Open access peer-reviewed chapter

Lipid Polymer Hybrid Nanoparticles: A Novel Approach for Drug Delivery

Written By

Nayab Tahir, Muhammad Tahir Haseeb, Asadullah Madni, Farzana Parveen, Muhammad Muzamil Khan, Safiullah Khan, Nasrullah Jan and Arshad Khan

Submitted: September 12th, 2018 Reviewed: June 27th, 2019 Published: October 24th, 2019

DOI: 10.5772/intechopen.88269

Chapter metrics overview

941 Chapter Downloads

View Full Metrics


Applications of nanotechnology and material sciences emerge in the development of various novel drug delivery systems that have been proven as promising clinically. Among these, liposomes, noisome, polymeric carriers and lipid-based delivery system were extensively explored and enter into clinical trials and clinical applications. However, each system has its own pros and cons in term of different physicochemical, pharmacokinetics and therapeutics aspects. Lipid-polymer hybrid carriers merge the potential benefit of these structural components and can be prepared by different approaches to improve the therapeutic outcomes. In this chapter, we provide the useful insight about the lipid-polymer hybrid nanoparticles (LPHNPs) that can be prepared by using the different structural components including the synthetic and natural polymers and lipids. Among these, we also explain the various methods to prepare the LPHNPs with various desired characteristics. Finally, the various therapeutic and clinical applications have been presented briefly.


  • lipid-polymer hybrid
  • nanoparticles
  • drug delivery
  • targeted release

1. Introduction

The advances in the field of nanotechnology and the material sciences have been open a new horizon for the development of various drug delivery systems (DDS) for the effective and efficient delivery of therapeutic and diagnostic agents [1]. During last few decades, many new DDS have been explored in term of their structural components and medical applications. These systems enhance the application of novel approaches toward the translational medicines by improving the preparation techniques and combing the natural and synthetic polymers and materials [2]. Formulation of these DDS helps to encapsulate a variety of chemotherapeutic agents, vaccines, proteins, antibodies, nucleic acids and diagnostic agents [3]. These agents might be encapsulated inside the core of NPs or might be adsorbed on the surface individually or in combination. These formulations enhance the pharmacokinetic and pharmacodynamics properties of the NPs by increasing the solubility, dispersion, permeability and overall bioavailability of the formulation. The release of the drug might be controlled passively or actively through various stimuli such as temperature, and pH [4]. All these factors results in the higher concentration of the entrapped drug that reached the systemic circulation that helps to attain the mean effective concentration without producing any toxic effects [5].

Among these DDS, polymeric nanoparticles (NPs), liposomes, niosomes, dendrimers and porous silicon NPs have been extensively employed in the pharmaceutical delivery. Polymeric NPs have versatility in term of their chemical composition and applications. Large type of chemical material based NPs were formulated such as polymeric NPs, Porous silicon NPs, Carbon nanotubes, Graphene NPs and quantum dot. All these DDS have their own pros and cons in term of drug loading, encapsulation, release and applicability [6]. Furthermore, all these DDS were decorated with different chemical reagents and ligands to impart the desired characteristics through modifying the physicochemical properties of the NPs including (1) enhanced means residence time and improved stability, (2) external stimuli driven drug release, (3) controlled and targeted delivery of various chemotherapeutics agents and (4) administration of various theranostic agents [7].

These nanocarriers have been explored due to their extensive potential applications and excellent in vitro performances, but these NPs still have poor in vivo properties in term of their poor solubility in various body fluids, rapid uptake and excretion by the body defense system, poor penetration among the various biological membranes and body tissues, uncontrolled fluctuations in the plasma levels of the active therapeutic components and dose related toxicity issues [8, 9].

