**4.1 Cancer therapy**

Doxorubicin loaded polymer-lipid hybrid nanoparticles (Dox-PLN) were designed and injected intratumorally in mice. At a dose of 0.1 and 0.2 mg, 70 and 100% tumor growth delay was observed, respectively. Dox-PLN treated mice have not shown any sign of toxicity and only 2 mice out of 15 exhibited transient fur


**65**

**Type of hybrid nanoparticles**

**Structural components**

**Physicochemical properties**

**Size (nm)** 139–180 nm, PDI 0.199

**Zeta potential**

**Entrapment efficiency**

70%

40% release in SGF and 50% in SIF, Diffusion based released

Antioxidant activity and sustained release

[14]

**Biological properties**

**Application**

**Reference**

Lipid-polymer hybrid

Dextran, bovine serum albumin (BSA), astaxanthin, prepared through organic solvent free homogenization and sonication technique, Precirol® ATO 5 (glyceryl palmitostearate)

Lipid-polymer hybrid

Erlotinib, single-step sonication method, polycaprolactone (PCL), hydrogenated soy phosphatidylcholine, 1,2-distearoyl-

159.6–173 nm, PDI 0.09–0.14

−1.22 to −47.3

18.1–66.4%

50% in first 3 h,

Anticancer,

[19]

lung cancer

100% in 24 h

sn-glycero-3-phosphoethanolamine-

N-methoxy(polyethylene glycol)-2000 (DSPE-PEG2000)

PLGA, paclitaxel, PVA

Lipid-polymer

Doxorubicin, stearic acid, tristearin,

290 nm

5%

Anticancer

[30]

HPESO (hydrolyzed polymer of

epoxidized soybean oil), Pluronic-F68

Carboxymethyl chitosan, paclitaxel,

200–300 nm

85.2 ± 3.3 and

Sustained release

Anticancer

[31]

formulation

83.8 ± 7.5%

1,2-dipalmitoyl-sn-glycero-3-

phosphocholine (DPPC), 1,2-distearoylsn-glycero-3-phosphoethanolamine

(DPPC)

hybrid

Lipid vesicles

200–300 nm

34.8 ± 1.6 to

Fast release in

Anticancer

[22]

first 3 days (60%)

followed by

slow first order

release for 21 days

(cumulative release

72%)

62.6 ± 7.9%

*Lipid Polymer Hybrid Nanoparticles: A Novel Approach for Drug Delivery*

*DOI: http://dx.doi.org/10.5772/intechopen.88269*


## *Lipid Polymer Hybrid Nanoparticles: A Novel Approach for Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.88269*

*Role of Novel Drug Delivery Vehicles in Nanobiomedicine*

**64**

**Type of** 

**Structural components**

**Physicochemical properties**

**Size (nm)**

**Zeta potential**

**Entrapment** 

**efficiency**

**Biological** 

**Application**

**Reference**

**properties**

**hybrid** 

**nanoparticles**

Lipid-polymer

Paclitaxel

186.9 ± 8.52

−29.5 ± 2.0

81.34 ± 3.41

T1/2 18.08

Brain targeting

[1]

in glioblastoma

multiform

AUC 0-∞ 109.21

MRT 30.06

PLGA

Soybean lecithin

DSPE-PEG (conjugated with folic acid)

Melatonin

180–218

+15.4 to −36.1

90.35

N/A

Ophthalmic

[2]

delivery

PLA

DDAB

CTAB

PLGA

85.1

Sustained release

Colon cancer

[4]

for 21 days

PDI 0.103

DOX in polymeric core and Sorafenib in

lipidic core

β-cyclodextrin

Dipalmitoyl glycerol phophocholine

(DPPC)

Distearoyl glycerol

phosphoethanolamine (DSPE)

PEG

Gemcitabine, hypoxia-inducible factor

141.8

−34

42

Pancreatic

[7]

cancer

1α, ε-polylysine co-polymer, PLGA,

mPEG, Lecithin, double emulsion

method and ultrasound assisted

self-assembly

Budesonide, PLGA,

PDI 0.09–0.14,

−3 to 54

20–36 and

Chronic

[13]

obstructive

pulmonary

disease (COPD)

