3.2.2 Wheat germ agglutinin (WGA) conjugated solid lipid nanoparticles

Conjugation of bioadhesive ligand molecules with SLNs helps in improving drug absorption/bioavailability by increasing residence time in the GIT and reducing

dosing frequency. Lectins (a group of diverse proteins/glycoproteins) are the bioadhesive ligand and have stable structure and receptor binding ability. It offers resistance to enzymatic digestion/degradation, which helps in its in vivo survival for a prolonged time period [22]. Wheat germ agglutinin (WGA) is an example of nontoxic plant lectin which binds particularly to N-acetyl-D-glucosamine and sialic acid on cell surfaces. Conjugation of WGA with SLNs could be helpful for targeted delivery of antitubercular drugs to the lungs.

WGA conjugated SLNs loaded with rifampicin (WRSLNs) were successfully developed for lungs specific delivery of rifampicin (RIF). The conjugation of WGA to RIF loaded SLN was carried out by two-steps carbodiimide reaction reported by Ertl et al. with slight modification [23]. Even after conjugation with the SLNs, the WGA retained its bio-recognition activity and sugar-binding specificity [24]. From the in vivo study result, the interaction of WRSLNs with porcine mucin was confirmed. However, non-conjugated SLNs did not show any conjugation with the porcine mucin. The WRSLNs were stable at refrigerated temperature and also in presence of electrolytes up to 1.0 M Na2SO4 concentration. The WRSLNs were 10 times more stable than RIF-SLN which could be owing to the steric stabilization by lectin present on nanoparticle surface. Prepared WRSLNs had shown narrow size distribution, controlled release of a drug, retention of biorecognition activity and improved physical stability of drug against electrolyte induced flocculation [25].

#### 3.2.3 Mannose conjugated solid lipid nanoparticles

Studies on tuberculosis revealed overexpression of the mannose receptors specifically on alveolar macrophages (AM) surfaces [26]. Keeping it in mind attempts were taken to develop mannosylated SLN to deliver antitubercular drugs targeting to alveolar macrophages which have higher affinity for mannose. Rifabutin loaded mannosylated SLNs were successfully developed. Manosylation was done by ring opening reactions followed by reaction of aldehyde groups of mannose in 0.1 M sodium acetate buffer (pH 4.0) with the amino groups of lipid. This leads to formation of Schiff's base (–N=CH–), which may then get reduced to secondary amine (–NH–CH2–) and remain in equilibrium with Schiff's base at basic pH. In vivo studies were conducted to evaluate for their cytotoxicity, targeting potential, AM uptake, and hematological studies. It was reported that mannosylation improved uptake (up to 6-fold) of rifabutin by the AM. Moreover, mannosylated rifabutin-SLNs were less immunogenic and helped in sustained delivery of drug. Thus, the mannosylated SLNs may be employed for AM targeted delivery of rifabutin for effective management of TB [27].

carcinoma—25%, and lung metastases—30%) [29]. These receptors allow folate derivatives to bind preferentially that permits intracellular incorporation of folate

Folate-conjugated copolymer of polyethylene glycol (PEG) and N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC) SLNs loaded with Paclitaxel (PTX) were successfully developed. The conjugation of folate- conjugated PEG and HTCC to RIF-SLN was carried out by carbodiimide mediated coupling chemistry. Pulmonary administration of the developed F-PEG-HTCC–SLNs selectively delivered the PTX to the lung's cancer cells with improved penetrability and prolonged lung residence. Moreover, the developed SLN significantly reduced the in vitro half-maximum inhibitory concentration of PTX in M109-HiFR cells [30]. List of SLNs and their different ligand conjugated forms for lungs targeting have

Drugs Target Model Comments Ref.

effect

by AMs.

lungs

to Lungs

RIF Mucin Porcine Controlled release of RIF [25]

RIF AM SD rats Improved drug uptake

DXM Lungs Mice Improved therapeutic

Improved hypoglycemic

efficacy targeting to

AM specific drug delivery. Enhanced therapeutic efficacy.

Alveolar cell site delivery of drug with enhanced antiproliferative efficacy.

Prolonged drug residence time, reduced

MIC

Targeted delivery of RIF

[12]

[14]

[17]

[21]

[27]

[28]

[30]

Insulin Lungs Male SD

RIF LfR Albino

RFB MR J774 &

PTX MR A549 &

PTX FR HeLa &

rats

rats

albino rats

Male albino rat

M109- HiFR cells

Targeted delivery of drugs to the brain for is gaining much more interest at the present time, not only for the treatment of brain tumor and other neurodegenerative disorders but also for their diagnosis. Brain targeted delivery of drugs is the most challenging task because of the presence of strongest physiological barrier, i.e.,

derivative by endocytosis.

Sl. no SLN (Type)

03 SLN SL,

04 Lf-SLNs

05 WGA-SLN

06 Msy-SLN

07 Msy-SLN

Table 1.

101

08 Ft-SLN CHO,

Lipids Preparation method

DOI: http://dx.doi.org/10.5772/intechopen.88268

double emulsion

Solid Lipid Based Nano-particulate Formulations in Drug Targeting

film hydration method

Ultrasonication with high pressure homogenization

SL Solvent injection method

> Single emulsification followed by solvent evaporation

TSN Modified solvent injection method

> Nano precipitation method

Modified solvent injection method

List of SLNs and their different ligand conjugated forms for lungs cells targeting.

01 SLN SA, PA Reverse micelle-

02 SLN SA, PA Modified lipid

GTS

SA, GMS

TSN, DSPE

GS

been summarized in Table 1.

