Journal of Biomaterials and Nanobiotechnology, 2011, 2, 567-575
doi:10.4236/jbnb.2011.225068 Published Online December 2011 (http://www.scirp.org/journal/jbnb)
567
Pulmonary Delivery: Innovative Approaches and
Perspectives
Carlotta Marianecci1, Luisa Di Marzio2, Federica Rinaldi1, Maria Carafa1*, Franco Alhaique1
1Department of Drug Chemistry and Technologies, “Sapienza”, University of Rome, Rome, Italy; 2Department of Drug Science,
University of Chieti “G. D’Annunzio”, Chieti, Italy.
Received October 6th, 2011; revised November 17th, 2011; accepted November 28th, 2011.
ABSTRACT
The respiratory system, as well as the skin, are organs in direct contact with the environment and they represent pos-
sible doors for the entrance of therapeutic agents into the body. Because of the increasing incidence of pulmonary dis-
eases with high mortality and morbidity, pulmonary drug delivery is emerging as a non-invasive and attractive ap-
proach for the treatment of several pathologies. It must be pointed out that the development of drug delivery systems for
pulmonary application requires a detailed knowledge of the lung, both in its healthy and disease state. Among the vari-
ous drug delivery systems considered for pulmonary application, nanocarriers show several advantages over other
conventional approaches for the treatment of respiratory diseases, for example prolonged drug release and cell-specific
targeted drug delivery. Nano-size drug carriers can incorporate various therapeutics (e.g., poorly water soluble drugs,
macromolecules) and show interesting features as drug delivery systems to the lung, such as: controlled release, pro-
tection from metabolism and degradation, decreased drug toxicity and targeting capabilities. Since gene therapy (e.g.
small interfering RNA, siRNA) is currently being developed for a wide range of acute and chronic lung diseases, in-
cluding CF, cancer and asthma, the use of nanocarriers for lung release/targeting represents a promising application
of such nano-sized structures. Despite the many promising proof of concepts of various delivery technologies reported
in this review, further efforts are needed to ensure the safety of long-term in vivo applications and the development of
scale up from laboratory to industry in order to reach, together with safety, large-scale production at affordable costs
of innovative lung delivery technologies.
Keywords: Pulmonary Delivery, Nanovectors
1. Introduction
The respiratory system, together with the skin, is an or-
gan in direct contact with the environment and it repre-
sents a possible door for the entrance of therapeutic com-
pounds into the body. Because of the increasing inci-
dence of pulmonary diseases with high mortality and
morbidity [1], pulmonary drug delivery is emerging as a
non-invasive and attractive approach for the treatment of
various pathogenic disorders. Such route of administra-
tion is acquiring an ever increasing interest also for sys-
temic administration of therapeutic agents. Potential ad-
vantages of this route over others, such as the intrave-
nous and the oral ones include:
 rapid drug deposition in the target organ, avoiding
high-dose exposures to the systemic circulation;
 rapid onset of drug action;
 lower systemic exposure and consequently reduced
side effects;
 evasion of first pass metabolism, because the drug-
metabolizing enzymes are in much lower concentra-
tions in the lungs than the gastrointestinal system and
liver [2].
In addition, the increasing interest in pulmonary drug
delivery is also attributed to the possibility to enhance the
bioavailability of molecules with high molecular weight,
in comparison with all the other non-injection routes of
delivery (oral, buccal, transdermal and nasal), which
were shown to be not capable to allow the permeation of
macromolecules unless absorption enhancers were used.
Furthermore, it must be pointed out that the penetration
enhancers, like surfactants and bile salts, may cause sig-
nificant non-reversible tissue damages, although they
increase the permeability of drugs through the epithelial
membrane [3,4]. Several therapeutic products are inves-
tigated for pulmonary delivery with the aim of obtaining

Pulmonary Delivery: Innovative Approaches and Perspectives 568
systemic or local activity. Administration of drugs di-
rectly to the lungs is the most appropriate route in the
treatment of asthma and other pulmonary diseases such
as tuberculosis, chronic obstructive pulmonary disease
and lung cancer.
