What happens to phospholipid when they are placed in water?

4 Phospholipids

Phospholipids (PLs) are also amphiphilic molecules like PEG-fatty acid glycerides. The structure of a phospholipid molecule contains two hydrophobic tails of fatty acids and one hydrophilic head of phosphate moiety, jointed together by an alcohol or glycerol molecule [90]. Due to this structural arrangement, PLs form lipid bilayers and are a key component of all the cell membranes. Based on the existence of the type of alcohol present, PLs can be categorized into two categories of glycerophospholipids and sphingomyelins. Glycerophospholipids contain a glycerol backbone and are the main type of PLs in the eukaryotic cells. Generally, naturally occurring glycerophospholipids have alpha structure and L-configuration. Based on the variation in the type of hydrophilic head group, glycerophospholipids can be further subclassified into subtypes such as phosphatidyl choline (PC), phosphatidyl ethanolamine (PE), phosphatidic acid (PA), phosphatidyl serine, phosphatidyl inositol, and phosphatidyl glycerol [91]. Similarly, other criteria can be used to subclassify the glycerophospholipids such as variation in the polar moiety length, variation in the number, saturation of aliphatic groups, and type of bonding (Table 6.3). Sphingomyelins contain a sphingosine backbone and are the integral part of the lipid bilayer of animal cell membranes. Shapiro and Flowers confirmed that biologic sphingomyelins have a d-erythro configuration [92]. A detail comparison between PC and sphingomyelins is given in Table 6.4.

Table 6.3. Different Classifications for Phospholipids

CriteriaChemical StructureExamplesHead group variationPhosphatidylcholine (PC)Phosphatidylethanolamine (PE)Phosphatidic acid (PA)Phosphatidylglycerol (PG)Phosphatidylserine (PS)Apolar moieties lengthDimyristoyl PCDipalmitoyl PCDistearoyl PCAliphatic groups saturationUnsaturated
Dioleoyl PCSaturated
Distearoyl PCType of bonding between aliphatic chains and glycerolEster bond
Distearoyl PEEther bond
Choline plasmalogen
Ethanolamine plasmalogenThe number of aliphatic chainsOne acyl groups
LysophospholipidsTwo acyl groups
Dioleoyl PE

Table 6.4. Comparison Between Phosphatidylcholine and Sphingomyelin Phospholipids

CriteriaPhosphatidylcholinesSphingomyelinsBackboneGlycerolSphingosineDouble bond in amide-linked acyl chains1.1–1.5 cis-double bonds0.1–0.35 cis-double bondsHydrophobic region saturationLower saturationsHigher saturation than PCsAcyl chain lengthMore than 20 and asymmetric16–18 carbon long chain and symmetricPhase transition temperature (Tc)30°C30–45°C, higher than PCsInteraction with cholesterolPC-cholesterol bilayer has less compressibility and higher permeability to waterSM-cholesterol bilayer has high compressibility and lower permeability to water

PLs, one of the main components of cell membranes, have an excellent biocompatibility profile. Due to their amphiphilic nature, PLs can form self-assembly supermolecular structures in aqueous media under certain conditions [93,94]. Also, like other surfactants, PLs can be used to stabilize emulsion. PLs can be obtained from both natural and synthetic types of sources. The most widely used sources of natural PLs are vegetable oils such as soybean and sunflower. PLs can also be obtained from animal tissues such as egg yolk [95]. Although both egg yolks and soybeans are the major sources for PLs, there is a difference in content and species of PLs (Table 6.5). The PLs such as PC, PE, lyso phosphatidyl choline, and lyso phosphatidyl ethanolamine can be isolated and purified for pharmaceutical use from natural sources. Semisynthetic PLs are prepared by a change in head, tail group, or both on natural PLs, for example, the hydrogenation of natural unsaturated PLs into saturated PLs of higher melting point and oxidation stability [91]. Synthetic PLs are prepared by attaching both polar and apolar moieties to a glycerol backbone via formation of an ester or ether bond linkage. Additionally, the synthesis of sphingomyelins is more complex than that for the glycerophospholipids. Synthetic PL preparation, isolation, and purification is always a costlier process than that from natural sources. However, the synthetic PLs have a relatively higher purity and stability than natural PLs.

Table 6.5. Comparison Between Egg Yolk and Soybean Phospholipids

CriteriaEgg Yolk PLsSoybean PLsProportion of PCsHigherLowerLong chain poly unsaturated fatty acidsArachidonic acid and docosahexaenoic acid presentAbsentSphingomyelinsPresentAbsentSaturation level of fatty acidsHigherLowerPosition of FA•

sn-1 position for saturated fatty acid.

sn-2 position for unsaturated fatty acid.

PLs can form many types of assemblies in water due to their amphiphilic nature. Generally, three different types of shapes—micelles, PLs bilayer, and hexagonal (HII) phase (Fig. 6.1)—are formed [96,97]. Lysophospholipids can be represented as an inverted cone molecular shape due to a larger head group and a single hydrophobic chain. This inverted cone shape results in the formation of a micellar system. As shown in the figure, the cone-shape arrangement results in HII shape, whereas the cylindrical molecular shape favores the formation of a PLs bilayer. The PLs bilayer or liposome formation can be affected by various factors that promote conversion of lamellar phase to HII phase:

For smaller PE head group, increase in acyl chain unsaturation, length, and temperature results in HII phase formation.