27–80

136–169 nm

dioleoyltrimethylammonium propane

(DOTAP), double emulsion solvent

evaporation method

Lipid-polymer

hybrid

Lipid-polymer

hybrid

Lipid-polymer

hybrid

hybrid


**67**

**Type of hybrid nanoparticles**

**Structural components**

**Physicochemical properties**

**Size (nm)**

PLGA, Curcumin, 1,2-dipalmitoyl-

sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-

3-phosphoethanolamine-N-

[succinyl(polyethylene glycol)-2000] (DSPE-PEG), emulsion/solvent evaporation technique

Poly(ethylene glycol)-distearoylphos

phatidylethanolamine (PEG-DSPE), emulsifying-solvent evaporation method, egg yolk phosphatidylcholine, plasmid DNA

Poly-(β-amino ester) (PBAE), double

230 ± 40 to 300 ± 50,

32 ± 8 to 42 ± 8

mRNA based

[40]

vaccine

PDI 0.100 ± 0.05 to

0.182 ± 0.10

225 ± 8 nm

−10 to 0 mV

78–82%

50% of siRNA

[41]

released in 12–20 h

emulsion/solvent evaporation, PLGA,

Phospholipids

siRNA, PLGA, PEG, modified doubleemulsion solvent evaporation technique,

lecithin

PLGA, siRNA, Particle Replication in

198 ± 3.45 to

−3.45 ± 1.9 to

32–46%

Prostate cancer

[42]

5.29 ± 1.5

207 ± 4.461, PDI

0.045 ± 0.009 to

0.092 ± 0.005

178.6 ± 3.7 nm to

+23.4 ± 1.5 mV

53.29 ± 0.30 to

89.72% drug

Topical

[43]

antibiotic

released in 24 h

72.34 ± 0.23

to

+41.5 ± 3.4 mV

220.8 ± 0.66 nm,

PDI 0.206 ± 0.36 to

0.383 ± 0.66

Nonwetting Templates (PRINT) process

Lipid-polymer

hybrid

Lipid-polymer

hybrid

Lipid-polymer

Norfloxacin, PLA, emulsification solvent

evaporation method, PVA, carbopol

K-940

hybrid

128 nm

+35.2

Lipid-polymer hybrid

150 nm, 171.6 ± 8.2 nm in DI water and 177.3 ± 6.2 nm in PBS, PDI of 0.174 ± 0.023 and 0.159 ± 0.026

**Zeta potential**

**Entrapment efficiency**

12%

30% in first 5 h

Anticancer

[38]

**Biological properties**

**Application**

**Reference**

*Lipid Polymer Hybrid Nanoparticles: A Novel Approach for Drug Delivery*

[39]

Nonviral gene delivery

*DOI: http://dx.doi.org/10.5772/intechopen.88269*


#### *Lipid Polymer Hybrid Nanoparticles: A Novel Approach for Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.88269*

*Role of Novel Drug Delivery Vehicles in Nanobiomedicine*

**66**

**Type of** 

**Structural components**

**Physicochemical properties**

**Size (nm)**

**Zeta potential**

**Entrapment** 

**efficiency**

**Biological** 

**Application**

**Reference**

**properties**

**hybrid** 

**nanoparticles**

Lipid-polymer

Doxorubicin, epoxidized soyabean oil,

80–350 nm

−19.7 ± 0.65

60–80%

50% drug released

Anticancer

[32]

(breast cancer)

in first few hours

and additional

10–20% in 2 weeks

Pluronic F68

hybrid

Lipid-polymer

Mitoxantrone hydrochloride, dextran

130.3 ± 4.7 to

−19.9 ± 1.4 to

97.4%

Sustained 86.9%

Anticancer

[33]

at 72 h, Cmax (ng/

mL) 421.6 ± 24.6,

t1/2 (h) 8.49 ± 1.23,

AUC0-t (ng/mL.h)

690.9 ± 83.5,

AUC0-∞ (ng/mL.h)

722.6 ± 94.1

−31.6 ± 0.8

136.7 ± 8.6

sulfate, Cremophor (polyethoxylated

castor oil), emulsificationultrasonication method Sorafenib, PLGA, Single-step

150–200 nm (average

−19 to −55

85%

Highly vascular

[34]

hepatocellular

carcinoma

175.25 ± 1.82 nm), PDI

0.148 ± 0.004

nanoprecipitation, D-α-tocopherol

polyethylene glycol 1000 succinate,

TPGS, dioleoylphosphatidic acid

(DOPA)