In case of low molecular weight drugs, numerous
studies were focused on local application for the treat-
ment of chronic respiratory diseases such as asthma and
chronic obstructive pulmonary disease (COPD). At the
same time, several recent studies indicated how pulmo-
nary delivery may offer great potential for large mole-
cules, such as proteins and peptides, for both local tar-
geting and systemic effect; i.e., for the treatment of res-
piratory diseases and other pathologies such as thrombo-
sis and diabetes mellitus. In this sense, inhalation can
represent the most favourable non-invasive route of ad-
ministration for insulin (5.8 kDa) because insulin bioa-
vailability can reach 37% following inhalation while it
reaches at most 1% following oral, sublingual, nasal or
transdermal administration without chemical enhancers
[5,6]. The first inhaled insulin product, Exubera®, was
approved in January 2006 but it was withdrawn from the
market already in October 2007 due to disappointing
sales.
Another inhaled insulin product, AFREZZA™, is cur-
rently under review by the FDA for the treatment of type
1 and type 2 diabetes [7,8]. AFREZZA™ is an ultra rapid
acting insulin comprising Technosphere® insulin powder
in unit dose cartridges for administration with the inhaler.
The Technosphere® powder formulation is prepared by
precipitating insulin from a solution onto preformed
diketopiperazine particles, which readily dissolve once in
the lung environment. AFREZZA™ appears to overcome
several limitations of Exubera®. Technosphere® insulin
is both rapidly absorbed and eliminated and its pharma-
cokinetic profile mimics more closely normal physiol-
ogic insulin release than injection of regular insulin as
well as of rapid-acting analogues
Gene delivery to the lungs is mainly focused on the
localized delivery of drugs to the site of action, the lungs
and airways, including lung cancer, genetic disorders
affecting the airways (cystic fibrosis, alpha-1-antitrypsin
deficiency), obstructive lung diseases (asthma), and vac-
cination. Only one inhaled therapeutic protein is cur-
rently available on the market. It is recombinant human
deoxyribonuclease I (Dornase alfa) indicated for the
treatment of cystic fibrosis (CF) and marketed since
1994.
Recombinant human deoxyribonuclease I is a glyco-
protein of 37 kDa, which selectively cleaves DNA. In CF
patients, retention of viscous purulent secretions in the
airways contributes both to reduced pulmonary function
and to exacerbation of infection. These pulmonary secre-
tions contain very high concentrations of extracellular
DNA released by degenerating leukocytes. Dornase alfa
is delivered to CF patients by inhalation of an aerosol
mist produced by a pneumatic nebulizer; it hydrolyses
the DNA in airway secretions and reduces their viscosity.
A significant disadvantage of inhalation therapy is the
relatively short duration of drug action demanding multi-
ple daily inhalation maneuvers, ranging up to 9 times a
day [9].
Strategies for further advancements of inhalation
therapy include the development of aerosolizable carrier
systems with the aim to improve the drug effect, as well
as patient’s convenience and compliance. Today, re-
searchers have made great strides in the development of
pulmonary delivery technologies, both in terms of inhaler
design and progresses in nanoscale carrier engineering.
Today there are three main different classes of devices
for pulmonary drug delivery: nebulizers, Metered Dose
Inhalers (MDIs), and Dry Powder Inhalers (DPIs). These
inhalers are based on different delivery mechanisms, and
require different types of drug formulations. Furthermore,
the development of new bioactive compounds such as
nucleic acids and proteins, require the design of innova-
tive delivery technologies.
Among the various drug delivery systems considered
for pulmonary application, nanocarriers demonstrate
several advantages for the treatment of respiratory dis-
eases, for example prolonged drug release and cell-spe-
cific targeted drug delivery.
The development of an innovative nanocarrier, able to
deliver the drug to the desired site of action, is highly
dependent on the nature of the active substance and on its
desired site and mode of action (Figure 1).
