**9. Specific applications of biodegradable NPs**

Attractive features, such as increased dissolution velocity, increased saturation solubility, improved bioadhesivity, versatility in surface modification and ease of post-production processing, have widened the applications of nanosuspensions for various routes. One major problem with the intravenous administration of colloidal particles is their interaction with the reticulo-endothelial system [212]. The applications of nanosuspensions in parenteral and oral routes have been very well investigated and applications in pulmonary and ocular delivery have been discovered. However, their applications in buccal, nasal and topical delivery are still awaiting exploration [213].

drug nanoparticle is contained, leading to even distribution of the drug in the lungs as compared to the microparticulate form of the drug. In regular suspension aerosols many droplets are drug free and others are highly filled with the drug, directing to uneven delivery and circulating of the drug in the lungs. Nanosuspensions could be utilized in all available types of nebulizer [224]. In a recent study, antitubercular drugs (rifampicin, isoniazid and pyrazinamide) were incorporated into various formulations of solid lipid particles ranged from 1.1–2.1 μm and formulations were nebulized to guinea pigs by mouth for direct pulmonar delivery [212]. Similarly, conditions such as pulmonary aspergillosis can easily be targeted by using suitable drug candidates, such as amphotericin B, in the form of pulmonary nanosus‐

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Nanosuspensions can assay to be a advantage for drugs that show poor solubility in lachrymal fluids. For delivery of such drugs, approaches such as suspensions and ointments have been proposed. Although suspensions present advantages such as extended residence time in a culdesac (which is desirable for most ocular diseases for effective treatment) and avoidance of the high tonicity produced by water-soluble drugs, their actual performance depends on the native solubility of the drug in lachrymal fluids. Thus, the intrinsic decomposition rate of the drug in lachrymal fluid governs its release and ocular bioavailability [226]. An approach that has recently been investigated to achieve the desired duration of action of the drug is the formu‐ lation of polymeric nanosuspensions loaded with the drug [212]. Ocular drug administration via SLN has been reported several times. Ocular drug administration via SLN has been reported several times [227]. Cavalli et al (2002) evaluated SLN as carriers for ocular delivery of tobramycin in rabbit eyes. As a result SLN significantly enhanced the drug bioavalability in the aqueous humor within 6 hours [228]. In addition, poly-cationic polymers may be useful penetration enhancers for ocular drug delivery [229]. De Campos et al. discovered the potential of cyclosporin-A loaded nanoparticles for the management of extraocular disorders, i.e. keratoconjunctivitis sicca or dry eye disease. They reported that the advantages of these systems in ocular drug delivery contain their ability to contact intimately with the corneal and conjunctival surface, thereby increasing delivery to external ocular tissues without compro‐ mising inner ocular structures and systemic drug exposure, and to provide these target tissues with long term drug level [230]. De Salamanaca et al. have reported that chitosan nanoparticles readily penetrate conjunctival epithelial cells and are well suffered at the ocular surface of

There is a great interest in the development of drug delivery systems that could allow an efficient and sitespecific transport of drugs to the target tissues affected by the disease. One of the most challenging barriers in the body is the blood–brain barrier (BBB) [232]. Endothelial cells of the BBB limit the solute movement into the brain by regulating transport mechanisms at the cell surface. These transport mechanisms help to keep the harmful substances out of the brain in order to maintain homeostasis [233]. Besides the development of simple prodrugs, an

pensions instead of using stealth liposomes [225].

**9.3. Ocular delivery**

rabbits [231].