4. Solid lipid nanoparticles for brain targeting

Overexpression of mannose receptors in case of lungs cancer was reported by numerous investigators. The mannosylated-distearoyl phosphatidyl-ethanolamine SLNs loaded with paclitaxel (PTX) was developed for lungs targeted delivery of PTX. Manosylation was done by ring opening reaction followed by reaction of an aldehyde group of mannose with the free amine group provided by stearylamine and DSPE in sodium acetate buffer (pH 4.0). The stability testing data indicated that SLNs formulations stored at 4 2°C were more stable than those stored at 27 2°C. It was revealed that mannosylated SLNs deliver significantly higher concentration of drug to the alveolar cell sites and showed improved antiproliferative efficacy as compared to PTX solution and PTX-SLNs [28].

#### 3.2.4 Folate conjugated solid lipid nanoparticles

The folate receptors (α- form) are overexpressed on the surface of lung tumor cells. The extents of the overexpression are different in different types of lung tumors (adenocarcinomas—72%, squamous cell carcinomas—51%, small cell


Table 1.

dosing frequency. Lectins (a group of diverse proteins/glycoproteins) are the bioadhesive ligand and have stable structure and receptor binding ability. It offers resistance to enzymatic digestion/degradation, which helps in its in vivo survival for a prolonged time period [22]. Wheat germ agglutinin (WGA) is an example of nontoxic plant lectin which binds particularly to N-acetyl-D-glucosamine and sialic acid on cell surfaces. Conjugation of WGA with SLNs could be helpful for targeted

WGA conjugated SLNs loaded with rifampicin (WRSLNs) were successfully developed for lungs specific delivery of rifampicin (RIF). The conjugation of WGA to RIF loaded SLN was carried out by two-steps carbodiimide reaction reported by Ertl et al. with slight modification [23]. Even after conjugation with the SLNs, the WGA retained its bio-recognition activity and sugar-binding specificity [24]. From the in vivo study result, the interaction of WRSLNs with porcine mucin was confirmed. However, non-conjugated SLNs did not show any conjugation with the porcine mucin. The WRSLNs were stable at refrigerated temperature and also in presence of electrolytes up to 1.0 M Na2SO4 concentration. The WRSLNs were 10 times more stable than RIF-SLN which could be owing to the steric stabilization by lectin present on nanoparticle surface. Prepared WRSLNs had shown narrow size distribution, controlled release of a drug, retention of biorecognition activity and improved physical stability of drug against electrolyte induced flocculation [25].

Studies on tuberculosis revealed overexpression of the mannose receptors specifically on alveolar macrophages (AM) surfaces [26]. Keeping it in mind attempts were taken to develop mannosylated SLN to deliver antitubercular drugs targeting to alveolar macrophages which have higher affinity for mannose. Rifabutin loaded mannosylated SLNs were successfully developed. Manosylation was done by ring opening reactions followed by reaction of aldehyde groups of mannose in 0.1 M sodium acetate buffer (pH 4.0) with the amino groups of lipid. This leads to formation of Schiff's base (–N=CH–), which may then get reduced to secondary amine (–NH–CH2–) and remain in equilibrium with Schiff's base at basic pH. In vivo studies were conducted to evaluate for their cytotoxicity, targeting potential, AM uptake, and hematological studies. It was reported that mannosylation improved uptake (up to 6-fold) of rifabutin by the AM. Moreover, mannosylated rifabutin-SLNs were less immunogenic and helped in sustained delivery of drug. Thus, the mannosylated SLNs may be employed for AM targeted delivery of rifabutin for

Overexpression of mannose receptors in case of lungs cancer was reported by numerous investigators. The mannosylated-distearoyl phosphatidyl-ethanolamine SLNs loaded with paclitaxel (PTX) was developed for lungs targeted delivery of PTX. Manosylation was done by ring opening reaction followed by reaction of an aldehyde group of mannose with the free amine group provided by stearylamine and DSPE in sodium acetate buffer (pH 4.0). The stability testing data indicated that SLNs formulations stored at 4 2°C were more stable than those stored at 27 2°C. It was revealed that mannosylated SLNs deliver significantly higher concentration of drug to the alveolar cell sites and showed improved antiproli-

The folate receptors (α- form) are overexpressed on the surface of lung tumor cells. The extents of the overexpression are different in different types of lung tumors (adenocarcinomas—72%, squamous cell carcinomas—51%, small cell

ferative efficacy as compared to PTX solution and PTX-SLNs [28].

3.2.4 Folate conjugated solid lipid nanoparticles

100

delivery of antitubercular drugs to the lungs.

Role of Novel Drug Delivery Vehicles in Nanobiomedicine

3.2.3 Mannose conjugated solid lipid nanoparticles

effective management of TB [27].

List of SLNs and their different ligand conjugated forms for lungs cells targeting.

carcinoma—25%, and lung metastases—30%) [29]. These receptors allow folate derivatives to bind preferentially that permits intracellular incorporation of folate derivative by endocytosis.

Folate-conjugated copolymer of polyethylene glycol (PEG) and N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC) SLNs loaded with Paclitaxel (PTX) were successfully developed. The conjugation of folate- conjugated PEG and HTCC to RIF-SLN was carried out by carbodiimide mediated coupling chemistry. Pulmonary administration of the developed F-PEG-HTCC–SLNs selectively delivered the PTX to the lung's cancer cells with improved penetrability and prolonged lung residence. Moreover, the developed SLN significantly reduced the in vitro half-maximum inhibitory concentration of PTX in M109-HiFR cells [30].

List of SLNs and their different ligand conjugated forms for lungs targeting have been summarized in Table 1.
