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Liposomes, solid lipid nanoparticles (SLNs), nanolipid carriers (NLCs), phytosomes, etc., are lipid-based nanocarriers. The functionality of lipid-based carrier systems is based on the type and arrangement of the constituent lipids [11, 12]. Both solid and liquid lipids can be used in the preparation of these carrier systems. Alec Bangham discovered liposomes in early 1960s and defined them as vesicular structures consisting of bilayers of phospholipids and hydrophilic aqueous compartment(s) arranged concentrically [13]. The fluidity of the bilayer depends on the degree of saturation of phospholipids used in the preparation of liposomes. Relatively rigid and stable bilayers are formed by saturated phospholipids with long acyl chains (e.g., dipalmitoylphosphatidylcholine) in comparison to those formed using unsaturated lipids like phosphatidylcholine from natural sources (egg or soybean phosphatidylcholine) [14].

Figure 2.1 Diagrammatic representation of various nanoparticulate carriers: (a) liposome; (b) gold nanoparticle (GNP); (c) dendrimers; (d) quantum dots; (e) solid lipid nanoparticle (SLN); (f) nanostructured lipid carriers (NLC); (g) nanoemulsion; (h) micelles; (i) polymeric nanoparticle (nanocapsules); (j) polymeric nanoparticle (nanospheres); (k) nanoscaffolds; and (l) inverse micelle.

Table 2.1a Classification of nanoparticulate carrier systems.

Nanoparticulate carrier systems
Lipid-based systems	Micellar systems	Thernostics	Polymer-based systems	Self-emulsifying drug delivery systems
LiposomesSolid lipid nanoparticlesNanolipid carriers pH-sensitive lipid carriersThermo-responsive lipid carriers	Micelles	Gold nanoparticlesIron oxide nanoparticlesQuantum dots	Polymeric nanoparticles	Self-emulsifying drug delivery systems (SEDDSs)Self-micro-emulsifying drug delivery systems (SMEDDSs)

Table 2.1b Targeted treatment of tuberculosis using various nano-carrier-based drug delivery system.

Nanoparticulate carriers	Mechanism of action	Effect	References
Chitosan-based nanoparticles (CNPs)	Cellular uptake and upregulate expression of CD-80/86/40/MHC-II molecule on RAW264.7 cells	ROS generation and oxidative stress may lead to DNA damage	[6]
Ag85B-ESAT6-PLGA nanoparticle	Internalized by the THP-1 human macrophages increase in the production of total serum IgG, IFNγ, and TNFα cytokine levels	Immunomodulation and protection against Mtb	[7]
Pep-H conjugated gold nanoparticles (Pep-H-AuNPs)	Antimycobacterial activity against in vitro active as well as dormant tubercle bacilli	Pep-H showed marked reduction in intracellular mycobacterial growth & modulate host immune system	[8]
SPIO-MtbsAb-nanoparticles	Endocytosis	Target mycobacterial antigen and diagnose extrapulmonary TB	[9]
G5 RIF-EDA-PPI mannosylated dendrimer	Inhibition of the subunit of the bacterial RNA polymerase, which inhibits gene transcription	Increase in the cellular uptake of RIF-loaded mannosylated PPI dendrimers in alveolar macrophages (AM)	[10]

Depending on the number of lipid bilayers, the liposomes can be classified as unilamellar vesicles (ULVs) or multilamellar vesicles (MLVs). ULVs consist of a single lipid bilayer (50–250 nm in diameter) with a large aqueous core, providing a suitable site for loading of hydrophilic drugs. Having an onion-peel arrangement of concentric lipid bilayers up to 5 μm in diameter, MLVs can be used to incorporate lipid-soluble drugs in higher concentrations [15]. Based on the lipid concentration present in the liposomes, rate and extent of drug release vary, the fastest being from ULVs. The liposomes are prepared most commonly by thin-film hydration method; however, other techniques like modified ethanol injection, supercritical reverse-phase evaporation, spray-drying, freeze-drying, etc. are also used for the preparation of liposomes [16].

Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are dispersions of lipids in aqueous solutions of surfactants and offer advantages of solid particles, liposomes, and emulsions in a combined form. NLCs are prepared using both solid (fat) as well as liquid (oil) lipids, whereas SLNs contain lipids in solid form in the range of 0.1–30% (w/w) [1]. Solid lipids create a highly ordered lipid matrix, which results in leaching of drugs during storage, so on incorporation of liquid lipids imperfections are introduced in the matrix, which helps to reduce expulsion of drugs during storage and also increases the loading efficiency of active compounds [17]. Lipids such as triglycerides (tricaprin, trimyristin, tripalmitin, etc.), hydrogenated coco glycerides, hard fat types (glycerol monostearate, palmitic acid, stearic acid), and emulsifiers such as egg lecithin, soybean lecithin, phosphatidylcholine, poloxamer, polysorbate, etc. can be used in the preparation of these lipid carriers. The preparatory methods for the SLNs and NLCs include high-pressure homogenization, hot and cold homogenization, solvent evaporation, and emulsion-based methods [18]. Phospholipids are phosphorous containing amphiphilic molecules with a hydrophilic head and a hydrophobic core comprising of acyl chains linked to alcohol. These serve as excellent surface-active or wetting agents with emulsifying properties and can be suitably used in formulation of both hydrophilic and hydrophobic drugs. The properties of phospholipids can be altered by varying the structural make-up of constituent functional groups (aliphatic chain, head groups, and alcohols). Based on the type of alcoholic moieties present in phospholipids, they are of two types: glycerophospholipids and sphingomyelins. The properties of glycerophospholipids can be further modified by varying the head group and length and saturation of hydrophobic side chains. Examples include: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidic acid (PA), phosphatidylinositol (PI), phosphatidylglycerol (PG), and cardiolipin (CL) [19]. Sphingomyelins are of animal origin with a backbone of sphingosine and are essential constituents of animal cell membranes. Sphingomyelins exhibit more saturated hydrophobic regions in comparison to glycerophospholipids and hence have lower affinity towards water [20]. Phospholipids are used in the formulation of lipid based-drug delivery systems such as liposomes, solid lipid nanoparticles, nanostructured lipid carriers, etc. [21].

The success of liposomes as drug carriers can be validated by the plethora of FDA-approved liposomal drug preparations. AmBisome and Doxil marked the triumph of liposomal-based drug delivery systems. Doxil was the first FDA-approved liposomal preparation introduced in the U.S.A. market in the year 1995 for the treatment of ovarian cancer and Kaposi’s sarcoma [1]. Apart from pharmaceutical applications, liposomal-based systems caught the fancy of farming- and food-based industries as this provided an effective platform for formulation of unstable moieties like antioxidants, antimicrobial, bioactive elements, and flavors [22]. Stealth liposomes, a class of second-generation liposomes, have been used for loading deoxyribonucleic acid for their application in biosensing [23].

One of the prominent fields of application of lipid-based drug delivery systems is that of site-specific delivery. PEGylated-lipid nanoparticles (PLNs) containing N-Butylphthalide (dl-NBP) encapsulated in conjugated to Fas ligand antibody (PLNs-Fas) to specifically target ischemic region of brain showed accumulation in OX42 positive microglia cells. Nanoformulated dl-NBP showed significantly better recovery of brain injury and neurological deficit after ischemia and that too at a lower dose in comparison to plain non-encapsulated dl-NBP [24]. Similarly, cytotoxicity studies of camptothecin-loaded SLNs in glioma and macrophage human cell lines showed very low inhibitory concentration (IC50) values. In vivo biodistribution studies of intravenously administered SLNs in rats resulted in significant accumulation of camptothecin in brain in comparison to peripheral organs [25]. Insulin loaded in SLNs functionalized with wheat germ agglutinin-N-glutaryl-phosphatidylethanolamine (WGA-N-glut-PE), when delivered orally to rats, was not only protected against degradation in the gastrointestinal tract but also showed approximately sevenfold increase in its relative bioavailability in comparison to subcutaneously injected insulin [26]. Functionalization with ligands creates optimum contact between the carrier and the target biological surface and also promotes internalization, thereby promoting drug absorption.

Another area of potential application of these colloidal carriers is that of immunotherapy for the delivery of genes (DNA, siRNA, miRNA). Vimentin siRNA and doxorubicin loaded on asialoglycoprotein receptors (ASGPR) targeting-ligand-based liposomes were prepared via electrostatic interaction of galactose linked-cationic liposomal doxorubicin for treatment of hepatocellular carcinoma (HCC). These targeted liposomes showed high specific affinity for human hepatocellular carcinoma cells in comparison to other cells (non-hepatic) [27]. Jiang et al. prepared arginine-glycine-aspartic acid (RGD) modified liposomes containing siRNA (lipoplex) for down-regulation of P-glycoprotein (P-gp) to stimulate effective therapeutic accumulation of doxorubicin in multidrug-resistant tumor cells. Sequential administration of siRNA-lipoplex and RGD modified liposomal doxorubicin showed optimal cellular transfection and tumor inhibition both in vitro and in vivo [28]. In a similar study, galactosylated liposomes/DNA complexes were injected intraperitonally in mice for the delivery of genes into liver. The study showed significant in vivo gene transfection in liver via asialoglycoprotein receptor-mediated endocytosis [29]. Positive results of lipoplexed siRNA for downregulation in the expression and synthesis of PRDM14 genes in the MCF7 breast cancer cells has also been reported [5]. Kuo et al. formulated cationic solid lipid nanoparticles (CSLNs) of saquinavir using cationic stearylamine, dioctadecyldimethyl ammonium bromide, non-ionic compritol 888 ATO, and cacao butter as oil phase and polysorbate 80 as surfactant. A sustained release of saquinavir from CSLNs was observed, and hence, these carriers could be used for the delivery of saquinavir treatment of human immunodeficiency viruses [30].