Steric Stabilizers for Cubic Phase Lyotropic Liquid Crystal Nanodispersions (Cubosomas)

ARTICLE IN PRESS

Steric Stabilizers for Cubic Phase Lyotropic Liquid Crystal Nanodispersions (Cubosomes) Josephine Y.T. Chong*,†,{, Xavier Mulet†, Ben J. Boyd*,1, Calum J. Drummond†,{,1 *

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Science, Monash University (Parkville Campus), Parkville, Victoria, Australia † CSIRO Materials Science and Engineering, Clayton, Victoria, Australia { School of Applied Sciences, College of Science, Engineering and Health, RMIT University, Melbourne, Victoria, Australia 1 Corresponding authors: e-mail address: [email protected]; [email protected]

Contents 1. An Intr Introd oduc ucti tion on to Cubo Cuboso some mes: s: Self Self-A -Ass ssem embl blyy of Lipi Lipids ds and and Surf Surfac acta tant ntss 2. Applications of Cubosomes in Nanotechnology 3. Preparation and Characterization of Cubosomes 3.1 Preparation of cubosomes 3.2 Characterization of cubosomes 4. Agents for the Stabilization of Cubosomes 4.1 Classes of steric stabilizers for cubosome dispersions 5. Future Developments in the Stabilization of Cubosomes 6. Conclusion Acknowledgments References

2 5 14 14 15 15 18 43 46 46 47

Abstract Lyotropic liquid crystalline nanostructured particles, such as cubosomes, have grown in popularity as drug delivery systems in the last few years. These systems require steric stabilizers to maintain colloidal stability in an aqueous medium, with Pluronic ® F127, a block copolymer, being the most commonly employed stabilizer. However, in recent years, alternative, more effective stabilizers, as well as rationally designed systems with opportunities for further biofunctionalization have been reported. The purpose of this chapter is to collate and collectively interpret studies in the field of steric stabilization of this important emerging class of nanoparticles for drug and medical imaging agent delivery.

Advances in Planar Lipid Bilayers and Liposomes ISSN 1554-4516 http://dx.doi.org/10.1016/bs.adplan.2014.11.001

# 2015

Elsevier Inc. All rights reserved.

1

ARTICLE IN PRESS 2

Josephine Josephine Y.T. Chong Chong et al.

1. AN INTR INTROD ODUC UCTI TION ON TO CUBO CUBOSO SOME MES: S: SE SELF LF-A -ASS SSEM EMBL BLY Y OF LIPIDS AND SURFACTANTS

Cubosomes are lipid-based particles, approximately 200 nm in diameter, which can be formed in excess water by dispersing cubic phases that possess an infinite lipid bilayer draped on a minimal surface. The cubic phase is often denoted with a “Q” or “V” annotation in the literature. The first observation of a cubic phase in lipid–water systems was reported by Luzzati et al. in 1960 [1] 1960 [1].. The cubic phase possessed the crystallographic space group with symmetry Ia3d (Q (Q230) and its internal structure was confirmed in 1967 [2,3].. Since, six other cubic phases have been discovered with crystallo[2,3] graphic space group symmetries Pn3m (Q224) [4,5], [4,5], Im3m (Q229) [6–8], [6–8], Fm3m (Q225) [9] [9],, Pm3n (Q223) [4,10] [4,10],, Fd3m (Q227) [7,11–14] [7,11–14],, and P4332 (Q212) [7] [7].. These These cubic cubic phases phases may be classi classifie fied d as bicont bicontinu inuous ous cubic cubic phases, with the exception of Q 223 and Q227, which are discontinuous or discrete micellar cubic phases. Recently, a new lyotropic liquid crystalline phase was reported based on a three-dimensional (3D) hexagonal closepacked cked arra arran ngem gement ent of inve invers rsee micel icellles of spa space gro group symm symmet etry ry P6 3Immc [15]. [15]. Bicontinuous cubic phases have an internal structure based on the periodic minimal surfaces [16–18] surfaces [16–18].. In the bicontinuous cubic phase, the lipid bilayer is arranged in a periodic 3D structure. By mapping the bilayers onto the surface of infinite periodic minimal surfaces, the mean curvature at any point on the surface is zero. The mean curvature H is defined as ½( K 1 + K 2), in which K 1 and K 2 are two principal curvatures. A minimal surface is a surface with H 0 at all points, so that every point on the surface is a balanced saddle point. There are three types of inverse cubic phases identified in lipid systems (Fig. (Fig. 1) 1) [16–18] [16–18].. The first is the Q230 cubic phase, which has an Ia3d crystallographic space group symmetry and is based on the Schoen gyroid (G) minimal surface. The second is the Q224 cubic phase, which has a Pn3m crystallographic space group symmetry and is based on the Schwartz diamond (D) minimal surface. The third is the Q 229 cubic phase, which has an Im3m crys crysta tall llog ogra raph phic ic spac spacee grou group p symm symmet etry ry and and is base based d on the the Schwartz primitive (P) minimal surface. The size of the two distinct interpenetrating aqueous water channels in these space group symmetries can be calculated as they are a function of the surfactant or amphiphilic lipid composition and the space group and can range from 4 to 20 nm in diameter, whic which h is suff suffic icie ient ntly ly larg largee to acco accomm mmod odat atee cert certai ain n wate waterr-so solu lubl blee ¼

ARTICLE IN PRESS 2


1. AN INTR INTROD ODUC UCTI TION ON TO CUBO CUBOSO SOME MES: S: SE SELF LF-A -ASS SSEM EMBL BLY Y OF LIPIDS AND SURFACTANTS

Cubosomes are lipid-based particles, approximately 200 nm in diameter, which can be formed in excess water by dispersing cubic phases that possess an infinite lipid bilayer draped on a minimal surface. The cubic phase is often denoted with a “Q” or “V” annotation in the literature. The first observation of a cubic phase in lipid–water systems was reported by Luzzati et al. in 1960 [1] 1960 [1].. The cubic phase possessed the crystallographic space group with symmetry Ia3d (Q (Q230) and its internal structure was confirmed in 1967 [2,3].. Since, six other cubic phases have been discovered with crystallo[2,3] graphic space group symmetries Pn3m (Q224) [4,5], [4,5], Im3m (Q229) [6–8], [6–8], Fm3m (Q225) [9] [9],, Pm3n (Q223) [4,10] [4,10],, Fd3m (Q227) [7,11–14] [7,11–14],, and P4332 (Q212) [7] [7].. These These cubic cubic phases phases may be classi classifie fied d as bicont bicontinu inuous ous cubic cubic phases, with the exception of Q 223 and Q227, which are discontinuous or discrete micellar cubic phases. Recently, a new lyotropic liquid crystalline phase was reported based on a three-dimensional (3D) hexagonal closepacked cked arra arran ngem gement ent of inve invers rsee micel icellles of spa space gro group symm symmet etry ry P6 3Immc [15]. [15]. Bicontinuous cubic phases have an internal structure based on the periodic minimal surfaces [16–18] surfaces [16–18].. In the bicontinuous cubic phase, the lipid bilayer is arranged in a periodic 3D structure. By mapping the bilayers onto the surface of infinite periodic minimal surfaces, the mean curvature at any point on the surface is zero. The mean curvature H is defined as ½( K 1 + K 2), in which K 1 and K 2 are two principal curvatures. A minimal surface is a surface with H 0 at all points, so that every point on the surface is a balanced saddle point. There are three types of inverse cubic phases identified in lipid systems (Fig. (Fig. 1) 1) [16–18] [16–18].. The first is the Q230 cubic phase, which has an Ia3d crystallographic space group symmetry and is based on the Schoen gyroid (G) minimal surface. The second is the Q224 cubic phase, which has a Pn3m crystallographic space group symmetry and is based on the Schwartz diamond (D) minimal surface. The third is the Q 229 cubic phase, which has an Im3m crys crysta tall llog ogra raph phic ic spac spacee grou group p symm symmet etry ry and and is base based d on the the Schwartz primitive (P) minimal surface. The size of the two distinct interpenetrating aqueous water channels in these space group symmetries can be calculated as they are a function of the surfactant or amphiphilic lipid composition and the space group and can range from 4 to 20 nm in diameter, whic which h is suff suffic icie ient ntly ly larg largee to acco accomm mmod odat atee cert certai ain n wate waterr-so solu lubl blee ¼