The most important domains of these nanocarriers include the polymeric DDS and the lipid based vesicular systems. The polymeric DDS provide the variety in term of their structural materials and chemical composition [6]. Different polymers include from the synthetic and natural sources have been employed for the medical applications. These DDS include the polymeric NPs, mesoporous silicon NPs, metal coated NPs, inorganic NPs, dendrimers and the carbon nanotubes [10]. Vesicular DDS include the liposome and noisome. These were defined as the single and the multilayer lipid vesicles while the niosomes were made up of nonionic surfactants instead of the phospholipids [11]. These novel systems provide excellent compatibility with other ingredients, higher and simultaneous encapsulation of the hydrophilic and lyophilic therapeutic moieties and due to lipid nature it provide better pharmacokinetic profiles that might lead to improved therapeutic response of the encapsulated drug. But still this system might suffer from some draw back in term of drug leakage, stability problems and difficulty in the scale up of the process [12].

The above-mentioned problems associated with these DDS including liposomes and polymeric nanoparticles can be overcome by merging their structural components by formulating the lipid-polymer hybrid nanoparticles (LPHNPs). These NPs combine the potential benefits and reduce the different drawbacks of all the individual structural components [13]. These hybrid particles might be produced in different morphologies including the core shell and matrix type LPHNPs. The core or the central material may be encapsulated in single and/or multiple layers of the lipid on the polymeric core materials that also provide the site for the surface modification with different targeting moieties and ligands that help to induce the desired characteristics in the DDS [14].

In this chapter, the different structural components such as lipids and polymers were explained along with the different formulation methods to prepare the LPHNPs along with various process parameters and their pros and cons.


2. Structural components and their arrangement mechanism

The core and the shell materials might include different polymeric materials, oils, metal oxides, organic and inorganic compound from the natural and synthetic sources that successfully employed for the fabrication of the NPs. These systems have been composed of following major layers and components given as fellows

  1. The inner most layer consist of different polymers, organic and inorganic materials that act as a core material. These core materials might be coated with other agents or may form a matrix structure that then functionalized by using the different targeting moieties. These cores of the NPs might encapsulate the hydrophilic or hydrophobic drugs [15].

  2. The second layer of these hybrid NPs is fabricated with the natural or derived lipid that impart the desired pharmacokinetic properties to the DDS. This layer encapsulates the central polymeric core and enhances the compatibility with the biological system. While it also act as a permeability control barrier that limit the release of loaded therapeutic agent as a function of water penetration [16].

  3. The third layer is composed of either lipid or polymer-conjugate that help in the functionalization or surface decoration of the NPs to provide the desired therapeutic of pharmacokinetic effects in term of target specific release and improved retention time of the NPs in the biological system [17].

The mechanism of the arrangement in different layers and their compilation with each other might need further investigation. However, different mechanisms explored indicate that the arrangement and fusion process are based on the method of preparation (that were discussed in the next section). In the two-step conventional method, the layer might be due to formation of lipid by layer that get adhere to the core particle that followed by the integration due to hydrophilic and hydrophobic interaction among the lipid and polymer component. However, in the single-step method, the most investigated and revealed mechanism is the precipitation of the lipid component on the polymeric core material. Some newer techniques might also involve the self-assembling of these structural components (Figure 1) [18].

Figure 1.

Schematic diagram of the lipid-polymer hybrid nanoparticles.


3. Method of preparation

Various formulation methods have been designed and employed for the preparation of LPHNPs based on the chemical and physical nature of the structural components and the desired therapeutic purpose or outcome. These hybrid DDS include the lipid-polymer, lipid metal, polymer-inorganic hybrid, metal (Gold, Silver or Iron) along with polymer hybrid NPs have investigated and employed for the clinical use. Conventionally, two different approaches have been investigated including the two-step and single-step processes. First approach employed the mixing of the inner core and the outer layers to prepare the LPHNPs. While the single-step approach the lipid and polymer that are assembled using the different mechanisms to form the LPHNPs that overcome the drawback of individual components.