**9.4. Brain delivery**

#### **9.1. Oral delivery**

In recent years, significant research has been done using nanoparticles as oral drug delivery vehicles. Oral delivery of drugs using nanoparticles has been shown to be far superior to the delivery of free drugs in terms of bioavialability, residence time, and biodistribution [214]. Oral drug delivery is the choicest route for drug administration because of its non-invasive nature [215]. The drugs may also be susceptible to gastrointestinal degradation by digestive enzymes. The advantage of using polymeric nanoparticles is to permit encapsulation of bioactive molecules and maintain them against enzymatic and hydrolytic degradation [214] The use of submicron-size particular systems in oral drug delivery, especially peptide drugs, has attracted considerable pharmaceutical interest [216]. The efficacy or proficiency of the orally adminis‐ tered drug commonly depends on its solubility and absorption through the gastrointestinal tract. Therefore, a drug candidate that represents poor aqueous solubility and/or decomposi‐ tion-rate limited absorption is believed to possess low and/or highly variable oral bioavaila‐ bility [212]. Despite numerous studies providing evidence that oral delivery of encapsulated antigens can efficiently elicit immune responses, up to now, less studies report a protection induced by antigen loaded particles administrated by the oral route against a challenge with the pathogen [217]. Fattal et al. achieved the protection of mice against *S. typhimurium* following oral administration of *S. typhimurium* phosphorylcholine antigen encapsulated in PLGA particles [218]. Pinto and Muller (1999) incorporated SLN into spherical pellets and investigated SLN release for oral administration [219]. Orally administered antibiotics such as atovaquone and bupravaquone replicate this problem very well. Nanosizing of such drugs can lead to a dramatic increase in their oral absorption and consequently bioavailability [212].

#### **9.2. Pulmonary delivery**

Besides its non-invasive nature, pulmonary drug delivery has many other advantages compared to alternative drug delivery strategies, containing a large surface area for solute transport, rapid drug uptake, and improved drug bioavailability [220, 221]. Delivery of antimicrobial agents to the lung via systemic NP administration is persistent and potentially harmful upon systemic exposure to the drugs. Alternatively, various NPs exhibiting prefer‐ ential accumulation in the lung and other organs have been tried. It was reported that intratracheally administered antibiotics loaded NPs were able to penetrate through the alveolar-capillary barrier into the systemic circulation and accumulate in extrapulmonary organ containing liver, spleen, bone, and kidney [222]. Micronization of drugs plays an important role in improving the drug dosage form and therapeutic efficiency today. If a drug is micronized into microspheres with suitable particle size, it can be addressed directly to the lung by the mechanical prevention of capillary bed in the lungs [223]. Nanosuspensions may demonstrate to be an ideal approach for delivering drugs that display poor solubility in pulmonary secretions [212]. Furthermore, because of the nanoparticulate nature and uniform size distribution of nanosuspensions, it is very likely that in each aerosol droplet at least one drug nanoparticle is contained, leading to even distribution of the drug in the lungs as compared to the microparticulate form of the drug. In regular suspension aerosols many droplets are drug free and others are highly filled with the drug, directing to uneven delivery and circulating of the drug in the lungs. Nanosuspensions could be utilized in all available types of nebulizer [224]. In a recent study, antitubercular drugs (rifampicin, isoniazid and pyrazinamide) were incorporated into various formulations of solid lipid particles ranged from 1.1–2.1 μm and formulations were nebulized to guinea pigs by mouth for direct pulmonar delivery [212]. Similarly, conditions such as pulmonary aspergillosis can easily be targeted by using suitable drug candidates, such as amphotericin B, in the form of pulmonary nanosus‐ pensions instead of using stealth liposomes [225].

#### **9.3. Ocular delivery**

have been discovered. However, their applications in buccal, nasal and topical delivery are

In recent years, significant research has been done using nanoparticles as oral drug delivery vehicles. Oral delivery of drugs using nanoparticles has been shown to be far superior to the delivery of free drugs in terms of bioavialability, residence time, and biodistribution [214]. Oral drug delivery is the choicest route for drug administration because of its non-invasive nature [215]. The drugs may also be susceptible to gastrointestinal degradation by digestive enzymes. The advantage of using polymeric nanoparticles is to permit encapsulation of bioactive molecules and maintain them against enzymatic and hydrolytic degradation [214] The use of submicron-size particular systems in oral drug delivery, especially peptide drugs, has attracted considerable pharmaceutical interest [216]. The efficacy or proficiency of the orally adminis‐ tered drug commonly depends on its solubility and absorption through the gastrointestinal tract. Therefore, a drug candidate that represents poor aqueous solubility and/or decomposi‐ tion-rate limited absorption is believed to possess low and/or highly variable oral bioavaila‐ bility [212]. Despite numerous studies providing evidence that oral delivery of encapsulated antigens can efficiently elicit immune responses, up to now, less studies report a protection induced by antigen loaded particles administrated by the oral route against a challenge with the pathogen [217]. Fattal et al. achieved the protection of mice against *S. typhimurium* following oral administration of *S. typhimurium* phosphorylcholine antigen encapsulated in PLGA particles [218]. Pinto and Muller (1999) incorporated SLN into spherical pellets and investigated SLN release for oral administration [219]. Orally administered antibiotics such as atovaquone and bupravaquone replicate this problem very well. Nanosizing of such drugs can lead to a dramatic increase in their oral absorption and consequently bioavailability [212].