ARTICLE IN PRESS 3

Steric Stabilizers for Cubosomes

Figure Figure 1 Minim Minimal al surfac surfaces es of the Schoen Schoen gyroid gyroid (G), (G), Schwar Schwartz tz diamo diamond nd (D), (D), and Schwartz primitive (P). Images were generated using Mathematica V.9, based on the equations obtained from [19] from [19]..

compounds [17,20–22] compounds [17,20–22].. The amount of water accommodated in the cubic phases as well as the size of the water channels increases from G to D to P minimal surface phases [17] phases [17].. Cubic phases are typically prepared using lipids. Lipids are often amphiphilic, philic, which means means that that they they are are partl partly y hydrophil hydrophilic ic and and partly partly hydrophob hydrophobic. ic. Usually the hydrophilic portion is depicted as a “head,” with the hydrophobic portion as the “tail” in illustrations. Some surfactants or amphiphilic lipid–water systems are known to form a variety of different lyotropic liquid crystalline phases. Lyotropic liquid crystals are often termed “mesophases,” representing intermediate states of matter between an isotropic liquid and a solid crystal. The different lipid geometries and their resultant self-assembled self-assembled structures that form in the presence of a solvent can be understood using the critical packing parameter (CPP) concept [23] concept [23].. CPP is often defined using Eq. (1) CPP

v ¼

a l

(1)



where v is is the volume of the hydrophobic tail(s), a is the polar headgroup area, and l is is the length of the hydrophobic chain of the surfactant. The lamellar phase has a structure with no interfacial curvature (i.e., CPP 1) because under the CPP concept the surfactants or amphiphilic lipids occupy an apparently cylindrical space (Fig. ( Fig. 2). 2). The mesophases can be classified under two categories subdivided into two two topo topolo logi gica call lly y dist distin inct ct regi region ons: s: type type 1/I 1/I (“no (“norm rmal al” ” or oiloil-in in-w -wat ater er (O/W (O/W)) )) or type type 2/II 2/II (“re (“reve vers rse” e” or wate waterr-in in-o -oil il (W (W/O /O)) )) [24]. [24]. Type 1 mesophases, which include discontinuous micellar cubic, hexagonal, and biconti continu nuous ous cubic cubic phases phases,, are compos composed ed of surfa surfact ctan ants ts or amph amphiph iphil ilic ic lipi lipids ds that that have an overall geometry that occupy an apparently cone shape space ( Fig. 2), 2), ¼

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Figure 2 An illustration of the main types of lyotropic liquid crystal phases depending on the interf interface ace curvat curvature ure (mole (molecul cular ar shape shape or concen concentra tratio tion n in water) water).. The mesoph mesophase asess are denoted as I1, I2 (discrete micellar cubic phase), H 1, H2 (hexagonal phase), V 1, V 2 (bicontinuous cubic phase), and L (lamellar phase). α

ARTICLE IN PRESS Steric Stabilizers for Cubosomes

5

whereby CPP < 1. This conical geometry consequently results in the formation of spheres and cylindrical rods. In contrast, type 2 mesophases, which include the reverse discontinuous micellar cubic, reverse hexagonal, and reverse bicontinuous cubic phases, are composed of surfactants or amphiphilic lipids with an inverse cone shape space (Fig. (Fig. 2), 2), whereby CPP > 1. This geometry results in the formation of inverse spheres and cylindrical rods (Fig. (Fig. 2). 2). Factors effecting v (volume (volume of the hydrophob hydrophobic ic tail(s)) tail(s)),, a (polar (polar headgr headgroup oup area), area), and and l (len (lengt gth h of the the hydr hydroophobic chain of the surfactant) are summarized by Malmsten [25] [25].. In lyotropic liquid crystal phases, the solvent concentration is a variable that will partly dictate the self-assembly behavior [26] behavior [26].. In contrast, thermotropic tropic liquid crystal crystal phase phase transiti transitions ons are only dependen dependentt on temperatu temperature re and pressure [26] pressure [26].. The order/sequence of self-assembly phases that are typically observed as the surfactant/lipid concentration increases in an amphiphilic lipid/ lipid/wat water er system system is micell micelles, es, micell micellar ar cubic, cubic, hexago hexagonal nal,, bicont bicontinu inuous ous cubic, lamellar, and their respective reverse phases, as illustrated in Fig. 2 [27–29].. [27–29] Materials which have been reported to form cubic phase systems have been listed by Fontell in 1990 [30] 1990 [30].. These materials include anionic and cationic “soaps,” zwitterionic and nonionic surfactants, and amphiphilic lipids of biological origin, such as monoglycerides, sphingolipids, and phospholipids, and also galactolipids, glycolipids, and tetra ether lipids [30] [30].. Since then reviews have reported that inverse bicontinuous cubic phases have been been obse observ rved ed for for many many diff differ eren entt type typess of lipi lipids ds,, incl includ udin ing g mono mono-acylgl acylglyce ycerid rides, es, glycol glycolipi ipids ds,, urea, urea, and urea-l urea-like ike amphip amphiphil hiles es and and monomonoethanolamides ethanolamides [31–33]. [31–33]. The amphiphilic lipids most commonly used in lipi lipid d lyot lyotro ropi picc liqu liquid id crys crysta tall rese resear arch ch have have been been glyc glycer eryl yl mono monool olea eate te (GMO), a food emulsifier, and phytantriol, a cosmetic ingredient (Fig. ( Fig. 3) 3) due to their low cost, ease of availability, and potential biocompatibility based on their history of use in other fields.

2. APPLIC APPLICATI ATIONS ONS OF CUBOSO CUBOSOME MES S IN NANOTECHNOLOGY

The aforementioned lyotropic liquid crystal systems are thermodynamically stable and for the case of the reversed phases or lamellar phase can be dispersed into smaller particles that retain the complex internal nanostructure in the presence of a stabilizer. Dispersions of these bulk “parent”

ARTICLE IN PRESS 6

Josephine Y.T. Chong et al.