3.1 Two-step conventional method

Two-step method was the most primitive and frequent method applied for the preparation of different hybrid nanoparticles and other DDS. In the method, the different layers comprise of structurally, different components were separately fabricated and then co incubated to make a complete particle by using the various approaches including the adsorption, self-assembling and encapsulation. The core and shell morphology might be obtained and the various hybrid nanoparticles were obtained by using the sonication [19], solvent emulsification, solvent evaporation [13], nanoprecipitation [20], extrusion, high speed homogenizers and other techniques. However, the selection of the method is based on the physicochemical properties of the loaded drug, size of the core particle and the desired properties that you want to introduce in the NP formulation [18]. For example, the single-step method has been chosen when the encapsulating materials are miscible with the coating substance and soluble in the organic solvent [21].

This method involves multiple preparatory steps to prepare the polymeric core materials and then the lipid vesicles by the different techniques. The polymeric core material might be prepared by dissolving the polymer in a suitable solvent and then precipitated into some nonsolvent phase. Finally, the both components are co-incubated and mixed under gentle stirring for certain time period to allow them to get assembled into lipid-polymer hybrid particles [22, 23]. The mixing may be carried out by vortexing, thin film hydration, probe sonication or extrusion processes so that the final LPHNPs were obtained. These processes actually provide the energy for the mixing, layering or adsorption of the outer coating material on the polymeric core material that might be strengthen by the electrostatic forces among these structural components.

3.2 Modified two-step method

Different modifications have been suggested in the conventional two-step process for the fabrication of the LPHNPs. These modifications might include the use spray drying and lithographic molding along with the freeze drying [24]. The inner central core of the NPs have been prepared with the process that further suspended or dispersed in any suitable organic solvent containing the different structural components of the LPHNPs [2]. Different studies indicate the formulation of LPHNPs loaded with various antibiotics agents including levofloxacin, ciprofloxacin and isoniazid in the form of freeze dried powders for the inhalation therapy that were entrapped in the mono or multiple layers of the lipid shell. The coating of the lipid might provide the core shell morphology to the NPs. This modification in the preparation of the NPs added advantage in term of better inhalation efficiency and greater control on the overall average particle size of the LPHNPs relative to the conventional method [25]. The nanoparticles and hybrid microfiber fabrication are the some other examples that utilized the polyglutamic acid, poly lysine and various grade of PLG and PLA using the freeze-drying method [26, 27].

3.3 Single-step preparation method

The poor entrapment and easy leakage of the drug from the polymeric core of the LPHNPs prepared by the conventional two-step methods urged the development of some newer methods that overcome these shortcomings and enhance the therapeutic efficiency of the prepared formulation [14, 28]. The development of single-step method provides the way to control the particle size, PDI, uniformity of the structural components. It also overcomes the variability in different batches and other properties of the LPHNPs in term of their physicochemical properties and stability. The method involves the single preparatory step that considers the mixing of two different phases containing the lipid and polymer in each of the given phase. The mixing process followed by the self-assembling of the structural components that either make the matrix or core shell morphology [29].

Various techniques in the single-step preparation method might include the single or double emulsification method, sonication technique, nanoprecipitation, solvent evaporation method and solvent diffusion method.


4. Biomedical applications

LPNs have been prepared for efficient encapsulation and delivery of the wide range of therapeutic agents either alone or in combinations. LPNs have wide range of applications in cancer therapy and delivery of protein based therapeutic agents, i.e., small interfering RNA, nucleic acid and genes delivery etc. Additionally, LPNs can be used for oral drug delivery of many drugs [46]. LPN has wide range of applications in gene and DNA delivery, vaccines and diagnostic imaging agents as shown in Figure 2 [2].

Figure 2.

Applications of lipid-polymer hybrid nanocarriers [46].