Improved
Pulmonary
Delivery
Active Substance
Polymers and/or
Amphiphilic molecules
Size Absorption
Site
Partition
Coefficient
Nanovectors
Size
Design according to
clinical purposes
Increased
bioavaliability
Mass Density
Deposition
Place
Improved
Pulmonary
Delivery
Improved
Pulmonary
Delivery
Active SubstanceActive Substance
Polymers and/or
Amphiphilic molecules
Polymers and/or
Amphiphilic molecules
SizeSize Absorption
Site
Absorption
Site
Partition
Coefficient
Partition
Coefficient
NanovectorsNanovectors
SizeSize
Design according to
clinical purposes
Increased
bioavaliability
Mass DensityMass Density
Deposition
Place
Deposition
Place
Improved
Pulmonary
Delivery
Active Substance
Polymers and/or
Amphiphilic molecules
Size Absorption
Site
Partition
Coefficient
Nanovectors
Size
Design according to
clinical purposes
Increased
bioavaliability
Mass Density
Deposition
Place
Improved
Pulmonary
Delivery
Improved
Pulmonary
Delivery
Active SubstanceActive Substance
Polymers and/or
Amphiphilic molecules
Polymers and/or
Amphiphilic molecules
SizeSize Absorption
Site
Absorption
Site
Partition
Coefficient
Partition
Coefficient
NanovectorsNanovectors
SizeSize
Design according to
clinical purposes
Increased
bioavaliability
Mass DensityMass Density
Deposition
Place
Deposition
Place
Figure 1. Factors affecting pulmonary delivery.

Pulmonary Delivery: Innovative Approaches and Perspectives569
2. Practical Address in Pulmonary Delivery
The development of drug delivery systems for pulmonary
application requires a detailed knowledge of the lung in
its healthy, as well as various diseased states. The lung
consists of two functional parts, the airways (trachea,
bronchi, and bronchioles) and the alveoli (gas exchange
areas). The primary functions of the lungs are to enable
gas exchange between the blood and the external envi-
ronment, and to maintain homeostatic systemic pH. The
respiratory system is composed of the trachea, which
bifurcates into the bronchi. The bronchi continue to
branch into smaller bronchioles, and ultimately the ter-
minal bronchi, which end with the alveolar sacs.
Gas exchange between airspaces and blood capillaries
occurs in the respiratory region, which includes the res-
piratory bronchioles, the alveolar ducts and the alveolar
sacs.
The surface area of the alveolar epithelium reaches
100 m2, which is enormous as compared to the 0.25 m2
surface area of the airways [10,11]. The alveoli have a
thin, single cell layer. The distance from the air in the
alveolar lumen to the capillary blood flow is less than
400 nm. The large surface area of the alveoli and the
intimate air-blood contact in this region make the alveoli
less well protected against inhaled substances, such as
nanoparticles, as compared to the airways [12]. Despite
the numerous advantages above reported, pulmonary
administration of drugs shows, at the same time, several
problems related, for instance, to the various clearance
mechanisms and the mucous layer. Mucociliary clear-
ance is one of the most important defence mechanisms to
eliminate dust and microorganisms in the lungs [13]. The
mucus is produced by goblet cells and sub-mucosa
glands. It covers the entire airway surface and its thick-
ness ranges from 5 μm to 55 μm [14,15]. It consists of an
upper gel phase made of 95% water, 2% mucin, a highly
glycosylated and entangled polymer, as well as salts,
proteins and lipids [16]. A periciliary liquid layer under-
lies the mucus gel and its low viscosity allows effective
cilia beating. The coordinated, rhythmic beating of the
cilia constantly moves this mucous layer toward the
proximal airways, where it is either swallowed or expec-
torated (mucociliary clearance). Particles settling in the
peripheral lung have been reported to have a residence
time of approximately 24 hr in a healthy adult patient.
Pulmonary surfactants are responsible for biophysical
stabilizing activities and innate defence mechanisms.
They line the alveolar epithelial surfaces and overflow
into the conductive airways so that the surfactant film is
continuous between alveoli and central airways [17].
Pulmonary surfactants are composed of phospholipids
(80%, half of which being dipalmitoylphosphatidylcho-
line), neutral lipids (5% - 10%, mainly cholesterol), spe-
cific surfactant proteins (5% - 6%) and non-specific pro-
teins (3% - 4%) [18].