Besides its non-invasive nature, pulmonary drug delivery has many other advantages compared to alternative drug delivery strategies, containing a large surface area for solute transport, rapid drug uptake, and improved drug bioavailability [220, 221]. Delivery of antimicrobial agents to the lung via systemic NP administration is persistent and potentially harmful upon systemic exposure to the drugs. Alternatively, various NPs exhibiting prefer‐ ential accumulation in the lung and other organs have been tried. It was reported that intratracheally administered antibiotics loaded NPs were able to penetrate through the alveolar-capillary barrier into the systemic circulation and accumulate in extrapulmonary organ containing liver, spleen, bone, and kidney [222]. Micronization of drugs plays an important role in improving the drug dosage form and therapeutic efficiency today. If a drug is micronized into microspheres with suitable particle size, it can be addressed directly to the lung by the mechanical prevention of capillary bed in the lungs [223]. Nanosuspensions may demonstrate to be an ideal approach for delivering drugs that display poor solubility in pulmonary secretions [212]. Furthermore, because of the nanoparticulate nature and uniform size distribution of nanosuspensions, it is very likely that in each aerosol droplet at least one

still awaiting exploration [213].

172 Application of Nanotechnology in Drug Delivery

**9.1. Oral delivery**

**9.2. Pulmonary delivery**

Nanosuspensions can assay to be a advantage for drugs that show poor solubility in lachrymal fluids. For delivery of such drugs, approaches such as suspensions and ointments have been proposed. Although suspensions present advantages such as extended residence time in a culdesac (which is desirable for most ocular diseases for effective treatment) and avoidance of the high tonicity produced by water-soluble drugs, their actual performance depends on the native solubility of the drug in lachrymal fluids. Thus, the intrinsic decomposition rate of the drug in lachrymal fluid governs its release and ocular bioavailability [226]. An approach that has recently been investigated to achieve the desired duration of action of the drug is the formu‐ lation of polymeric nanosuspensions loaded with the drug [212]. Ocular drug administration via SLN has been reported several times. Ocular drug administration via SLN has been reported several times [227]. Cavalli et al (2002) evaluated SLN as carriers for ocular delivery of tobramycin in rabbit eyes. As a result SLN significantly enhanced the drug bioavalability in the aqueous humor within 6 hours [228]. In addition, poly-cationic polymers may be useful penetration enhancers for ocular drug delivery [229]. De Campos et al. discovered the potential of cyclosporin-A loaded nanoparticles for the management of extraocular disorders, i.e. keratoconjunctivitis sicca or dry eye disease. They reported that the advantages of these systems in ocular drug delivery contain their ability to contact intimately with the corneal and conjunctival surface, thereby increasing delivery to external ocular tissues without compro‐ mising inner ocular structures and systemic drug exposure, and to provide these target tissues with long term drug level [230]. De Salamanaca et al. have reported that chitosan nanoparticles readily penetrate conjunctival epithelial cells and are well suffered at the ocular surface of rabbits [231].