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

Type of hybrid nanoparticlesStructural componentsPhysicochemical propertiesBiological propertiesApplicationReference
Size (nm)Zeta potentialEntrapment efficiency
Lipid-polymer hybridPaclitaxel
Soybean lecithin
DSPE-PEG (conjugated with folic acid)
186.9 ± 8.52−29.5 ± 2.081.34 ± 3.41T1/2 18.08
AUC 0-∞ 109.21
MRT 30.06
Brain targeting in glioblastoma multiform[1]
Lipid-polymer hybridMelatonin
180–218+15.4 to −36.190.35N/AOphthalmic delivery[2]
DOX in polymeric core and Sorafenib in lipidic core
Dipalmitoyl glycerol phophocholine (DPPC)
Distearoyl glycerol phosphoethanolamine (DSPE)
PDI 0.103
Sustained release for 21 daysColon cancer[4]
Lipid-polymer hybridGemcitabine, hypoxia-inducible factor 1α, ε-polylysine co-polymer, PLGA, mPEG, Lecithin, double emulsion method and ultrasound assisted self-assembly141.8−3442Pancreatic cancer[7]
Lipid-polymer hybridBudesonide, PLGA, dioleoyltrimethylammonium propane (DOTAP), double emulsion solvent evaporation methodPDI 0.09–0.14, 136–169 nm−3 to 5420–36 and 27–80Chronic obstructive pulmonary disease (COPD)[13]
Lipid-polymer hybridDextran, bovine serum albumin (BSA), astaxanthin, prepared through organic solvent free homogenization and sonication technique, Precirol® ATO 5 (glyceryl palmitostearate)139–180 nm, PDI 0.19970%40% release in SGF and 50% in SIF, Diffusion based releasedAntioxidant activity and sustained release[14]
Lipid-polymer hybridErlotinib, single-step sonication method, polycaprolactone (PCL), hydrogenated soy phosphatidylcholine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DSPE-PEG2000)159.6–173 nm, PDI 0.09–0.14−1.22 to −47.318.1–66.4%50% in first 3 h, 100% in 24 hAnticancer, lung cancer[19]
PLGA, paclitaxel, PVA200–300 nm34.8 ± 1.6 to 62.6 ± 7.9%Fast release in first 3 days (60%) followed by slow first order release for 21 days (cumulative release 72%)Anticancer[22]
Lipid-polymer hybridDoxorubicin, stearic acid, tristearin, HPESO (hydrolyzed polymer of epoxidized soybean oil), Pluronic-F68290 nm5%Anticancer[30]
Lipid vesiclesCarboxymethyl chitosan, paclitaxel, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DPPC)200–300 nm85.2 ± 3.3 and 83.8 ± 7.5%Sustained release formulationAnticancer[31]
Lipid-polymer hybridDoxorubicin, epoxidized soyabean oil, Pluronic F6880–350 nm−19.7 ± 0.6560–80%50% drug released in first few hours and additional 10–20% in 2 weeksAnticancer (breast cancer)[32]
Lipid-polymer hybridMitoxantrone hydrochloride, dextran sulfate, Cremophor (polyethoxylated castor oil), emulsification-ultrasonication method130.3 ± 4.7 to 136.7 ± 8.6−19.9 ± 1.4 to −31.6 ± 0.897.4%Sustained 86.9% 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 ± 94.1Anticancer[33]