Figure 3 The chemical structures of amphiphilic lipids: (A) phytantriol and (B) glycerol monoleate.

phases have been given the suffix “-osome.” For example, dispersions from the lamellar, hexagonal, and cubic phases are known as “liposomes,” “hexosomes,” and “cubosomes,” respectively. Liposomes have been extensively used as drug delivery vehicles with 12 clinically approved liposomal drug formulations currently on the market and 22 liposomal drugs undergoing clinical trials [34,35]. Particles based on other lyotropic liquid crystalline structures such as cubosomes (inverse bicontinuous cubic phase, Fig. 4) and hexosomes (inverse hexagonal phase) are also being developed as potential drug delivery systems [37,38]. The key advantages of these nanostructured particles compared to liposomes include their ordered 3D mesoporous internal structure with potential for controllable release and their increased lipid volume fraction per particle, which provides a large lipophilic area for containing poorly water-soluble lipophilic therapeutics [39,40]. The lyotropic liquid crystalline structure and dimensions of the phase, specifically the water channels, determine the release rate of drugs from within the lyotropic liquid crystal phase [41,42]. The phases can accommodate molecules of varying properties [43,44]. A recent study by Zabara and Mezzenga reported the controlled


7

Figure 4 An illustration of the particle morphology and applications of the cubosome. The cryo-FESEM images display the 3D particle morphology of cubosomes and are adapted from Rizwan et al. [36].

release of encapsulated protein within Q224 cubic nanostructured particles by doping the mesophase with a hydration-modulating agent that causes an increase in the diameter of the water channels [45]. In a similar manner, the swelling of the aqueous domain can also be manipulated with polysaccharides, as illustrated by Mezzenga et al. [46]. The possibility of controlled drug release from nonlamellar lyotropic liquid crystalline systems is one of the main attractive features for using these systems for drug delivery. Examples of therapeutics which have been incorporated into cubosomes for investigating their potential as drug delivery systems are listed in Table 1. Cubosomes have been studied for administration via ocular, dermal, intradermal, mucosal, intranasal, oral, percutaneous, intraperitoneal, intratympanic, and intravenous routes, as presented in Table 1. In addition, studies have also been performed on the interaction of nanostructured particles with model and cell membranes [102] and blood components [103], for their biocompatibility within the body as effective drug delivery systems.

Table 1 A table listing examples of the therapeutics and lipid composition of drug-loaded cubosomes as drug nanocarriers Administration Bioactive molecule (peptide, drug) Matrix constituent Stabilizer route (if applicable) References

Silver sulfadiazine Hinokitiol Soluble extracts of Korean barberry 5(6)-Tetramethylcarboxy rhodamine-labeled OVA257–264

Glyceryl monooleate Glyceryl monooleate Glyceryl monooleate Phytantriol

Pluronic®F127

Topical

[47]

®

Dermal

[48]

®

Dermal

[49]

®

Transcutaneous

Pluronic F127 Pluronic F127 Pluronic F127 ®

[50]

Herbal extracts (obtained from Poria cocos, Glyceryl monooleate Thuja orientalis, Espinosilla, Lycium chinense Mill , Coix lacryma- jobi , and Polygonum multiflorum Thunberg )

Pluronic F127

Skin (for hair regrowth)

[51]

Alpha lipoic acid

Myverol™ 18-99

Pluronic®F127

Skin

[52]

Saponin adjuvant Quil A and monophosphoryl lipid A

Phytantriol

Pluronic®F127

In vitro (skin)

[53]

Triclosan

Glyceryl monooleate

Pluronic®F127

In vitro (skin)

[54]

KIOM-MA-128 (water-soluble extract)

Glyceryl monooleate

Pluronic®F127

In vitro (skin)

[55]

Houttuynia cordata (water-soluble extract)

Glyceryl monooleate

Pluronic®F127

In vitro (skin)

[56]

Tacrolimus

Glyceryl monooleate

Pluronic®F127

Intradermal

®

Glyceryl monooleate

Pluronic F127

Mucosal

Dexamethasone

Glyceryl monooleate

Pluronic®F127

Ocular

[59]

Flurbiprofen

Glyceryl monooleate

Pluronic®F127

Ocular

[60]

Cyclosporine A

Glyceryl monooleate

Pluronic®F127

Ocular

[61]

5-FC oleyl carbamate (pro-drug)

5-FC oleyl carbamate

Pluronic®F127

Oral

[62]

Curcumin/piperine

Phytantriol

Pluronic®F127

Oral

[63]

Amphotericin B

Phytantriol

Pluronic®F127

Oral

[64,65]

Cinnarizine

Phytantriol or glyceryl monooleate

Pluronic®F127

Oral

[66]

Cyclosporine A

Glyceryl monooleate

Pluronic®F127

Oral

[67]

Ibuprofen

Phytantriol

Pluronic®F127

Oral

[68]

Insulin

Glyceryl monooleate

Pluronic®F127

Oral

[69]

20(S)-protopanaxadiol/piperine

Glyceryl monooleate

Pluronic®F127

Oral

[70,71]

Simvastatin

Glyceryl monooleate

Pluronic®F127

Omapatrilat Coenzyme Q10 Coenzyme Q10 Coenzyme Q10

Glyceryl monooleate Glyceryl monooleate Glyceryl monooleate Glyceryl monooleate Glyceryl monooleate

[58]

Oral

[72]

®

Oral

[73]

®

Oral

[73]

®

Oral

[74]

®

Oral

[74]

®

Oral

[74]

Pluronic F127 Pluronic F68 Pluronic F127 Pluronic F108 Pluronic F68

Continued

Table 1 A table listing examples of the therapeutics and lipid composition of drug-loaded cubosomes as drug nanocarriers—cont'd Administration Bioactive molecule (peptide, drug) Matrix constituent Stabilizer route (if applicable) References

Coenzyme Q10

Phytantriol

Pluronic®F127

Oral

P R E S S

[57]

Clotrimazole

Omapatrilat

A R T I C L E I N

[74]

A R T I C L E I N P R E S S

Dexamethasone

Glyceryl monooleate

Pluronic®F127

Ocular

[59]

Flurbiprofen

Glyceryl monooleate

Pluronic®F127

Cyclosporine A 5-FC oleyl carbamate (pro-drug) Curcumin/piperine

Glyceryl monooleate 5-FC oleyl carbamate Phytantriol

Ocular

[60]

®

Ocular

[61]

®

Oral

[62]

®

Oral

[63]

®

Pluronic F127 Pluronic F127 Pluronic F127

Amphotericin B

Phytantriol

Pluronic F127

Oral

[64,65]

Cinnarizine


Pluronic®F127

Oral

[66]

Cyclosporine A

Glyceryl monooleate

Pluronic®F127

Oral

[67]

Ibuprofen

Phytantriol

Pluronic®F127

Oral

[68]

Insulin

Glyceryl monooleate

Pluronic®F127

Oral

[69]

20(S)-protopanaxadiol/piperine

Glyceryl monooleate

Pluronic®F127

Oral

[70,71]

Simvastatin

Glyceryl monooleate

Pluronic®F127

Oral

[72]

Omapatrilat

Glyceryl monooleate

Pluronic®F127

Oral

[73]

Omapatrilat

Glyceryl monooleate

Pluronic®F68

Oral

[73]

Coenzyme Q10

Glyceryl monooleate

Pluronic®F127

Oral

[74]

Coenzyme Q10

Glyceryl monooleate

Pluronic®F108

Oral

[74]

Coenzyme Q10

Glyceryl monooleate

Pluronic®F68

Oral

[74]


Continued


Coenzyme Q10

Phytantriol

Pluronic®F127

Oral

[74]

Coenzyme Q10

Phytantriol

Pluronic®F108

Oral

[74]

Coenzyme Q10

Phytantriol

Pluronic®F68

Oral

[74]

Paclitaxel

Soy phosphatidylcholine/ glycerol dioleate

Polysorbate 80

Oral

[75]

Baicalin/KiOM-C

Glyceryl monooleate

Pluronic®F127

In vitro (small intestine adsorption)

[76]

S-164 (water-soluble extract)

Glyceryl monooleate

Pluronic®F127


[77]

Odorranalectin/streptavidin

Glyceryl monooleate

Pluronic®F127

Intranasal

Indomethacin

Glyceryl monooleate

Pluronic®F127

Percutaneous

Bromocriptine

Glyceryl monooleate

Pluronic®F127

Intraperitoneal

Adjuvants imiquimod and monophosphoryl lipid A

Phytantriol

Pluronic®F127

Intravenous

[81]