With high salt concentration, unsaturated PE, PG, CL, and PA can prefer HII phase.

At low pH, protonation of the carboxyl group of PS and phosphate group of PA results in transition toward HII phase.

Due to their several advantages, PLs have been used as an additive in several drug delivery systems. PLs can serves several purposes in drug delivery systems:

modified drug release

bioavailability enhancement

lymphatic transport

reduced drug-related side effects

modified transdermal permeation

act as stabilizer (surfactants, solubilizer, permeation enhancer)

PLs have also been used as a valuable additive in development of various nanocarriers. Physiologically, PC acts as nourishment for brain functions and as a substrate of synthesis of the neurotransmitter acetylcholine. Synthetic PLs are better in terms of quality and stability, but cost is higher than natural PLs. Although both egg phosphatidyl choline (EPC) and soybean phosphatidyl choline (SPC) can be used for developing liposomes, EPC are favored over SPC. EPC liposomes have a higher drug loading capacity and lower leakage rate [98]. For example, Doxil contains hydrogenated soybean phosphatidylcholine (HSPC) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[(polyethylene glycol)-2000] (PEG-DSPE) as a phospholipid to form stable liposomes with less phase transition tendency in physiologic conditions [99].

PEs play an important role in membrane fusion due to less hydration tendency. Similarly, PE-based liposomes also have a better interaction with the lipid bilayer. Dioleoyl phosphatidyl ethanolamine (DOPE) is used to develop pH-sensitive liposomes that can avoid the drug degradation by enzymes during endocytosis [100]. But to allow formation of liposomes, a carboxylic acidic group containing materials must be added. The anionic acidic groups provide electrostatic stabilization by repulsion at neutral pH, and liposomes remain stable. At acidic pH, carboxylic groups become protonated, which causes conversion of laminar form into HII phase. This unstable phase allows aggregation, fusion, and drug release in acidic pH environment. Further, addition of DSPE-PEG to DOPE promotes the formation of liposomes, as well as increase the in vivo circulation time of liposomes [101].

The phase transition temperature (Tc) property of PLs can be utilized for the development of temperature-sensitive liposomes. Liposomes made up of PLs having Tc higher than the physiologic temperature can release drugs in cancer tissues associated with hyperthermia. At higher temperature the gel form transits into a liquid crystalline phase to release encapsulated drugs from the liposomes. Dipalmitoyl phosphatidylcholine (DPPC) has a Tc value of 41°C and is used for developing thermosensitive liposomes [102,103]. Further, drug-loading capacity and release rate of DPPC liposomes can be improved by adding other PLs such as distearoyl phosphatidylcholine (DSPC) and HSPC. However, for promoting drug release at tumor site the Tc of combinations of PLs should not exceed the range of 39–42°C. The optimum Tc value of 39–40°C was reported for the PEGylated liposomes of DPPC and lysolipid monopalmitoyl phosphocholine (MPPC) [104,105].

In general, the elimination of liposomes containing PLs such as PS, PG, and PA is very rapid due to MPS. This phagocytosis of liposomes depends on the hydrophilicity at the surface [106,107]. The presence of ganglioside and PI results in decreased uptake of liposomes by MPS and prolonged circulation time. The circulation time of liposomes also depends on the membrane fluidity. The liposomes with a rigid bilayer have a reduction in clearance by MPS [108,109]. The addition of high Tc (e.g., DSPC) and rigid PLs (e.g., sphingomyelins) results in improvement in circulation time of liposomes. The presence of a more stable amide bond (difficult to break in vivo) and intermolecular hydrogen bonding potential make a solid lipid bilayer of liposome.

Recently, the circulation time of liposomes has been improved by PEGylation at the surface. But PEGylated liposomes are also associated with accelerated blood clearance phenomenon on repeated injection [110,111]. The formation of anti-PEG IgM promotes rapid detection and clearance of PEGylated liposomes on subsequent exposures [112,113]. This ABC phenomenon of liposomes was found more for unsaturated PLs (e.g., SPC, EPC, and egg sphingomyelins) than that for saturated PLs (e.g., DPPC and HSPC). Additionally, this ABC phenomenon can also be observed for conventional liposomes. However, unlike PEGylated liposomes, the conventional liposomes elicit ABC phenomenon only at high dose (5 μmol/kg) and not at lower lipid dose of 0.001 μmol/kg [114].

The cationic lipid dimethyl dioctadecyl ammonium (DDA) has also been used to form cationic liposomes. Cationic liposomes have a benefit of better cell uptake, but at the same time, cationic nature also limits their use due to undesirable toxicity. Yusuf et al. developed a novel lyophilized liposome by combining both cationic lipid DDA and TPGS [115]. The cell uptake of these liposomes was improved due to the slippery action of nanoparticles through mucus due the presence of TPGS and electrostatic attraction between the cationic lipid and negatively charged nasal mucosa. Cationic liposomes also bind with anionic DNA and form a neutral system known as “Lipoplex” for gene delivery.

Cholesterol is also added to liposome formulation with PLs as a membrane-stabilizing additive. The presence of cholesterol in the lipid bilayer improves the stability of liposomes and also reduces the bilayer's permeability. This permeability alteration of the bilayer results in a reduction in encapsulated drug leakage during circulation.

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