Mitomycin C, PLA, Soybean

215.6 ± 5.1 nm, PDI

−25.88 ± 2.39

95% 74.93 ± 3.93 to

87.2 ± 4.28 to

Anticancer

[36]

96.9 ± 4.93% in

5 days

81.34 ± 3.41%

Anticancer

[35]

0.143

phosphatidylcholine (SPC), PEG, folate

Paclitaxel, PLGA, 1,2-distearoylsn-glycero-3-phosphoethanolamine (DSPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG-2000), folic acid, soybean lecithin

Lipid-polymer

hybrid

Lipid-polymer

Nanoprecipitation process, PLGA, PEG,

25 nm

−10 to −50

20%

50% in first 12 h and

Anticancer

[37]

remaining in 72 h

docetaxel

hybrid

hybrid


**69**

*Lipid Polymer Hybrid Nanoparticles: A Novel Approach for Drug Delivery*

roughing. These results indicated that Dox-PLN expressed a good cytotoxic activity

Paclitaxel loaded LPNs were prepared with a size range of 200–300 nm for oral administration. Theses LPNs were designed to withstand harsh gastrointestinal tract conditions and improve the bioavailability of paclitaxel. On comparison with Taxol, 1.5- and 5.5-fold increase in bioavailability and elimination half-life was observed, respectively. Additionally, reduction in the reticuloendothelial system mediated uptake by liver and spleen was noted due to stealth characteristics of

To overcome the multidrug resistance (MDR) of anticancer drugs, a new strategy was adopted in which doxorubicin loaded solid lipid nanoparticles (SLNs) were complexed with anionic polymer. Due to high encapsulation efficiency (60–80%) of doxorubicin, the cytotoxicity in tumor cells was increased to 8-fold. Due to physical interaction between drug and polymer and smaller size of nanoparticles (80–350 nm), drug was difficult to clear from target cells by efflux pump [32]. Another strategy to counter MDR is to synthesize lipid-anionic dextran sulfate hybrid carriers loaded with mitoxantrone hydrochloride. The interaction between cationic drug (mitoxantrone hydrochloride) and anionic dextran not only increased drug accumulation but also enhanced the cytotoxicity in breast cancer cell lines. Sustained release of drug (86.9%) was maintained for 72 h with an encapsulation

Sorafenib is an antiangiogenic agent used in highly vascular hepatocellular carcinoma (HCC). The development of resistance during HCC therapy is mainly due to activation of CXC receptor type 4 (CXCR4). Gao et al. developed PLGA nanoparticles loaded with sorafenib and evaluated the antitumor activity both in vitro and in vivo. On comparing with control group, sorafenib loaded PLGA nanoparticles have shown an improved survival in HCC model, delay in progression of tumor and

Mitomycin C is a water soluble drug and major disadvantages associated with this drug are poor water stability, rapid elimination and lacking in target specificity. A sustained (up to 120 h) and effective delivery of mitomycin C from LPH

against solid tumors and improved the therapeutic efficacy [30].

biopolymer blanket of these LPNs [31].

*Applications of lipid-polymer hybrid nanocarriers [46].*

efficiency of 97.4% [33].

**Figure 2.**

enhanced antiangiogenic effect [34].

*DOI: http://dx.doi.org/10.5772/intechopen.88269*

*Lipid Polymer Hybrid Nanoparticles: A Novel Approach for Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.88269*

*Role of Novel Drug Delivery Vehicles in Nanobiomedicine*

**68**

**Type of** 

**Structural components**

**Physicochemical properties**

**Size (nm)**

**Zeta potential**

**Entrapment** 

**efficiency**

**Biological** 

**Application**

**Reference**

**properties**

**hybrid** 

**nanoparticles**

Lipid-polymer

Lidocaine, Chitosan, Cholesterol,

71.2 ± 2.8 to

−4.6 ± 0.7 to

78.6 ± 4.3 to

40% in 8 h and

Local anesthetic

[44]