Fluorescein isothiocyanate-ovalbumin/Quil A®

Phytantriol

Pluronic®F127

Intravenous

[82]

Paclitaxel

Glyceryl monooleate

Pluronic®F127/ mPEG2kDSPE

Intravenous

[83]

[78]

[79]

[80]



Coenzyme Q10 Coenzyme Q10

Phytantriol Phytantriol

Pluronic®F127

Oral

[74]

®

Oral

[74]

®

Pluronic F108

Coenzyme Q10

Phytantriol

Pluronic F68

Oral

[74]

Paclitaxel


Polysorbate 80

Oral

[75]

Baicalin/KiOM-C

Glyceryl monooleate

Pluronic®F127


[76]

S-164 (water-soluble extract)

Glyceryl monooleate

Pluronic®F127


[77]

Odorranalectin/streptavidin

Glyceryl monooleate

Pluronic®F127

Intranasal

Indomethacin

Glyceryl monooleate

®

Percutaneous

®

Pluronic F127

[78]

Glyceryl monooleate

Pluronic F127

Intraperitoneal

Adjuvants imiquimod and monophosphoryl lipid A

Phytantriol

Pluronic®F127

Intravenous

[81]

Fluorescein isothiocyanate-ovalbumin/Quil A®

Phytantriol

Pluronic®F127

Intravenous

[82]

Paclitaxel

Glyceryl monooleate


Intravenous

[83]

Propofol


Polysorbate 80

Intravenous

[84]

Somatostatin


Polysorbate 80

Intravenous

[85]

Earthworm fibrinolytic enzyme (protein)

Glyceryl monooleate/ propylene glycol

Pluronic®F127

Intratympanic

Ovalbumin


Pluronic®F127

α-Chymotrypsinogen A (protein)

Glyceryl monooleate

MO-PEG2000 [poly(ethylene glycol) monooleate]

[88]

Carrier-free human recombinant brainderived neurotrophic factor

Glyceryl monooleate/ eicosapentaenoic acid

D-α -Tocopherol

[89]

Annexin V (protein)

Phytantriol

Pluronic®F127

[90]

Curcumin

Glyceryl monooleate

Pluronic®F127

[91]

[80]

[86] [87]

poly(ethylene glycol) 1000 succinate (V1000)

Continued


Quercetin

Glyceryl monooleate

Pluronic®F108

P R E S S

[79]

Bromocriptine

A R T I C L E I N

[92]


Paclitaxel

Glyceryl monooleate


Intravenous

[83]

Propofol


Polysorbate 80

Intravenous

[84]

Somatostatin


Polysorbate 80

Intravenous

[85]

Earthworm fibrinolytic enzyme (protein)

Glyceryl monooleate/ propylene glycol

Pluronic®F127

Intratympanic

Ovalbumin


Pluronic®F127

α-Chymotrypsinogen A (protein)

Glyceryl monooleate

MO-PEG2000 [poly(ethylene glycol) monooleate]

[88]

Carrier-free human recombinant brainderived neurotrophic factor

Glyceryl monooleate/ eicosapentaenoic acid

D-α -Tocopherol

[89]

Annexin V (protein)

Phytantriol

Pluronic®F127

Curcumin

Glyceryl monooleate

[86] [87]


poly(ethylene glycol) 1000 succinate (V1000) ®

Pluronic F127

[90]

[91] Continued


Quercetin

Glyceryl monooleate

Pluronic®F108

Camptothecin

Glyceryl monooleate

Pluronic®F108 and folic acid

Dacarbazine

Glyceryl monooleate

Pluronic®F127

[94–96]

Carbamazepine (CBZ), coenzyme Q10 (CoQ10), cholesterol (Chl, sterol), phytosterols (PSs, plant sterols)

Glyceryl monooleate

Pluronic®F127

[97]

Diazepam, griseofulvin, propofol, rifampicin

Myverol™ 18-99

Pluronic®F127

[98]

50-Deoxy-5-fluoro-N 450(phytanyloxycarbonyl) cytidine (phytanyl pro- Deoxy-5-fluoro-N 4drug analogue of capecitabine) (phytanyloxycarbonyl) cytidine

Pluronic®F127

[99]

Hydrocortisone

Phytantriol

Pluronic®F127

[39,100]

Atropine

Phytantriol

Pluronic®F127

[39,100]

Transretinol

Phytantriol

Pluronic®F127

[39,100]

Diazepam

Phytantriol

Pluronic®F127

[39,100]

Prednisolone

Phytantriol

Pluronic®F127

[39,100]

Dexamethasone

Phytantriol

Pluronic®F127

[39,100]

Progesterone

Phytantriol

Pluronic®F127

[39,100]

Haloperidol

Phytantriol

Pluronic®F127

[39,100]

Levofloxacin

Phytantriol

Pluronic®F127

[39,100]

[92] [93]



Quercetin

Glyceryl monooleate

Pluronic®F108

®

[92]

Camptothecin

Glyceryl monooleate

Pluronic F108 and folic acid

Dacarbazine

Glyceryl monooleate

Pluronic®F127

[94–96]

Carbamazepine (CBZ), coenzyme Q10 (CoQ10), cholesterol (Chl, sterol), phytosterols (PSs, plant sterols)

Glyceryl monooleate

Pluronic®F127

[97]

Diazepam, griseofulvin, propofol, rifampicin

Myverol™ 18-99

Pluronic®F127

[98]

[99]

®

50-Deoxy-5-fluoro-N 450(phytanyloxycarbonyl) cytidine (phytanyl pro- Deoxy-5-fluoro-N 4drug analogue of capecitabine) (phytanyloxycarbonyl) cytidine

Pluronic F127

Hydrocortisone

Pluronic®F127

Atropine


[93]

[39,100]

®

[39,100]

®

Pluronic F127

Transretinol

Phytantriol

Pluronic F127

[39,100]

Diazepam

Phytantriol

Pluronic®F127

[39,100]

Prednisolone

Phytantriol

Pluronic®F127

[39,100]

Dexamethasone

Phytantriol

Pluronic®F127

[39,100]

Progesterone

Phytantriol

Pluronic®F127

[39,100]

Haloperidol

Phytantriol

Pluronic®F127

[39,100]

Levofloxacin

Phytantriol

Pluronic®F127

[39,100]

Indometacin

Phytantriol

Pluronic®F127

[39,100]

Hydrocortisone

Myverol™ 18-99K

Pluronic®F127

[39,100]

Atropine

Myverol™ 18-99K

Pluronic®F127

[39,100]

Transretinol

Myverol™ 18-99K

Pluronic®F127

[39,100]

Diazepam

Myverol™ 18-99K

Pluronic®F127

[39,100]

Prednisolone

Myverol™ 18-99K

Pluronic®F127

[39,100]

Dexamethasone

Myverol™ 18-99K

Pluronic®F127

[39,100]

Progesterone

Myverol™ 18-99K

Pluronic®F127

[39,100]

Haloperidol

Myverol™ 18-99K

Pluronic®F127

[39,100]

Levofloxacin

Myverol™ 18-99K

Pluronic®F127

[39,100]

[39,100]

Indometacin

Myverol™ 18-99K

DOPURu (amphiphilic ruthenium-based molecule)

1,2-Dioleoyl-snglycero-3phosphocholine (DOPC) and 1,2dioleoyl-sn-glycero-3phosphoethanolamine (DOPE)

®

Pluronic F127

[101]