Sorafenib, PLGA, Single-step nanoprecipitation, D-α-tocopherol polyethylene glycol 1000 succinate, TPGS, dioleoylphosphatidic acid (DOPA)150–200 nm (average 175.25 ± 1.82 nm), PDI 0.148 ± 0.004−19 to −5585%Highly vascular hepatocellular carcinoma[34]
Mitomycin C, PLA, Soybean phosphatidylcholine (SPC), PEG, folate215.6 ± 5.1 nm, PDI 0.143−25.88 ± 2.3995%Anticancer[35]
Lipid-polymer hybridPaclitaxel, PLGA, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG-2000), folic acid, soybean lecithin74.93 ± 3.93 to 81.34 ± 3.41%87.2 ± 4.28 to 96.9 ± 4.93% in 5 daysAnticancer[36]
Lipid-polymer hybridNanoprecipitation process, PLGA, PEG, docetaxel25 nm−10 to −5020%50% in first 12 h and remaining in 72 hAnticancer[37]
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 technique150 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 ± 0.02612%30% in first 5 hAnticancer[38]
Lipid-polymer hybridPoly(ethylene glycol)-distearoylphosphatidylethanolamine (PEG-DSPE), emulsifying-solvent evaporation method, egg yolk phosphatidylcholine, plasmid DNA128 nm+35.2Nonviral gene delivery[39]
Poly-(β-amino ester) (PBAE), double emulsion/solvent evaporation, PLGA, Phospholipids230 ± 40 to 300 ± 50, PDI 0.100 ± 0.05 to 0.182 ± 0.1032 ± 8 to 42 ± 8mRNA based vaccine[40]
Lipid-polymer hybridsiRNA, PLGA, PEG, modified double-emulsion solvent evaporation technique, lecithin225 ± 8 nm−10 to 0 mV78–82%50% of siRNA released in 12–20 h[41]
Lipid-polymer hybridPLGA, siRNA, Particle Replication in Nonwetting Templates (PRINT) process198 ± 3.45 to 207 ± 4.461, PDI 0.045 ± 0.009 to 0.092 ± 0.005−3.45 ± 1.9 to 5.29 ± 1.532–46%Prostate cancer[42]
Lipid-polymer hybridNorfloxacin, PLA, emulsification solvent evaporation method, PVA, carbopol K-940178.6 ± 3.7 nm to 220.8 ± 0.66 nm, PDI 0.206 ± 0.36 to 0.383 ± 0.66+23.4 ± 1.5 mV to +41.5 ± 3.4 mV53.29 ± 0.30 to 72.34 ± 0.2389.72% drug released in 24 hTopical antibiotic[43]
Lipid-polymer hybridLidocaine, Chitosan, Cholesterol, cetyltrimethyl ammonium bromide, 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), hyaluronic acid71.2 ± 2.8 to 145.6 ± 5.9 nm, PDI 0.09 ± 0.02 to 0.19 ± 0.02−4.6 ± 0.7 to +32.7 ± 4.678.6 ± 4.3 to 85.2 ± 3.140% in 8 h and remaining in 72 hLocal anesthetic therapy[44]
Lipid-polymer hybridTenofovir disoproxil fumarate, melt emulsification-probe sonication technique239 nm−42.1 ± 2.46 to −55.39 ± 3.1287.14%, 63.83
±3.74 to 90.84 ± 5.73%
85.34 ± 5% at the end of 12 hAntiviral[45]

