**4.2 Gene delivery**

*Role of Novel Drug Delivery Vehicles in Nanobiomedicine*

therapeutic outcomes [36].

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

by preventing metastasis and impairing circulating tumor cells [38].

makes these nanoparticles a potential delivery system for erlotinib [19].

*(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].*

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

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

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**Figure 3.**

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 systemically for cancer therapy [47–50].

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 with serum proteins [52].

Effective gene delivery through nonviral vectors with reduced toxicity was developed 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].

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 be adjusted [53].

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 of nonsmall cell lung cancer [54].

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 concentration of polymer and lipid. This localized siRNA then modifies the release, physicochemical properties and transfection efficiencies [55].

#### **4.3 Theranostic agents**

LPNs not only used for delivering of therapeutic agent but also used for diagnostic purpose. Different type of imaging agents such as quantum dots, fluorescent dyes and iron oxide are incorporated in polymer core. Lipid-polymer and lipid-quantum dot nanoparticles were prepared in a single step with narrow size distribution [56]. Physicochemical properties can be controlled by varying the experimental conditions. Such multicomponent nanoparticles can be used therapy and diagnosis simultaneously.

LPNs are used for theranostic purposes in which phospholipids are attached on one side of polymer chain and fluorophores are linked on the other side. LPNs were designed to incorporate MRI contrast agent, gadolinium, chelated with lipid-PEG in PLGA core. These agents have shown effective uptake of nanoparticles within 3 h by J-774 cells [57]. Instead of conjugation with imaging agent, fluorescence dye was uploaded in LPNs core surrounded by lipid-PEG shell. The final size of such nanoparticles was in the range from 20 to 30 nm and bright fluorescence was observed due to lipid tail and polymeric core [58].

#### **4.4 Stimuli responsive LPNs**

Stimuli responsive drug delivery systems have the ability to deliver therapeutic agents at target sites in a controlled manner with minimum side effects. LPNs comprise of magnetic beads. Stimuli responsive drug delivery system has the advantage to deliver the therapeutic agent in a controlled manner at target site. In a core (PLGA) shell (soyabean lecithin) nanoparticle system, magnetic beads were used for stimuli responsive release of camptothecin when exposed to radio frequency magnetic field. The release of drug was increased by 60% using radio frequency which significantly decreased the mouse breast cancer cell growth. Such system can be beneficial in cancer chemotherapy due to easy preparation, bio-stability and site specific drug delivery [59].

#### **4.5 Miscellaneous pharmacological applications**

Hepatitis C is a chronic disease which leads to liver cirrhosis and hepatocellular carcinoma. LPNs are used to label HCV viral particles for their detection, possible interaction and entrance pathway into host cells [60].

SLNs are developed for topical administration of norfloxacin using solvent evaporation method. These nanoparticles have shown antimicrobial activity against *Staphylococcus aureus* and *Pseudomonas aeruginosa* and could be used for the treatment of burn wound and topical infections. SLNs have shown 89.72% drug release after 24 h and passed the skin irritation and stability tests [43].

LPNs have recently used for improving the local anesthetic action of lidocaine. Two different kinds of nanocarriers, i.e., liposomes and LPNs were prepared and evaluated the skin permeation ability, in vitro and in vivo drug release studies, encapsulation efficiency and particle size. Results indicated that LPNs has better and improved efficacy of lidocaine as compared to liposomal delivery system due to smaller size (88.6 nm). The steady state flux of LPNs was found to be 65.4 μg/h/cm2 which showed increased skin permeation capacity [44].

LPNs were used for nasal delivery of an antiviral drug, tenofovir using melt emulsification-probe sonication technique. Intranasal flux of 135.36 μg/cm2 /h and enhanced fluidity improved the drug permeation through membrane phospholipids, which increase the bioavailability of the drug [45].

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**Author details**

Muhammad Muzamil Khan<sup>2</sup>

\*, Muhammad Tahir Haseeb1

\*Address all correspondence to: nayabtahir132@gmail.com

provided the original work is properly cited.

, Safiullah Khan2

2 Department of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 College of Pharmacy, University of Sargodha, Sargodha, Pakistan

, Asadullah Madni<sup>2</sup>

, Nasrullah Jan2

, Farzana Parveen2

and Arshad Khan2

,

Nayab Tahir1

Pakistan

*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*