therapy

remaining in 72 h

85.2 ± 3.1

+32.7 ± 4.6

145.6 ± 5.9 nm,

PDI 0.09 ± 0.02 to

0.19 ± 0.02

239 nm

−42.1 ± 2.46 to

87.14%, 63.83

85.34 ± 5% at the

Antiviral

[45]

end of 12 h

±3.74 to

90.84 ± 5.73%

−55.39 ± 3.12

cetyltrimethyl ammonium bromide,

1,2-dilauroyl-sn-glycero-3-

phosphocholine (DLPC), hyaluronic acid

Tenofovir disoproxil fumarate, melt

emulsification-probe sonication

technique

Lipid-polymer

hybrid

hybrid

**Figure 2.** *Applications of lipid-polymer hybrid nanocarriers [46].*

roughing. These results indicated that Dox-PLN expressed a good cytotoxic activity against solid tumors and improved the therapeutic efficacy [30].

Paclitaxel loaded LPNs were prepared with a size range of 200–300 nm for oral administration. Theses LPNs were designed to withstand harsh gastrointestinal tract conditions and improve the bioavailability of paclitaxel. On comparison with Taxol, 1.5- and 5.5-fold increase in bioavailability and elimination half-life was observed, respectively. Additionally, reduction in the reticuloendothelial system mediated uptake by liver and spleen was noted due to stealth characteristics of biopolymer blanket of these LPNs [31].

To overcome the multidrug resistance (MDR) of anticancer drugs, a new strategy was adopted in which doxorubicin loaded solid lipid nanoparticles (SLNs) were complexed with anionic polymer. Due to high encapsulation efficiency (60–80%) of doxorubicin, the cytotoxicity in tumor cells was increased to 8-fold. Due to physical interaction between drug and polymer and smaller size of nanoparticles (80–350 nm), drug was difficult to clear from target cells by efflux pump [32]. Another strategy to counter MDR is to synthesize lipid-anionic dextran sulfate hybrid carriers loaded with mitoxantrone hydrochloride. The interaction between cationic drug (mitoxantrone hydrochloride) and anionic dextran not only increased drug accumulation but also enhanced the cytotoxicity in breast cancer cell lines. Sustained release of drug (86.9%) was maintained for 72 h with an encapsulation efficiency of 97.4% [33].

Sorafenib is an antiangiogenic agent used in highly vascular hepatocellular carcinoma (HCC). The development of resistance during HCC therapy is mainly due to activation of CXC receptor type 4 (CXCR4). Gao et al. developed PLGA nanoparticles loaded with sorafenib and evaluated the antitumor activity both in vitro and in vivo. On comparing with control group, sorafenib loaded PLGA nanoparticles have shown an improved survival in HCC model, delay in progression of tumor and enhanced antiangiogenic effect [34].

Mitomycin C is a water soluble drug and major disadvantages associated with this drug are poor water stability, rapid elimination and lacking in target specificity. A sustained (up to 120 h) and effective delivery of mitomycin C from LPH

nanoparticles was observed with improved encapsulation efficiency of 95%. Improved cell uptake and site specific accumulation of drug are the major advantages of LPNs [35]. Paclitaxel and folic acid loaded polymer-lipid hybrid nanoparticles were prepared to bypass the tight junctions of blood-brain barrier (BBB) and target the glioma cells. The survival time of mice was increased to 42 days as compared to free paclitaxel which last only 18 days. These targeted nanoparticles have shown better pharmacokinetics and biodistributions which result in better therapeutic outcomes [36].

Ultra-small lipid-polymer hybrid nanoparticles were fabricated using modified nanoprecipitation method. The prepared nanoparticles loaded with docetaxel have the size of 25 nm which exhibited a better antitumor activity than Taxotere. It was observed that the survival time of Taxotere treated mice were 44 days whereas more than half of the mice treated with ultra-small nanoparticles survived for 64 days. These ultra-small nanoparticles have better biodistribution properties and enhanced permeation ability [37]. Long circulating PLGA nanoparticles loaded with curcumin were fabricated to counter cancer metastasis. The adhesion of cancer cells onto endothelial cells and vascular deposition were reduced by 70 and 50%, respectively. Therefore, these nanoparticles could improve the therapeutic efficacy by preventing metastasis and impairing circulating tumor cells [38].