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].

4.2 Gene 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 systemically for cancer therapy [47, 48, 49, 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 aureusand Pseudomonas aeruginosaand 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].


  1. 1. Zhang L et al. Self-assembled lipid−polymer hybrid nanoparticles: A robust drug delivery platform. ACS Nano. 2008;2(8):1696-1702
  2. 2. Hadinoto K, Sundaresan A, Cheow WS. Lipid–polymer hybrid nanoparticles as a new generation therapeutic delivery platform: A review. European Journal of Pharmaceutics and Biopharmaceutics. 2013;85(3):427-443
  3. 3. Vikulina AS, Skirtach AG, Volodkin DV. Hybrids of polymer multilayers, lipids, and nanoparticles. Mimicking the cellular microenvironment. Langmuir. 2019;35(26):8565-8573
  4. 4. Mieszawska AJ et al. Synthesis of polymer–lipid nanoparticles for image-guided delivery of dual modality therapy. Bioconjugate Chemistry. 2013;24(9):1429-1434
  5. 5. Gong J et al. Polymeric micelles drug delivery system in oncology. Journal of Controlled Release. 2012;159(3):312-323
  6. 6. Fan J et al. Targeted anticancer prodrug with mesoporous silica nanoparticles as vehicles. Nanotechnology. 2011;22(45):455102
  7. 7. Zhao X et al. Co-delivery of HIF1α siRNA and gemcitabine via biocompatible lipid-polymer hybrid nanoparticles for effective treatment of pancreatic cancer. Biomaterials. 2015;46:13-25
  8. 8. Madni A et al. Liposomal drug delivery: A versatile platform for challenging clinical applications. Journal of Pharmacy & Pharmaceutical Sciences. 2014;17(3):401-426
  9. 9. Mehnert W, Mäder K. Solid lipid nanoparticles: production, characterization and applications. Advanced Drug Delivery Reviews. 2012;64:83-101
  10. 10. Prabaharan M et al. Gold nanoparticles with a monolayer of doxorubicin-conjugated amphiphilic block copolymer for tumor-targeted drug delivery. Biomaterials. 2009;30(30):6065-6075
  11. 11. Khan MI, Madni A, Peltonen L. Development and in-vitro characterization of sorbitan monolaurate and poloxamer 184 based niosomes for oral delivery of diacerein. European Journal of Pharmaceutical Sciences. 2016;95:88-95
  12. 12. Wakaskar RR. General overview of lipid–polymer hybrid nanoparticles, dendrimers, micelles, liposomes, spongosomes and cubosomes. Journal of Drug Targeting. 2018;26(4):311-318
  13. 13. Leng D et al. Engineering of budesonide-loaded lipid-polymer hybrid nanoparticles using a quality-by-design approach. International Journal of Pharmaceutics. 2018;548(2):740-746
  14. 14. Wang T et al. Solid lipid–polymer hybrid nanoparticles by in situ conjugation for oral delivery of astaxanthin. Journal of Agricultural and Food Chemistry. 2018;66(36):9473-9480
  15. 15. Chaudhary Z et al. Lipid polymer hybrid carrier systems for cancer targeting: A review. International Journal of Polymeric Materials and Polymeric Biomaterials. 2018;67(2):86-100
  16. 16. Pimentel-Moral S et al. Lipid nanocarriers for the loading of polyphenols—A comprehensive review. Advances in Colloid and Interface Science. 2018;260:85-94
  17. 17. Negi JS. Nanolipid materials for drug delivery systems: A comprehensive Review. In: Characterization and Biology of Nanomaterials for Drug Delivery. 2019. pp. 137-163
  18. 18. Mukherjee A et al. Lipid–polymer hybrid nanoparticles as a next-generation drug delivery platform: State of the art, emerging technologies, and perspectives. International Journal of Nanomedicine. 2019;14:1937
  19. 19. Mandal B et al. Development and in vitro evaluation of core–shell type lipid–polymer hybrid nanoparticles for the delivery of erlotinib in non-small cell lung cancer. European Journal of Pharmaceutical Sciences. 2016;81:162-171