ARTICLE IN PRESS 14


Recent reviews by Rizwan et al. [104] and Conn and Drummond [33]



Progesterone

Phytantriol

Pluronic®F127

[39,100]

Haloperidol

Phytantriol

Pluronic®F127

[39,100]

Levofloxacin

Phytantriol

Pluronic®F127

[39,100]

Indometacin

Phytantriol

Pluronic®F127

[39,100]

Hydrocortisone

Myverol™ 18-99K

Pluronic®F127

[39,100]

Atropine

Myverol™ 18-99K

Pluronic®F127

[39,100]

Transretinol

Myverol™ 18-99K

Pluronic®F127

[39,100]

Diazepam

Myverol™ 18-99K

Pluronic®F127

[39,100]

Prednisolone

Myverol™ 18-99K

Pluronic®F127

[39,100]

Dexamethasone

Myverol™ 18-99K

Pluronic®F127

[39,100]

Progesterone

Myverol™ 18-99K

Pluronic®F127

[39,100]

Haloperidol

Myverol™ 18-99K

Pluronic®F127

[39,100]

Levofloxacin

Myverol™ 18-99K

Pluronic®F127

[39,100]

Indometacin

Myverol™ 18-99K

Pluronic®F127

[39,100]

DOPURu (amphiphilic ruthenium-based molecule)

1,2-Dioleoyl-snglycero-3phosphocholine (DOPC) and 1,2dioleoyl-sn-glycero-3phosphoethanolamine (DOPE)

[101]

ARTICLE IN PRESS 14


Recent reviews by Rizwan et al. [104] and Conn and Drummond [33] have collected examples where lyotropic liquid crystalline nanostructured particles accommodate biologically active molecules such as vitamins, enzymes, and other proteins, as well as crystallizing membrane proteins, which have important application for membrane protein crystallization, biosensors, biofuel applications, as well as in drug delivery. Owing to the highsurface area of the internal mesophase structure (up to 400 m2/g) [105], the cubic phase can be used to incorporate these biologically active molecules (e.g., globular proteins), which have similar dimensions to the water channels in the bicontinuous cubic phases [89]. In other recent developments, cubosomes are also being investigated for the containment of contrast agents for medical imaging applications [106–108], and capabilities as a cell-free bio-sensing platform [109]. Apart from drug delivery and biomedical applications, the use and application of lyotropic liquid crystalline nanostructured particles is also relevant within the food industry (e.g., solubilization of food bioactives within lyotropic liquid crystalline mesophases) [110,111] and agriculture industry (e.g., delivery of plant agrochemicals) [112]. Therefore, any research into the colloidal stability and retention of internal structure of nanostructured particles is relevant to several research fields.


ARTICLE IN PRESS 14


Recent reviews by Rizwan et al. [104] and Conn and Drummond [33] have collected examples where lyotropic liquid crystalline nanostructured particles accommodate biologically active molecules such as vitamins, enzymes, and other proteins, as well as crystallizing membrane proteins, which have important application for membrane protein crystallization, biosensors, biofuel applications, as well as in drug delivery. Owing to the highsurface area of the internal mesophase structure (up to 400 m2/g) [105], the cubic phase can be used to incorporate these biologically active molecules (e.g., globular proteins), which have similar dimensions to the water channels in the bicontinuous cubic phases [89]. In other recent developments, cubosomes are also being investigated for the containment of contrast agents for medical imaging applications [106–108], and capabilities as a cell-free bio-sensing platform [109]. Apart from drug delivery and biomedical applications, the use and application of lyotropic liquid crystalline nanostructured particles is also relevant within the food industry (e.g., solubilization of food bioactives within lyotropic liquid crystalline mesophases) [110,111] and agriculture industry (e.g., delivery of plant agrochemicals) [112]. Therefore, any research into the colloidal stability and retention of internal structure of nanostructured particles is relevant to several research fields.

3. PREPARATION AND CHARACTERIZATION OF CUBOSOMES

3.1. Preparation of cubosomes For the preparation of any cubosome dispersion, there are three main components, required; these are (i) lipid, (ii) steric stabilizer, and (iii) an aqueous solution, which is typically water or a buffer system. Boyd et al. and Guo et al. have extensively reviewed and listed established preparation methodologies used for producing cubosome dispersions [113,114]. In summary, there are two main approaches typically used to produce cubosome dispersions: (i) top-down and (ii) bottom-up approaches. The top-down approach requires the dispersion of an extremely viscous lipid or bulk cubic phase into the aqueous solution usually using sonication. The high energy created by sonication can also be produced by high-pressure homogenization and shearing. Since the report of this approach by Ljusberg-Wahren in 1996 [115], high-pressure homogenization and sonication are still the most frequently used techniques in the preparation of cubosomes [113,114]. This


15

is probably because it is a rapid method for forming uniform dispersions with a particle size below 200 nm and low polydispersity. The bottom-up approach is one in which a single phase solution is diluted into a two phase regime of cubosomes coexisting with an excess aqueous phase. An advantage of this method compared to the top-down approach is that it requires less energy input to generate dispersions. The key factor in the bottom-up approach is the presence of a hydrotrope (e.g., chloroform, ethanol), which is miscible with water-insoluble lipids to create single phase liquid precursors and prevents the formation of lyotropic liquid crystals at high concentration.

3.2. Characterization of cubosomes In order to verify that the dispersed particles prepared using the desired preparation technique are indeed “cubosomes,” characterization techniques, such as visual assessment, dynamic light scattering, cross-polarized light microscopy, small angle X-ray scattering (SAXS), and cryo-transmission electron microscopy (cryoTEM), are employed. Although these may not be the only characterization techniques used for cubosome analysis, these are the major techniques used in the literature to date. These techniques have been well established and used with great success in distinguishing different aspects of the lyotropic liquid crystalline nanostructured particle, such as particle size and lyotropic liquid crystal phase/nanostructure type. Quantifying the stability of dispersions (i.e., cubosome and hexosome dispersions) was initially performed using a stability analyzer, the LUMiFuge ®, which is a specialist instrument designed to quantify stability principally for emulsion or other colloidal systems [116,117]. This method only allowed one sample to be measured at any given time. However, recently an accelerated stability assay has been developed enabling highthroughput qualitative analysis for multiple samples [118].

4. AGENTS FOR THE STABILIZATION OF CUBOSOMES

Although the internal mesophase of lyotropic liquid crystalline particles is thermodynamically stable, cubosomes are often less colloidally stable than regular emulsions in an aqueous solution. Therefore, a steric stabilizer is required to retain colloidal stability [119]. The van der Waals forces driving flocculation, and consequent coalescence and creaming of typical O/W