Core-shell LPN was fabricated to deliver erlotinib using single-step sonication method. In vitro cellular uptake, colony forming assay and luminescent cell viability assay was performed in human lung adenocarcinoma cell line (**Figure 3**). The mean particle size of LPN is 170 nm and entrapment efficiency of 66% with excellent storage stability. The enhanced and efficient uptake of these LPN by cancer cells makes these nanoparticles a potential delivery system for erlotinib [19].

**Figure 3.**

*(A) Confocal microscopy images of erlotinib loaded CSLPHNPs uptake in A549 cells after 1 and 4 h, (B) in vitro cellular viability result in A549 cells after 72 h, and (C) colony formation assay in A549 cells [19].*

**71**

*Lipid Polymer Hybrid Nanoparticles: A Novel Approach for Drug Delivery*

Plasmid DNA, miRNA and siRNA are now gaining much of the interest of researchers for cancer therapy. Both miRNA and siRNA have different origin and mechanism but similar physicochemical properties. miRNA is endogenous in nature and target the mRNA by developing imperfect pairing and hence act by mRNA degradation, mRNA endonucleolytic cleavage or suppression of translation. siRNA is exogenous in nature and primarily act by endonucleolytic cleavage of target mRNA. siRNA has single mRNA target whereas miRNA has multiple targets. Plasmid DNA carries the recombinant gene or gene of interest and can be administered locally of

Lot of challenges is associated with effective gene delivery especially for cancer therapy. Viral vectors are also facing problems such as development of immunity and inflammatory response, limited carrying ability of DNA and short shelf life [51]. Therefore, the research has now been shifted to nonviral vectors due to nonimmunogenicity, nontoxicity, low cost and feasibility in large scale production. Polyethylene glycol (PEG) and its copolymers have widely used for gene delivery because of its low toxicity, increase water solubility and reduced ability to interact

Effective gene delivery through nonviral vectors with reduced toxicity was developed

Core shell LPN was fabricated using three different methods for incorporation of DNA and the resulted nanoparticles were in the range from 100 to 400 nm. Surface adsorbed DNA, encapsulated DNA and combination of adsorbed and encapsulated DNA are three important methods for fabrication of these nanoparticles. For sustained release of active ingredient, combination method is employed which is necessary for booster vaccination followed by decline release. For primary vaccination (strong and short effective delivery), surface adsorbed mechanism is followed. By adjusting the concentration of different ingredients, the drug release properties can

SiRNA delivery through cationic complexes such as polyplexes and lipoplexes has many disadvantages, e.g., development of inflammatory responses, instability and toxicity etc. Small size (100 nm) with prolong circulation time nanoparticles containing siRNA was developed using PLGA. These hybrid nanoparticles has 80% encapsulation efficiency of siRNA without any significant degradation until 24 h. Immunofluorescence studies revealed the in vitro apoptosis and >90% knockdown

LPNs are also used for incorporation of mRNA for mRNA vaccines. mRNA was complexed with LPN through electrostatic adsorption to develop 150–300 nm size nanoparticles. These newly developed nanoparticles have shown successful transfection through intranasal route and taken up by dendritic cells with minimum toxicity [40]. A novel approach, modified double emulsion/solvent evaporation method, was used to fabricate hollow core/shell LPNs in which PLGA core was surrounded by lipid shell attached with PEG chains. The size of nanoparticles was 230 nm, 80% encapsulation efficiency and 50% siRNA was sustained release for 12–20 h. Moreover, enhanced gene silencing ability was also observed with profound inhibition of gene expression in xenograft tumor [41]. PLGA/siRNA nanoparticles coated with lipids are prepared using Particle Replication in Non wetting Templates technique and exhibited 32–46% encapsulation efficiency for the treatment of prostate cancer [42]. siRNA was localized in PLGA core at high concentration by varying the

by emulsification solvent evaporation method. The particle size of newly developed positively charged LPN is in the range from 130 to 240 nm. Fluorescent protein was complexed with plasmid DNA by adsorption and transfection efficiencies was recorded

as 37.2 and 34% for LPN and commercially available product, respectively [39].

*DOI: http://dx.doi.org/10.5772/intechopen.88269*

systemically for cancer therapy [47–50].

with serum proteins [52].

be adjusted [53].

of nonsmall cell lung cancer [54].

**4.2 Gene delivery**