  20. 20. Dave V et al. Lipid-polymer hybrid nanoparticles: Synthesis strategies and biomedical applications. Journal of Microbiological Methods. 2019;160:130-142
  21. 21. Chaisri W, Hennink WE, Okonogi S. Preparation and characterization of cephalexin loaded PLGA microspheres. Current Drug Delivery. 2009;6(1):69-75
  22. 22. Dong Y, Feng S-S. Poly (D,L-lactide-co-glycolide)(PLGA) nanoparticles prepared by high pressure homogenization for paclitaxel chemotherapy. International Journal of Pharmaceutics. 2007;342(1-2):208-214
  23. 23. Paillard-Giteau A et al. Effect of various additives and polymers on lysozyme release from PLGA microspheres prepared by an s/o/w emulsion technique. European Journal of Pharmaceutics and Biopharmaceutics. 2010;75(2):128-136
  24. 24. Enlow EM, Luft JC, Napier ME, DeSimone JM. Potent engineered PLGA nanoparticles by virtue of exceptionally high chemotherapeutic loadings. Nano Letters. 2011;11(2):808-813
  25. 25. Wang H, Zhao P, Su W, Wang S, Liao Z, Niu R, et al. PLGA/polymeric liposome for targeted drug and gene co-delivery. Biomaterials. 2010;31(33):8741-8748
  26. 26. Hitzman CJ, Elmquist WF, Wattenberg LW, Wiedmann TS. Development of a respirable, sustained release microcarrier for 5-fluorouracil I: In vitro assessment of liposomes, microspheres, and lipid coated nanoparticles. Journal of Pharmaceutical Sciences. 2006;95(5):1114-1126
  27. 27. Keloglu N, Verrier B, Trimaille T, Sohier J. Controlled association and delivery of nanoparticles from jet-sprayed hybrid microfibrillar matrices. Colloids and Surfaces. B, Biointerfaces. 2016;140:142-149
  28. 28. Cheow WS, Hadinoto K. Factors affecting drug encapsulation and stability of lipid–polymer hybrid nanoparticles. Colloids and Surfaces. B, Biointerfaces. 2011;85(2):214-220
  29. 29. D'Addio SM, Prud'homme RK. Controlling drug nanoparticle formation by rapid precipitation. Advanced Drug Delivery Reviews. 2011;63(6):417-426
  30. 30. Wong HL et al. In vivo evaluation of a new polymer-lipid hybrid nanoparticle (PLN) formulation of doxorubicin in a murine solid tumor model. European Journal of Pharmaceutics and Biopharmaceutics. 2007;65(3):300-308
  31. 31. Joshi N et al. Carboxymethyl-chitosan-tethered lipid vesicles: Hybrid nanoblanket for oral delivery of paclitaxel. Biomacromolecules. 2013;14(7):2272-2282
  32. 32. Wong HL et al. A new polymer–lipid hybrid nanoparticle system increases cytotoxicity of doxorubicin against multidrug-resistant human breast cancer cells. Pharmaceutical Research. 2006;23(7):1574-1585
  33. 33. Zhang P et al. Novel nanostructured lipid-dextran sulfate hybrid carriers overcome tumor multidrug resistance of mitoxantrone hydrochloride. Nanomedicine: Nanotechnology, Biology and Medicine. 2012;8(2):185-193
  34. 34. Gao D-Y et al. CXCR4-targeted lipid-coated PLGA nanoparticles deliver sorafenib and overcome acquired drug resistance in liver cancer. Biomaterials. 2015;67:194-203
  35. 35. Li Y et al. Mitomycin C-soybean phosphatidylcholine complex-loaded self-assembled PEG-lipid-PLA hybrid nanoparticles for targeted drug delivery and dual-controlled drug release. Molecular Pharmaceutics. 2014;11(8):2915-2927
  36. 36. Agrawal U et al. Tailored polymer–lipid hybrid nanoparticles for the delivery of drug conjugate: Dual strategy for brain targeting. Colloids and Surfaces B: Biointerfaces. 2015;126:414-425
  37. 37. Dehaini D et al. Ultra-small lipid–polymer hybrid nanoparticles for tumor-penetrating drug delivery. Nanoscale. 2016;8(30):14411-14419
  38. 38. Palange AL et al. Lipid–polymer nanoparticles encapsulating curcumin for modulating the vascular deposition of breast cancer cells. Nanomedicine: Nanotechnology, Biology and Medicine. 2014;10(5):e991-e1002
  39. 39. Li J et al. A novel polymer-lipid hybrid nanoparticle for efficient nonviral gene delivery. Acta Pharmacologica Sinica. 2010;31(4):509
