*2.3.4. Green technology for the preparation of hybrid nanocarriers*

stirring or sonication. Good solvent being miscible with poor solvent diffuses into later, leav-

The core forming polymer and lipophilic drug are solubilized in a water-miscible organic solvent like acetone, acetonitrile or ethanol [57]. The lipids, inorganic salts or silica are dispersed in water with moderate heating (~60–75°C) and/or addition of hydroalcoholic mixtures for

The hydrophilic drugs are added to the aqueous phase containing dispersed lipids [58]. The polymer containing organic phase is then added dropwise to lipid dispersion with continuous stirring to precipitate the polymer into nanoparticles. The monodispersed hybrid nanoparticles are collected after suitable application of vortexing, homogenization or ultrasonication [55, 59]. Concurrent to the precipitation process, the self-assembly of lipid molecules around the polymer molecules occurs due to the hydrophobic interactions. The polymer core captures the hydrophobic tails of lipid while the heads are facing toward the aqueous phase [17, 60]. Continuous stirring of dispersion for several hours is helpful in uniform lipid coating of hybrid nanoparticles and to ensure the complete removal of organic solvent [55]. Rotary evaporator may also be helpful for the removal of organic solvents [58]. The literature suggests 10% ethanolic solution is employed for solubilization of lipids and PEG may enhance the stability of hybrid nanoparticles [61]. According to the study of Ling et al. [58], dextran sulfate and lecithin/PEG-PLGA hybrid nanoparticles can entrap higher

Wang et al. [62] developed PLGA/TPGS-lecithin hybrid nanoparticles using a modified nanoprecipitation method. The PLGA was dissolved in acetone while lipids were dispersed in either aqueous or 4% ethanolic aqueous solution. An inverse-phase nanoprecipitation method (i.e. aqueous phase was added dropwise into organic phase consisting of acetone, the PLGA and the paclitaxel). Initially, the formation of hybrid nanoparticles was slow due to the higher proportion of organic phase in the mixture. Continuous stirring and addition of water boosted the diffusion which leads to solidification of the hybrid nanoparticles. A stable hybrid nanoparticle formulation with low value of PDI (~0.1) was observed at 5:1 aqueous to organic phase ratio [62].

Sonication is a fast technique for the fabrication of hybrid nanoparticles which utilizes ultrasonic waves rather than vortexing, solvent evaporation or heating. In this method, the two solutions designated as organic and aqueous phases lead to formation of inner core (polymer) and outer shell or coating materials (lipids), respectively. The sonication has been employed by Fang et al. [63] for the fabrication of hybrid nanoparticles of lecithin-PEG and PLGA by using this approach. The PLGA was dissolved in acetonitrile while the lecithin and the PEG were added in 4% ethanol solution. The former solution was carefully pipetted into the hydro alcoholic solution (aqueous to organic ratio was kept as 10:1). The hybrid nanoparticles were produced as this 'cocktail' mixture was placed in sonicator bath for five minutes at a frequency of 42 kHz and a power of 100 W. The main advantage of this technique is the formation of stable hybrid nanoparticles with short processing time and production rate is 20 times than

ing behind the core nanoparticles due to the precipitation of the polymer [19].

proper dispersion of the lipids.

60 Advanced Technology for Delivering Therapeutics

amounts of hydrophilic moiety, the vincristine.

*2.3.3. Sonication*

other processes [63].

The use of green technology has revolutionized the synthesis of hybrid nanocarriers due to the ecofriendly procedures that mitigate the threats of toxic impurities and use of the organic solvents. These ecofriendly approaches also provided low operating cost, better stability, compatibility and minimum health hazards [68]. The literature has suggested the successful implementation of solvent free approaches to formulate nanosized systems for the targeted delivery of different therapeutic and diagnostic moieties.

The heat chill method has been employed to prepare micelles using the amphiphilic diblock and triblock copolymers of polycaprolactone (PCL) for the encapsulation of insulin without using any organic solvent and has provide better stability of the entrapped proteins which are liable to denaturation in the presence of different organic solvents [69].

Kumar et al. prepared the green PLGA-oil hybrid nanoparticles of resveratrol employing the acrysol oil (a derivative of castor oil) as nontoxic solvent. The nanoparticles have a smooth outer morphology with improved drug release and stability profile [70].

## *2.3.5. Preparation of organic/inorganic hybrid nanoparticles*

The concept of combining the characteristics of organic and inorganic components is quite old since the time of Egyptian inks. However, the modern organic-inorganic hybrid systems are not prepared by simple mixing these materials but may involve the weak electrostatic linkages (H-bonding or van der Waals forces) or strong chemical bonds, i.e., covalent bonds [71]. Multiple strategies are employed for the preparation of these hybrid particles. These include (i) polymerization of the different monomers, organosilanes and the metal oxides, (ii) selfassembly of different structural components at nanoblock level with different organic and metal components, (iii) the functionalization of preformed nanocarriers with different organic compounds and (iv) making the core with organic materials and coating with the silica and different metallic components [72, 73].



**Structural components**

PLA

DPPC

PEG-PE

Paclitaxel

194 ± 7

22 ± 4

87 ± 2

Folic acid modified polymer core lipid shell hybrid carrier for targeted

[39]

62 Advanced Technology for Delivering Therapeutics

anti-cancer therapy. Higher internalization up to 14.8 folds was

It also showed higher cytotoxicity than commercial preparation

(Taxol®). After 2 hours administration, it showed 3.70 fold higher bio

distribution than Paclitaxel injection.