ARTICLE IN PRESS 16


emulsion systems, are destabilizing factors of the colloidal nature of cubosome dispersions. An ideal stabilizer for cubosomes prevents unfavorable interaction between the hydrophobic domains on encounter between particles, without causing disruption to the inner cubic structure. Typically, this requires the formation of a steric and/or electrostatic-repulsive barrier between approaching particles. Stabilizers are therefore considered an essential component in liquidcrystalline nanostructured particle preparation. A further element of consideration for cubosomes is their high internal interfacial area, which may lead to stabilizer sequestration within the liquid crystalline nanostructure, which will reduce its contribution to colloidal stability [120]. Although a charged stabilizer can be applied to provide an electrostatic barrier to the flocculation of cubosomes, it is more common to utilize a steric stabilizer, as charged surfactant molecules have a high propensity to disrupt the internal phase structure of cubosomes [121]. Charged nanostructured particles, such as negatively charged liposomes, have also been reported to have a shorter half-life in the blood than neutral liposomes [122,123] and positively chargedliposomeswerefoundtobetoxicandquicklyremovedfromsystemic circulation [124]. It was reported that the surface charge (i.e., positive or negative) is a key determinant in complement-system activation by liposomes for both human and guinea-pig serum [125,126]. Stealth and steric hindrance are provided by polymers that have been reported to confer repellency to surfaces. They typically share similar properties, such as high hydrophilicity, the presence of hydrogen bond acceptors but absence of hydrogen bond donors, and electrical neutrality [127,128]. Polyethylene glycol (PEG) also known as polyethylene oxide (PEO) fits this profile, being an uncharged, hydrophilic polymer that is soluble in water. Due to its low toxicity and immunogenicity, PEG is considered to be the chemical moiety that yields the most effective steric repulsion barrier while improving the pharmacokinetics and pharmacodynamics of nanoscale drug delivery systems (e.g., stealth liposomes) [129–131]. PEG has been shown to be able to form a stealth corona around liposomes, significantly reducing the rapid uptake of intravenously injected particulate drug carriers by cells of the mononuclear phagocyte system (MPS) [132,133]. It has been demonstrated theoretically [134–137] and experimentally [138–143] that protein repellence of PEG coatings depends on both chain length and chain density, which jointly determine the thickness of the adlayer [127]. Steric stabilization of nanostructured particles is also highly dependent on the stabilizer concentration. Low stabilizer surface coverage often results in a


17

“mushroom” surface conformation of the stabilizer on the surface of the particle (Fig. 5). Increasing the density of PEG chains on the surface of the particle often results in a “brush” conformation of the stabilizing polymer, which is more effective in stabilization and protein repellence [144]. However, little is currently known on the optimal concentration of stabilizer for the preparation of cubosome dispersions, although 10% w/w is the standard concentration often used in their preparation, as it produces an aggregate-free dispersion [113]. Besides PEG length and concentration, it was also established by Thies in 1976 that stabilizer composition/structure and establishing a favorable balance between the anchoring unit (i.e., hydrophobic head) and extending unit (i.e., hydrophilic tail) were as equally important in achieving optimum stability performance when using copolymers as steric stabilizers [145]. This highlights the importance of assessing various copolymer structures as stabilizers for lyotropic liquid crystalline nanostructured particles, as it is

Figure 5 An illustration of some of the factors affecting steric hindrance between nanostructured particles: (A) the concentration of steric stabilizer used and (B) PEG length in steric stabilizer.

ARTICLE IN PRESS 18


possible that better copolymer structure configurations which will enable more effective stabilization have not yet been explored. Accordingly, steric hindrance and provision of stealth onto a nanostructured particle is also dependent on the concentration of steric stabilizer applied and the PEG length in the steric stabilizer (Fig. 5). In 1954, Heller and Pugh found that increasing the PEG length and concentration on their gold sols increased their stability [146]. This was later confirmed by Lee et al. in 1989, using a range of Poloxamers™ (Pluronic®L63, P65, P105, F68, F88, F108) and Poloxamine™ (Tetronic®908), with increasing hydrophilic PEG chain lengths on polystyrene beads. Whereby it was also found that increasing the PEG length also increased the stability of the beads, with Pluronic®F108 and Tetronic®908 being the best stabilizers from the series [147]. Pluronic®F108 was also used on polystyrene beads in 1998 achieving similar stability results [148]. Short PEG lengths on steric stabilizers may be unfavorable because there is insufficient distance created between neighboring particles. For this reason, typically the longer the PEG chain (e.g., Pluronic®F108) the better its effectiveness at providing stabilization to a hydrophobic particle. However, whilst PEG is regarded as an ideal hydrophilic domain for steric stabilizers for lyotropic liquid crystalline nanostructured particles, little is known about the ideal PEG chain length for establishing maximum steric stabilization effectiveness onto cubosomes.

4.1. Classes of steric stabilizers for cubosome dispersions The steric stabilizers which have been reported in the literature for preparing cubosome dispersions have been categorized into four groups: (i) amphiphilic block copolymers (i.e., Poloxamer ™ and Poloxamine™), (ii) PEGylated lipids (e.g., GMO-PEG, vitamin E TPGS, Tween®, 1,2-dimyristoylsn-glycero-3-phosphoethanolamine (DMPE)-PEG, DOPE-PEG, 1,2distearoylphosphatidylethanolamine (DSPE)-PEG), (iii) designer/customized lipid–copolymer series (e.g., poly(octadecyl acrylate)- block-poly(PEG methyl ether acrylate) (P(ODA)-b-P(PEGA-OMe)) series), and (iv) alternative steric stabilizers (e.g., bile salts, proteins, polysaccharide polymers, vitamins, and nanoparticles). These are summarized in Tables 2–4 and are described in more detail below. 4.1.1 Amphiphilic block copolymers Two classes of amphiphilic block copolymers have been reported as steric stabilizers for cubosomes to date. These are the Poloxamer ™ and Poloxamine ™.

Table 2 Amphiphilic block copolymers used as steric stabilizers for cubosomes reported in the general literature Space group of inner Stabilizer Lipid matrix constituent structure References Poloxamer™

Pluronic®F127

Phytantriol

Pn3m (Q224)

[36,39,53,64–66,68, 81,82,87,90,108, 109,118,120, 149–160]

Pluronic®F127

Phytantriol/dipalmitoyl phosphatidylserine (DPPS) Pn3m (Q224) or Im3m (Q229)

Pluronic®F127

1-O -(5,9,13,17-tetramethyloctadecanoyl)erythritol (EROCO C22)

Pn3m (Q224) and Im3m (Q229)

[161]

Pluronic®F127

1-O -(5,9,13,17-tetramethyloctadecyl)-β-Dxylopyranoside (β-XP)


[161–163]

Pluronic®F127

glycolipid 1-O -phytanyl-β-D-xyloside (β-XP)


[163]

Pluronic®F127

5-FC oleyl carbamate

Pn3m (Q224) and Ia3d (Q230)

[62]

Pluronic®F127

50-Deoxy-5-fluoro-N 4-(phytanyloxycarbonyl) cytidine

Pn3m (Q224) and Ia3d (Q230)

[99]

Pluronic®F127

Monolinolein (MLO)

Pn3m (Q224) at 25 C

[164]

[154]


°

Continued

Table 2 Amphiphilic block copolymers used as steric stabilizers for cubosomes reported in the general literature —cont'd Space group of inner Stabilizer Lipid matrix constituent structure References

Pluronic®F127

Monolinolein (MLO)/oil

Pn3m (Q224)

[165–168]

Fd3m (Q227)

[165–168]

Pluronic®F127

Monolinolein (MLO)/diglycerol monooleate (DGMO) or soybean PC/oil

Pn3m (Q224) or Im3m (Q229)

Pluronic®F127

Monoelaidin

Im3m (Q229)

Pluronic®F127

Myverol™ 18-99K

Pluronic®F127

RYLO MG 19

Pluronic®F127

Glyceryl monooleate

Pluronic®F127

Glyceryl monooleate/propylene glycol

Pluronic®F127

Glyceryl monooleate/soya phospholipids

Pluronic®F127

Glyceryl monooleate/oil

Pluronic®F127

Glyceryl monooleate/1-glycerol monooleyl ether (GME)

[169]

[170]

Pn3m (Q224) or Im3m (Q229)

[39,98,108,152,171]


[96,171]

Pn3m (Q224) or Im3m (Q229)

