 2008 ).
Inhalatory techniques can be classified according to the mechanism of aero-
solization (Misra et al. 2010 ) in: (i) nebulization is the generation of a mist of
droplets through the use of compressed air or oxygen and consists of dispersing
solid or phase-separated drug delivery systems into droplets suspended in a small
amount of medium; (ii) pressurized metered-dose inhaler (pMDI or MDI), the most
familiar technique of administering medication to the airways and lungs. Such a
device uses an aerosol propellant and a dose-metering valve to regulate the egress
of defined amounts of medication to the respiratory tract; (iii) dry powder inhalers
(DPI) represent an option that lies mid-way between nebulization of a medicament
in an external aqueous or gaseous phase, and its delivery under positive pressure
such as MDI. DPI relies on the indrawn breath of the patient to pull in a dry powder.
The aerosol is generated by turbulence-creating devices actuated by the airstream
of indrawn breath (Onoue et al. 2009 ). A technique usually employed in experi-
mental studies on tuberculosis, accomplishes pulmonary delivery by intratracheal