The amount of the polymer and lipid were optimized for highly

[45]

efficient hybrid system. Hybrid nanoparticles showed higher size and

drug encapsulation in comparison to polymeric carriers. Different

antibiotics like levofloxacin, ciprofloxacin and ofloxacin were

encapsulated. Ciprofloxacin showed less EE due to less lipophilicity.

Oppositely charged drug and lipid prevented nanoparticle formation

which was remedied by the addition of counter ionic surfactant.

Folate receptor mediated drug delivery of anti-cancer agent,

[52]

doxorubicin, resulted in higher cell internalization and enhanced cellkilling effect toward MCF-7 cells with a significantly lower IC50.

observed in flow cytometry.

PLGA

PEGylated

octadecyl-quaternized lysine

modified chitosan

Levofloxacin

420


19

4

5

260

+26

360


Ciprofloxacin

Ofloxacin

PLGA

Phosphatidylcholine (PC),

Stearic Acid (SA)

Doxorubicin

118.7 ±

15.19 ± 3.85

45.76 ± 6.58

0.75

PLGA

DEPE-PEG

Lecithin

PLGA

280 ± 70

(+) 40 ± 7

N/A

mRNA loaded pH sensitive particles reached cytosol offering low

[57]

cytotoxicity followed by translation at a frequency of ∼30%. Intranasal

administration of abovementioned system led to *in vivo* expression of

protein as soon as 6 hours after administration.

Vincristine loaded hybrid nanocarriers resulted in 3.3-fold increase in

[58]

apparent bioavailability, while its uptake was 12.4-fold higher than

plain drug solution.

DSPE-PEG

Poly (β-aminoester) poly-1

Vincristine

121.8–133


64.7 to 93.6

PLGA

Poly ethylene glycol (PEG)

Dextran sulfate

**Physicochemical properties**

**Size (nm)**

**Zeta potential** 

**Entrapment** 

**efficiency (%)**

**(mV)**

278 ± 16

(+) 20 to 50

N/A

Steric stabilization of hybrid nanoparticles was enhanced at least up to

[27]

150 mM NaCl (for more than 1 year at 4°C).

**Application**

**References**



**Structural components**

Resveratrol

375 ± 13


76 ± 4.2

G-PONHs have higher biocompatibility and stability, but moderate

[70]

cytotoxicity compared to standard NPs. It also involves the application

green synthesis approach for the hybrid nanocarriers

More drug reaches target site crossing Blood brain barrier and

[76]

64 Advanced Technology for Delivering Therapeutics

survival time for mice was PtxR-FPLNs (42 days), Ptx-FPLNs (38 days)

compared to PtxR (18 days) and Paclitaxal (14 days)

PLGA

Paclitaxel

186.9 ±


81.34 ± 3.41

8.52

Poly-lactic-co-glycolic acid

(PLGA)

Soybean lecithin

1,2-Distearoyl-sn-glycero-3-

phosphoethanolamine

(DSPE-PEG)

Melatonin

180–218

+15.4 to -36.1

90.35

Coating with cationic lipids provides sustained and prolonged drug

[77]

release, a pronounced benefit in ophthalmic application

Poly lactic acid (PLA)

Didodecyldimethylammonium

bromide (DDAB)

Cetyltrimethylammonium

bromide (CTAB)

Docetaxel

60–70


∼62

The system provides 62% entrapment efficiency and almost 50% drug

[78]

release in 20 hours. The incorporation of PEG provides stability over

120 hours. TC 50 value ranged between 4.58 and 5.55 mg.

Different lipid ratios were evaluated for the entrapment, particle size,

[79]

stability of the system. The current system provides that pH sensitive

release and targeting which aggregate the drug in the acidic tumor

The system indicates biphasic release of the drug in which the burst

[81]

release id presented in the initial hour. The cellular uptake was 83.3%

in L929 cells. It also provides better colloidal stability over 120 hours.

The system was loaded with the SiRNA. Which show the loading

[82]

capacity of up to 2.04%, entrapment efficiency 60% in the optimized

formulation. It provides the targetibility with the antibody and the

sustain release was demonstrated by 20% release over the study time.

microenvironment.

PLGA

DEPE-PEG2000

Soybean lecithin

PLGA

50–150

N/A

N/A

DSPE-PEG

Poly caprolacton (PCL)

58–2009


5.81–60.32

Glyceryl tripalmitate

Human IgG

135–799

+16.7 to +17.9

30.3–60

Poloxamer-188

**Physicochemical properties**

**Size (nm)**

**Zeta potential** 

**Entrapment** 

**efficiency (%)**

**(mV)**

**Application**

**References**


**Table 1.** Hybrid nanoparticles with different structural components and their applications. In conventional sol-gel approach, the hydrolysis process is used to obtain the hybrid system. The reaction involves the organically modified metal oxides which crosslinks with the polymers of multiple functionalities. These components may or may not be present in the organic solvents and possibly trapped within the inorganic material. However, use of self-assembling procedures in last few decades provided new methods for the fabrication. During the process, the inorganic materials (triblocks) were arranged by the use of organic surfactants. The preparation of the mesoporous hybrid with multiple functionalities provide highly porous surface which further modified based on the applications [74].

Shen and Shi [75] reported a method for preparation of the organic/inorganic hybrid based dendrimers. The metal or inorganic nanoparticles were entrapped in the dendrimers template to provide a modified surface morphology which can be tuned by different functional components to provide the biocompatibility and better colloidal stability [75] (**Table 1**).