Phospholipids are mainly responsible for the formation
of the surface active film at the respiratory air-liquid in-
terface. In water, phospholipids are self-organized in the
form of bilayers. Bilayers are also the structural form in
which surfactants are assembled and stored by pneu-
mocytes in lamellar bodies.
Specific surfactant proteins include SP-A, SP-B, SP-C
and SP-D. SP-A and SP-D are hydrophilic while SP-B
and SP-C are hydrophobic. SP-A is able to bind multiple
ligands, including sugars, Ca2+ and phospholipids. This
property allows SP-A to bind to the surface of pathogens,
contributing to their elimination from the airways. Rec-
ognition of SP-A by specific receptors on alveolar macro-
phages stimulates phagocytosis of the pathogens. SP-B is
strictly required for the biogenesis of pulmonary surfac-
tants and their packing into lamellar bodies. Both, SP-B
and SP-C promote the rapid transfer of phospholipids
from bilayers stores into air-liquid interfaces.
Luminal airway and alveolar macrophages are at the
forefront of lung defence and their primary role is to par-
ticipate in innate immune responses, such as, chemotaxis,
phagocytosis, and microbial killing [19]. They also down-
regulate adaptive immune responses and protect the lung
from T-cell-mediated inflammation [20]. Macrophages
are tightly applied on the surface of respiratory epithelia.
They are immersed in the lung lining fluid beneath the
surfactant film.
The lung presents a remarkably lower level of metabo-
lism than the gastrointestinal tract and liver. Yet, various
peptidases are distributed on the surface of different cell
types in the lung, including bronchial and alveolar
epithelial cells, submucosal glands, smooth muscles, en-
dothelial cells and connective tissue.
Proteases play an essential role in cell and tissue
growth, differentiation, repair, remodelling, cell migra-
tion and peptide-mediated inflammation [21]. Proteases
can also be released in the airspaces by activated macro-
phages and neutrophils in case of inflammatory reactions
in the respiratory tract [22]. Blood supply to the lungs is
divided among the pulmonary and systemic circulations.
The pulmonary circulation consists of the pulmonary
artery that leaves the right heart, branches into a dense
pulmonary capillary bed that surrounds the alveoli and
finally coalesces into the pulmonary vein that drains into
the left heart. One hundred percent of the cardiac output
flows through the pulmonary circulation. Its principal
functions are gas exchange with air in the alveoli and
nutrients supply to terminal respiratory units. The lungs
receive a second blood supply via the systemic circula-
tion, commonly referred to as the bronchial circulation.

Pulmonary Delivery: Innovative Approaches and Perspectives 570
The bronchial circulation originates from the aorta and
provides oxygenated blood and nutrients to all structures
of the tracheobronchial tree. Lymphatic vessels exist in
close proximity of major blood vessels and of the air-
ways [23].
This high level of vascularization, and the large sur-
face area combined with an extremely thin barrier be-
tween the pulmonary lumen and the capillaries, create
conditions that are well suited for efficient mass transfer
[24].
Particle deposition in the lungs occurs by inertial im-
paction, sedimentation. In order to evaluate the capacity
of inhaled particles to reach different regions of the res-
piratory tract, the so-called aerodynamic diameter of
such particles must be considered. The aerodynamic di-
ameter of a particle, daer, is equivalent to the diameter of
a unit density (ρ0) sphere that has the same terminal ve-
locity in still air as the particle:
0
aer
dd
X



where d is the geometric diameter of the particle, ρ is the
particle density and X is the particle dynamic shape fac-
tor denoting deviation of shape from sphericity [25].
Actually, particles larger than 5 μm in diameter are
generally subject to inertial impaction in the oropharyn-
geal region, or sedimentation in the bronchial region,
where delivered drug may be expected to have little sys-
temic therapeutic effect. At the other extreme, particles
with diameters substantially smaller than 1 μm, although
capable to reach the alveolar region, they are not capable
to deposit and are thus exhaled. Particles with aerody-
namic diameters between 1 and 5 μm are expected to
bypass deposition in the mouth and throat and effi-
ciently deposit in the lung periphery [26].