[48,49,51,54,55, 57–61,66,67, 69–73,76–80,87, 91,94–97,102,111, 119,152,155,159, 160,170,172–188]


[86]

Im3m (Q229)

[189]

Im3m (Q229)

[190]

Fd3m (Q227)

[190]


[191]



Pluronic®F127

Monolinolein (MLO)/oil

Pn3m (Q224)

227

Fd3m (Q ®

)

Monolinolein (MLO)/diglycerol monooleate (DGMO) or soybean PC/oil

Pn3m (Q ) or Im3m (Q229)

Pluronic®F127

Monoelaidin

Im3m (Q229)

Myverol™ 18-99K

Pluronic®F127

RYLO MG 19

Pluronic®F127

Glyceryl monooleate

Pluronic®F127

Glyceryl monooleate/propylene glycol

Pluronic®F127

Glyceryl monooleate/soya phospholipids

Pluronic F127

[165–168] [169]

224

Pluronic F127

®

[165–168]

224

Pluronic F127

®

Glyceryl monooleate/oil

[170]

Pn3m (Q ) or Im3m (Q229)

[39,98,108,152,171]


[96,171]

Pn3m (Q224) or Im3m (Q229)

[48,49,51,54,55, 57–61,66,67, 69–73,76–80,87, 91,94–97,102,111, 119,152,155,159, 160,170,172–188]


[86]

Im3m (Q229)

[189]

)

[190]

Fd3m (Q227)

[190]

229

Im3m (Q

Pluronic®F127



[191]

Pluronic®F127

Dimodan U/J (96% monoglycerides: 62% linoleate and 25% oleate)/tetradecane (oil)


[192]

Pluronic®F127

Dimodan U/J (96% monoglycerides: 62% linoleate and 25% oleate)


[193–195]

Pluronic®F127/mPEG2kDSPE

Glyceryl monooleate

Im3m (Q229)

[83]

Pluronic®F127/mPEG350DSPE Phytantriol

Pn3m (Q 224), Im3m [196] (Q229)



®

224

Phytantriol

Pn3m (Q ) and Im3m (Q229)

[196]

Pluronic®F127/β-casein mixture

Phytantriol

Pn3m (Q224)

[152]

Pluronic®F108

Phytantriol

Pn3m (Q224)

[118,160]

Pluronic®F108

Glyceryl monooleate

Pn3m (Q224)

[92,93,160]

Pluronic®F87

Phytantriol

Pn3m (Q224)

[160]

Pluronic®F87

Glyceryl monooleate

Im3m (Q229)

[160]

Pluronic®F68

Phytantriol

Pn3m (Q224)

[160]

P R E S S

Continued


Pluronic®F68

Glyceryl monooleate

Cubosome

[73,160]

P R E S S

A R T I C L E I N

[196]

Pluronic F127/mPEG2kDSPE

A R T I C L E I N

Pluronic®F127



[191]

Pluronic®F127



[192]

Pluronic®F127



[193–195]


Glyceryl monooleate

Im3m (Q229)

[83]

A R T I C L E I N


Pn3m (Q 224), Im3m [196] (Q229)



[196]


Phytantriol


[196]

Pluronic®F127/β-casein mixture

Phytantriol

Pn3m (Q224)

[152]

Pluronic®F108

Phytantriol

Pn3m (Q224)

[118,160]

Pluronic®F108

Glyceryl monooleate

Pn3m (Q224)

[92,93,160]

Pluronic®F87

Phytantriol

Pn3m (Q224)

[160]

Pluronic®F87

Glyceryl monooleate

Im3m (Q229)

[160]

Pluronic®F68

Phytantriol

Pn3m (Q224)

[160]

P R E S S

Continued


Pluronic®F68

Glyceryl monooleate

Cubosome

[73,160]

Pluronic®F68

Myverol™ 18-99K

Cubosome

[113]

Pluronic®P123

Phytantriol

Im3m (Q229)

[160]

Pluronic®P105

Phytantriol

Pn3m (Q224)

[160]

Pluronic®P105

Glyceryl monooleate

Im3m (Q229)

[160]

Pluronic®P104

Phytantriol

Im3m (Q229)

[160]

Pluronic®P104

Glyceryl monooleate

Im3m (Q229)

[160]

Pluronic®P84

Phytantriol


[160]


Polaxamine™

Poloxamine™ 908

Myverol™ 18-99K

Cubosome

[113]

Poloxamine™ 908/ Pluronic®F127 combinations

Myverol™ 18-99K

Cubosome

[113]

Table 3 PEGylated lipid copolymers used as steric stabilizers for cubosomes reported in the general literature PEG PEG Space group of inner MW units Lipid matrix constituent Stabilizer structure

References


Pluronic®F68 ®

Pluronic F68 ®

Pluronic P123

Glyceryl monooleate

Cubosome

[73,160]

Myverol™ 18-99K

Cubosome

[113]

Phytantriol

®

Pluronic P105

Glyceryl monooleate

Pluronic®P104

Phytantriol Glyceryl monooleate

Pluronic®P84

Phytantriol

[160]

)

[160]

)

[160]

Im3m (Q229)

[160]

Im3m (Q229)

[160]


[160]

Pn3m (Q

229

Im3m (Q

Pluronic P104

)

224

Pluronic P105

®

Im3m (Q

Phytantriol

®

229


Polaxamine™

Poloxamine™ 908

Myverol™ 18-99K

Cubosome

[113]

Poloxamine™ 908/ Pluronic®F127 combinations

Myverol™ 18-99K

Cubosome

[113]


References

PEGylated lipid

1,2-Dimyristoyl-snglycero-3-phosphoethanolamine-N PEG (DMPE-PEG550)

550

12

Dielaidoylphosphatidylethanola Im3m (Q229) mine (DEPE)

PEGylated monoolein (MO-PEG660)

660

15

Ia3d (Q230) and Pn3m 1,2Dioleoylphosphatidylethanolami (Q224) ne (DOPE)

[199]

1,2-Distearorylphosphatidylethanol amine-PEG (DSPE-PEG750)

750

17

1,2Cubosome Dioleoylphosphatidylethanolami ne (DOPE)

[200]

[197,198]

Polyoxyethylene (20) sorbitan monopalmitate (Tween®40)

900

20

Myverol™ 18-99K

Cubosome

[113]

Polyoxyethylene (20) sorbitan monooleate (Tween®80)

900

20

Glyceryl monooleate

Cubosome

[102]


900

20


Cubosome

[75,84,85]


900

20

Soy PE (L-αphosphatidylethanolamine)

Cubosome

[38]

D-alpha-Tocopheryl

1000

22

Phytantriol

Im3m (Q229)

PEO1000 succinate

[38]

(vitamin E TPGS) Continued

Table 3 PEGylated lipid copolymers used as steric stabilizers for cubosomes reported in the general literature —cont'd PEG PEG Space group of inner MW units Lipid matrix constituent Stabilizer structure

PEG1K20PHYT 30

1000

22

Phytantriol

229

Im3m (Q

)

References

[201]



References

PEGylated lipid

1,2-Dimyristoyl-snglycero-3-phosphoethanolamine-N PEG (DMPE-PEG550)

550

12

Dielaidoylphosphatidylethanola Im3m (Q229) mine (DEPE)


660

15

Ia3d (Q230) and Pn3m 1,2Dioleoylphosphatidylethanolami (Q224) ne (DOPE)

[199]


750

17


[200]

[197,198]

Polyoxyethylene (20) sorbitan monopalmitate (Tween®40)

900

20

Myverol™ 18-99K

Cubosome

[113]


900

20

Glyceryl monooleate

Cubosome

[102]