  40. 40. Su X et al. In vitro and in vivo mRNA delivery using lipid-enveloped pH-responsive polymer nanoparticles. Molecular Pharmaceutics. 2011;8(3):774-787
  41. 41. Shi J et al. Differentially charged hollow core/shell lipid–polymer–lipid hybrid nanoparticles for small interfering RNA delivery. Angewandte Chemie International Edition. 2011;50(31):7027-7031
  42. 42. Hasan W et al. Delivery of multiple siRNAs using lipid-coated PLGA nanoparticles for treatment of prostate cancer. Nano Letters. 2011;12(1):287-292
  43. 43. Dave V et al. Lipid-polymer hybrid nanoparticles: Development & statistical optimization of norfloxacin for topical drug delivery system. Bioactive Materials. 2017;2(4):269-280
  44. 44. Wang J et al. An alternative choice of lidocaine-loaded liposomes: Lidocaine-loaded lipid–polymer hybrid nanoparticles for local anesthetic therapy. Drug Delivery. 2016;23(4):1254-1260
  45. 45. Pokharkar VB, Jolly MR, Kumbhar DD. Engineering of a hybrid polymer–lipid nanocarrier for the nasal delivery of tenofovir disoproxil fumarate: Physicochemical, molecular, microstructural, and stability evaluation. European Journal of Pharmaceutical Sciences. 2015;71:99-111
  46. 46. Hallan SS et al. Lipid polymer hybrid as emerging tool in nanocarriers for oral drug delivery. Artificial Cells, Nanomedicine, and Biotechnology. 2016;44(1):334-349
  47. 47. Chitkara D, Mittal A, Mahato RI. miRNAs in pancreatic cancer: Therapeutic potential, delivery challenges and strategies. Advanced Drug Delivery Reviews. 2015;81:34-52
  48. 48. Chitkara D, Singh S, Mittal A. Nanocarrier-based co-delivery of small molecules and siRNA/miRNA for treatment of cancer. Therapeutic Delivery. 2016;7(4):245-255
  49. 49. Husain S et al. Gene therapy for cancer: Regulatory considerations for approval. Cancer Gene Therapy. 2015;22(12):554
  50. 50. Lam JK et al. siRNA versus miRNA as therapeutics for gene silencing. Molecular Therapy - Nucleic Acids. 2015;4:e252
  51. 51. Oh Y-K, Park TG. siRNA delivery systems for cancer treatment. Advanced Drug Delivery Reviews. 2009;61(10):850-862
  52. 52. Lee M, Kim SW. Polyethylene glycol-conjugated copolymers for plasmid DNA delivery. Pharmaceutical Research. 2005;22(1):1-10
  53. 53. Zhong Q et al. Optimization of DNA delivery by three classes of hybrid nanoparticle/DNA complexes. Journal of Nanobiotechnology. 2010;8(1):6
  54. 54. Zhu X et al. Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non-small cell lung cancer treatment. Proceedings of the National Academy of Sciences. 2015;112(25):7779-7784
  55. 55. Colombo S et al. Mechanistic profiling of the siRNA delivery dynamics of lipid–polymer hybrid nanoparticles. Journal of Controlled Release. 2015;201:22-31
  56. 56. Valencia PM et al. Single-step assembly of homogenous lipid−polymeric and lipid−quantum dot nanoparticles enabled by microfluidic rapid mixing. ACS Nano. 2010;4(3):1671-1679
  57. 57. Aryal S et al. Engineered magnetic hybrid nanoparticles with enhanced relaxivity for tumor imaging. Biomaterials. 2013;34(31):7725-7732
  58. 58. Kandel PK et al. Incorporating functionalized polyethylene glycol lipids into reprecipitated conjugated polymer nanoparticles for bioconjugation and targeted labeling of cells. Nanoscale. 2011;3(3):1037-1045
  59. 59. Kong SD et al. Magnetic field activated lipid–polymer hybrid nanoparticles for stimuli-responsive drug release. Acta Biomaterialia. 2013;9(3):5447-5452
  60. 60. Bathfield M et al. Synthesis of lipid-α-end-functionalized chains by RAFT polymerization. Stabilization of lipid/polymer particle assemblies. Macromolecules. 2008;41(22):8346-8353

Written By

Nayab Tahir, Muhammad Tahir Haseeb, Asadullah Madni, Farzana Parveen, Muhammad Muzamil Khan, Safiullah Khan, Nasrullah Jan and Arshad Khan

Submitted: September 12th, 2018 Reviewed: June 27th, 2019 Published: October 24th, 2019