3. Innovative Approaches in Lung Delivery
The successful integration of novel drugs with devices
capable of delivering defined doses to the respiratory
tract has resulted in a proven track record for inhalation
as a route of administration that limits systemic exposure
and provides localized topical delivery. Thus, a number
of orally inhaled products have been successfully devel-
oped over the last 50 years, providing symptomatic relief
to millions of patients with asthma and chronic obstruc-
tive pulmonary disease (COPD).
Nowadays, biopharmaceuticals and conventional drugs
are frequently engineered or incorporated in carriers in
order to direct their fate in preferential pathways [27,28].
Nano-size drug carriers can incorporate various thera-
peutics (e.g., poorly water soluble drugs) and present
several advantages for drug delivery to the lung include-
ing controlled release, protection from metabolism and
degradation, decreased drug toxicity and targeting capa-
bilities.
Nanotechnology is the engineering and manufacturing
of materials at the atomic and molecular scale. In its
strictest definition from the National Nanotechnology
Initiative, nanotechnology (NIH Roadmap Initiatives,
http://nihroadmap.nih.gov/initiatives.asp.), it refers to
structures roughly in the 1 - 100 nm size regime in at least
one dimension. Despite this size restriction, nanotech-
nology commonly refers to structures that are up to sev-
eral hundred nanometers in size and that are developed
by topdown or bottom-up engineering of individual com-
ponents [29]. Bioactive delivery nanosystems (nanocar-
riers) in general, and drug delivery in particular, consti-
tute a significant domain of nanomedicine.
Nanomedicine can be defined as the application of
nanotechnology to medicine. Artificial nanostructures are
of the same size as biological entities and can readily
interact with biomolecules on both the cell surface and
within the cell (Figure 2).
The understanding of the fate of nanomedicines in the
lungs is important because fate and therapeutic activity
are closely related. Interaction of nanomedicines with
cells of the respiratory system will determine the phar-
macodynamic response. For instance, the rapid uptake of
particles by alveolar macrophages can be a way of tar-
geting anti-tuberculosis drugs to this type of cells [30].
Conversely, macrophages uptake represents a clearance
pathway for drugs acting on other cells within the lungs
(e.g., β2mimetics) [31].
There are numerous types of nanoparticle systems now
being explored for drug delivery to lungs, especially in
cancer treatment [32]. The types of nanovectors used at
present in research for cancer therapeutic applications
include polymeric nanoparticles, protein nanoparticles,
ceramic nanoparticles, viral nanoparticles and metallic
nanoparticles [33].
A further innovation in the treatment of lung cancer
concerns the development of inhalable nanoparticles (NPs)
to obtain cytotoxicity mediated by alveolar macrophages
[34,35].
Lipid-based carrier systems, including liposomes and
their nanoversions (nanoliposomes), are among the most
promising encapsulation technologies employed in the
rapidly developing field of nanotechnology. Liposomes
are the most extensively investigated system for con-
trolled drug delivery to the lungs [36]. A few lipo-some-
encapsulated antibiotics have been delivered to the lungs
in phase II clinical trials. These include amikacin [37]
and ciprofloxacin [38]. Multiple treatment cycles with
ARIKACE™ (liposomal amikacin for inhalation) showed
sustained improvement in lung function with significant

Pulmonary Delivery: Innovative Approaches and Perspectives 571
1nm 10nm 100nm 1m
POLYMERS
AMPHIPHILES
Dendrimers Nanocapsules
Micelles
LiposomesNiosomes
1nm 10nm 100nm 1m
POLYMERS
AMPHIPHILES
Dendrimers Nanocapsules
Micelles
LiposomesNiosomes
1nm 10nm 100nm 1m
POLYMERS
AMPHIPHILES
Dendrimers Nanocapsules
Micelles
LiposomesNiosomes
Figure 2. Types of nanosize systems used for drug delivery and targeting. The blue axsis represents the diameters of
nanovectors.
reduction in bacterial density in CF patients who have
chronic Pseudomonas lung infections [39].