#### **9.4. Brain delivery**

There is a great interest in the development of drug delivery systems that could allow an efficient and sitespecific transport of drugs to the target tissues affected by the disease. One of the most challenging barriers in the body is the blood–brain barrier (BBB) [232]. Endothelial cells of the BBB limit the solute movement into the brain by regulating transport mechanisms at the cell surface. These transport mechanisms help to keep the harmful substances out of the brain in order to maintain homeostasis [233]. Besides the development of simple prodrugs, an emerging approach to circumvent the BBB is the use of liposomes, polymeric nanoparticles or solid lipid nanoparticles, in which the therapeutic drugs can be adsorbed or entrapped [234]. A drug can passively spread through the BBB in a more efficient manner after it is transformed into a more lipophilic prodrug. The same principle can be applied to brain targeting by delivering drugs on nanocarriers with enhanced lipophilicity. Fenart et al demonstrated that when polysaccharide nanoparticles were coated with a lipid bilayer, a 3 to 4-fold improvement in brain uptake without disruption of the BBB integrity was observed [235]. It has been reported that poly (butylcyanoacrylate) nanoparticles were able to deliver hexapeptide dalargin, doxorubicin and other agents into the brain which is significant because of the great difficulty for drugs to cross the BBB [236]. Recently dendrimers have been evaluated for CNS delivery of antiretrovira (ARVs) too. Polyamidoamine dendrimers loaded with lamivudine, a nucleo‐ side/nucleotide reverse transcriptase inhibitor (NRTI) commonly utilized in HIV treatment, were evaluated for their *in vitro* antiviral activity inMT2 cells infected with HIV-1. When loaded on dendrimeric nanocarriers, a 21-fold increase in cellular lamivudine uptake and 2.6-fold reduction in the viral p24 levels were observed when compared to the group treated with free drug solution [237]. In summary, nanoparticles are a very useful and universal method to deliver drugs to the brain. Industrial applications of the nanosphere technology would have several benefits: 1) Nanoparticles deliver drugs to the brain that normally do not cross the blood-brain barrier. 2) They reduce peripheral side effects of (approved) drugs that cross the BBB by increasing the relative dose of drugs reaching the brain; 3) Nanoparticles can also be used as a screening tool. Delivering drug candidates to the brain by nanosphere technology for initial screening of CNS activity obviates direct CNS injections [238].

Today the application of nanotechnology in drug delivery is widely expected to change the scenery of pharmaceutical and biotechnology industries for the foreseeable future. Targetspecific drug therapy and methods for early diagnosis of pathologies are the precedency

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research areas where nanotechnology would play a prominent role.

1 Biology Research Center, Zanjan Branch, Islamic Azad University, Zanjan, Iran

2 Department of Microbiology, Hidaj Branch, Islamic Azad University, Hidaj, Iran

diseases. Advanced Drug Delivery Reviews 2010; 62: 424–437.

ed Infections. PhD thesis. University of Basel; 2009.

ronment. Res. Microbiol 2007; 158:195–202.

[1] Tallury P, Malhotra A, Byrne L, Santra S. Nanobioimaging and sensing of infectious

[2] Baldoni D. Innovative Methods for the Diagnosis and Treatment of Implant-associat‐

[3] Yildiz F H. Processes control-ling the transmission of bacterial pathogens in the envi‐

[4] Silva M. Classical labeling of bacterial pathogens according to their lifestylein the host:inconsistencies and alternatives. Frontiers in microbiology 2012; 71(3): 1-7.

[5] Brubaker R R. Mechanisms of bacterial virulence. Annu.Rev. Microbiol 1985; 39: 21–

[6] Goodpasture E W. Intracellular parasitism and the cytotropism of viruses. South.

[7] Nahm M H, Apicella M A, Briles D E. Immunity to extracellular bacteria, in Funda‐ mental Immunology, ed.W.E. Paul (Philadelphia, PA, Lippincott-Raven) 1999;1373–

[8] Weiser J N, Nahm M H. Immunity to extracellular bacteria, in Fundamental Immu‐ nology, ed. W.E. Paul(Philadelphia: Lippincot Williams & Wilkins) 2008; 1182–1203.

[9] Sansonetti P. Phagocytosis of bacterial pathogens: implications in the host response.

**Author details**

**References**

50.

1386.

Med.J. 1936; 29: 297–303.

Semin.Immunol 2001;13: 381–390.

Mojtaba Salouti1\* and Azam Ahangari2

\*Address all correspondence to: saloutim@yahoo.com