A nanoscale liposomal formulation of amikacin has
been shown to slowly release the drug in rat lungs and to
penetrate Pseudomonas biofilms and CF sputum in vitro
[40].
Mitsopoulos and Suntres [41] reported that the deliv-
ery of N-acetylcysteine as a liposomal formulation im-
proves its effectiveness in counteracting Paraquat-in-
duced cytotoxicity.
Liposomal drug dry powder formulations, realized to
obtain novel devices capable of delivering defined doses
of drugs, represent promising tools for pulmonary drug
administration, such as selective localization of drug,
reduced local and systemic toxicities, increased patient
compliance and high dose loading.
In liposomal dry powder formulations, drug encapsu-
lating liposomes are homogenized, dispersed into the
carrier and converted into dry powder by using freeze
drying, spray drying or supercritical fluid technologies.
Huang et al. developed a formulation of liposomal
salbutamol sulfate (SBS) with high encapsulation effi-
ciency (more than 80%) formulated in a dry powder in-
haler (DPI) for the treatment of asthma, offering the
promising possibility of localized pulmonary liposomal
SBS delivery in the anhydrous state [42].
The most commonly used liposomes are composed of
lung surfactants and synthetic lipids. Liposomal formula-
tion have been proposed to delivery anticancer drugs,
corticosteroids, immunosuppressants, antimicotic drugs,
antibiotics for local pulmonary infections and CF and
opioid analgesics for pain management. Many of them
have reached the stage of clinical trials for the treatment
of several pulmonary diseases [43].
Surfactant vesicles are analogous to liposomes but
have several advantages over them and were proposed
for pulmonary delivery. A novel approach was developed
for the preparation of controlled release proniosome-
derived niosomes, using sucrose stearates as non-ionic
biocompatible surfactants for the nebulisable delivery of
cromolyn sodium [44]. An attempt has been made to
incorporate anti-tuberculosis drugs (ATD’s) in the pre-
pared niosomes. High encapsulation efficiency was ob-
tained and should an advantage to solve the problem of
multi-drug resistance in case of tuberculosis [45].
Various nonionic surfactants of sorbitan ester class
together with cholesterol were proposed to prepare nio-
somes containing rifampicin [46]; furthermore, Polysor-
bate 20 vesicles were studied in pulmonary glucocorticoid
delivery [47,48].
A new trend in vesicles lung delivery is addressed to
obtain efficient and safe vaccine delivery systems. A
liposomal vaccine (MLB) based on xenogeneic human
Basic fibroblast growth factor and monophosphoryl lipid
A (MPLA) was proposed to induce humoral immunity
through cross-reaction, to mediate Th1 immune response
preferentially and to enhance antitumor activity in vivo.
[49].
A promising application of nanocarriers to lung tar-
geting is related to gene delivery. Gene therapy is cur-

Pulmonary Delivery: Innovative Approaches and Perspectives 572
rently being developed for a wide range of acute and
chronic lung diseases, including CF, cancer and asthma.
Several authors [50-52] developed a highly efficient nano-
composite aerosol for pulmonary gene delivery, consist-
ing of a biodegradable polymer core.
Serious respiratory diseases, due to their lethality and
prevalence, have attracted particular attention as targets
of small interfering RNA (siRNA)—mediated therapeu-
tic agents, also because of lung’s accessibility leading to
both local and systemic effects. However, one of the
major challenges to achieve the siRNA therapeutic po-
tential in lung diseases is to deliver the siRNAs to the
lung tissue, in particular, to the target cells with high
efficiency and high specificity [53].
Several clinical trials have been conducted in order to
assess the efficacy and safety of pulmonary DNA deliv-
ery using viral and non-viral vectors, especially in the
case of CF. Yet, none of these formulations have been
pursued due to low transfection efficiency, transient gene
expression or immune elimination of the gene vector.
Identification of the barriers to cell transfection might
help to improve gene transfer efficiency of non-viral
vectors [51]. An efficient and safe cationic lipid, 6-
lauroxyhexyl lysinate (LHLN), was proposed to prepare
cationic liposomes. In vitro tests showed that, compared
with Lipofectamine2000, the new cationic liposome
formulation using LHLN exhibited lower cytotoxicity
and similar transfection efficiency in A549 and HepG2
lung cancer cells [54].
Ishitsuka et al. developed a multifunctional envelope-
type nano device (MEND), in which plasmid DNA is
condensed using a polycation to form a core particle that
is encapsulated in a lipid envelope, modified with the
IRQ peptide (IRQRRRR) to enhance transgene expres-
sion in lungs [55].
Clinical applications of liposomes and nanoparticles
for drug delivery to the respiratory tract are still in early
stages. The key to future innovation may lie at the inter-
face between biology and particle engineering. Improved
understanding of biological processes including particle
clearance, cellular targeting, intracellular trafficking, and
drug absorption are needed to better design formulations
that deliver to the “target” with the optimal balance of
pharmacodynamic, pharmacokinetic, and safety profiles.
More specifically, continued advances are needed in the
development of: 1) controlled release formulations; 2)
formulations with improved regional targeting within the
lungs (e.g., airway versus alveoli and vice versa); 3)
formulations containing active targeting moieties; 4)
formulation strategies for improving the systemic bioa-
vailability of inhaled macromolecules; 5) formulation
strategies for delivering macromolecules, including
siRNA and DNA into cells; and 6) formulations with
improved dose consistency. It is likely that such innova-
tion will require the development of novel excipients and
particle engineering strategies. Future innovation must
also take into account the changing marketplace and the
diverse set of customers (patient, healthcare professional,
heath authorities, payers, and politicians) who must be
satisfied. The pharmacoeconomics of new delivery sys-
tems will be closely scrutinized, so it is imperative that
cost factors should be taken into account. Otherwise, the
new technology option may overshoot the evolving in-
halation marketplace.
4. Toxicity of Nanoparticles to the Lung
Epidemiological studies have confirmed a positive cor-
relation between levels of particulate pollution and in-
creased morbidity and mortality rates among general
populations [56].
The adverse health effects seem to be dominated by
pulmonary symptoms. For instance, many reports have
addressed that occupational exposure of inhaled rigid
nanoparticles (NPs) can lead to respiratory diseases such
as pneumoconiosis (pulmonary fibrosis) and bronchitis
[57,58].
Increasing inhalation of ambient ultrafine particles has
been linked with exacerbation of respiratory symptoms
and mortality among COPD sufferers [59]. It has also
been documented that NPs can instigate oxidative stress
and cellular toxicity in various types of cells [60].
It was also reported that chronic exposure to NPs can
potentially predispose humans to lung inflammation and
increase the risk of COPD.
A concentration range of NPs within the level found in
ambience and in nanotechnology industries [61] can
promote mucin aggregation.
The second safety aspect of deep lung deposition is the
interaction of nanoparticles with the alveolar environ-
ment that is covered with a thin surfactant film. This film,
as above reported, has important physiological functions
such as the acceleration of gas exchange and the lower-
ing of the surface tension in the alveolar space. Such
functions may be compromised by inhalable nanoparti-
cles that may cause life threatening consequences. There-
fore, the compatibility of a delivery system with the al-
veolar environment must be always carefully considered
[62,63].
For these reasons vesicular nanocarriers, composed of
lung surfactants and/or synthetic amphiphiles may pro-
vide an efficient delivery system for the treatment of
pulmonary disorders due to their biocompatibility, bio-
degradability and non-toxic nature [64].
5. Conclusions
Despite the many promising proof of concepts of various

Pulmonary Delivery: Innovative Approaches and Perspectives573
delivery technologies, there is still a long way ahead that
must be covered. This means there are still many chal-
lenges that are being faced, which, in turn, mean there
are many chances for the academic and industrial scien-
tist to improve formulations and make a decisive impact.
Further research efforts are needed to ensure the safety
of long-term in vivo applications and the development of
scale up from laboratory to industry in order to reach,
within a few years, the safety and large-scale production
at affordable costs of innovative lung delivery technolo-
gies.
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