900

20


Cubosome

[75,84,85]


900

20

Soy PE (L-αphosphatidylethanolamine)

Cubosome

[38]

D-alpha-Tocopheryl

1000

22

Phytantriol

Im3m (Q229)

PEO1000 succinate


[38]

(vitamin E TPGS) Continued

Table 3 PEGylated lipid copolymers used as steric stabilizers for cubosomes reported in the general literature —cont'd PEG PEG Space group of inner MW units Lipid matrix constituent Stabilizer structure 229

References

PEG1K20PHYT 30

1000

22

Phytantriol

Im3m (Q

)

[201]

PEG1K25PHYT 25

1000

22

Phytantriol

Im3m (Q229)

[201]

PEG1K30PHYT 20

1000

22

Phytantriol


[201]

PEG1K40PHYT 10

1000

22

Phytantriol


[201]

1,3-Didodecyloxy-propane-2-ol-PEG (DDP(EO)30)

1300

30

GMO (RYLO MG 90)

Ia3d (Q230)

[202]

PEG-40-stearate

1800

40

Phytantriol

1,2-Dioleoylphosphatidylethanolami ne-PEG (DOPE-PEG)

2000

45

Glyceryl monooleate and cis-5,8,11,14,17eicosapentaenoic acid (20:5, EPA)


2000

45

Glyceryl monooleate


2000

45


[200,205]

1,2-distearoylphosphatidylethanol amine-PEG (DSPE-PEG2000)

2000

45

Soy phosphatidyl choline (SPC) Cubosome and glycerol dioleate (GDO)

[205]

Im3m (Q229)

Cubosome

Pn3m (Q224) or Im3m (Q229)

[203] [204]

[88]



PEG1K20PHYT 30 PEG1K25PHYT 25

1000 1000

22 22


Im3m (Q229)

229

Im3m (Q

)

224

References

[201]

[201]

PEG1K30PHYT 20

1000

22

Phytantriol

Pn3m (Q (Q229)

) and Im3m

[201]

PEG1K40PHYT 10

1000

22

Phytantriol


[201]


1300

30

GMO (RYLO MG 90)

Ia3d (Q230)

[202]

PEG-40-stearate

1800

40

Phytantriol

1,2-Dioleoylphosphatidylethanolami ne-PEG (DOPE-PEG)

2000

45

Glyceryl monooleate and cis-5,8,11,14,17eicosapentaenoic acid (20:5, EPA)


2000

45

Glyceryl monooleate


2000

45


[200,205]


2000

45


[205]

PEG-45-stearate

2000

45

Phytantriol

Im3m (Q229)

[203]

PEG2K10PHYT 40

2000

45

Phytantriol

Im3m (Q229)

[201]

PEG2K20PHYT 30

2000

45

Phytantriol


PEG2K25PHYT 25 PEG2K30PHYT 20 PEG2K40PHYT 10 PEG-50-stearate

2000 2000 2000 2200

45 45 45 50

Phytantriol Phytantriol Phytantriol Phytantriol

Im3m (Q229)

Cubosome

PEG-55-stearate

2400

55

Phytantriol

PEG3K10PHYT 40

3000

68

PEG3K20PHYT 30

3000


[201]

[201]

)

[201]

229

)

[201]

229

)

[203]

Im3m (Q

229

Im3m (Q ) and Ia3d (Q230) (coexisting with L3 phase)

[202,206]

Im3m (Q229)

[203]

Phytantriol


[201]

68

Phytantriol

Pn3m (Q224)

[201]

3000

68

Phytantriol

Pn3m (Q224)

[201]

3000

68

Phytantriol

Pn3m (Q224)

[201]

Continued


PEG3K40PHYT 10

3000

68

Phytantriol

224

Pn3m (Q

)

P R E S S

[88]

)

Im3m (Q

GMO (RYLO MG 90)

[204]

229

Im3m (Q

52

[203]

229

Im3m (Q

2300

Pn3m (Q224) or Im3m (Q229)


A R T I C L E I N

References

[201]



2000

45


PEG-45-stearate

2000

45

Phytantriol

Im3m (Q229)

[203]

PEG2K10PHYT 40

2000

45

Phytantriol

Im3m (Q229)

[201]

PEG2K20PHYT 30

2000

45

Phytantriol

Pn3m (Q224) and Im3m (Q229) 229

[205]

[201]

PEG2K25PHYT 25

2000

45

Phytantriol

Im3m (Q

)

[201]

PEG2K30PHYT 20

2000

45

Phytantriol

Im3m (Q229)

[201]

PEG2K40PHYT 10

2000

45

Phytantriol

Im3m (Q229)

[201]

PEG-50-stearate

2200

50

Phytantriol

Im3m (Q229)

[203]


2300

52

GMO (RYLO MG 90)

PEG-55-stearate

2400

55

Phytantriol

PEG3K10PHYT 40

3000

68

PEG3K20PHYT 30

3000

68


3000 3000

68 68

Im3m (Q229) and Ia3d (Q230) (coexisting with L3 phase)

[202,206]

Im3m (Q229)

[203]

Phytantriol


[201]

Phytantriol

Pn3m (Q224)

[201]


224

)

[201]

224

)

[201]

Pn3m (Q

Pn3m (Q


Continued


References

PEG3K40PHYT 10

3000

68

Phytantriol

Pn3m (Q

)

[201]

PEG4K10PHYT 40

4000

90

Phytantriol

Pn3m (Q224)

[201]

PEG4K20PHYT 30

4000

90

Phytantriol

Pn3m (Q224)

[201]

PEG4K25PHYT 25

4000

90

Phytantriol

Pn3m (Q224)

[201]

PEG4K30PHYT 20

4000

90

Phytantriol

Pn3m (Q224)

[201]

PEG4K40PHYT 10

4000

90

Phytantriol

Pn3m (Q224)

[201]


4100

92

GMO (RYLO MG 90)

PEG-100-stearate (Myrj®59)

4400

100

Phytantriol

1,3-Didodecyloxy-2-glycidyl-glycerolPEG (DDGG4-(EO)114)

5000

114

GMO (RYLO MG 90)

PEG6K10PHYT 40

6000

136

Phytantriol

PEG6K20PHYT 30

6000

136

PEG6K25PHYT 25

6000

136

PEG6K30PHYT 20

6000

136


[202,206]

Pn3m (Q224)

[118,203]


[202,206]

Pn3m (Q224)

[201]

Phytantriol

Pn3m (Q224)

[201]

Phytantriol

Pn3m (Q224)

[201]

Phytantriol

6000

136

Phytantriol

1,3-Didodecyloxy-2-glycidyl-glycerolPEG-1,3-didodecyloxy-2glycidyl-glycerol (DDGG -(EO)

6000

136

GMO (RYLO MG 90)

)

[201]

224

)

[201]

Pn3m (Q

PEG6K40PHYT 10

224

Pn3m (Q

Im3m (Q229) and Ia3d (Q230) (coexisting with L phase)

[202,206]



PEG3K40PHYT 10 PEG4K10PHYT 40 PEG4K20PHYT 30 PEG4K25PHYT 25

3000 4000 4000 4000

68 90 90 90


Pn3m (Q224)

224 224 224 224

Pn3m (Q

Pn3m (Q

Pn3m (Q

References

[201]

)

[201]

)

[201]

)

[201]

PEG4K30PHYT 20

4000

90

Phytantriol

Pn3m (Q

)

[201]

PEG4K40PHYT 10

4000

90

Phytantriol

Pn3m (Q224)

[201]


4100

92

GMO (RYLO MG 90)

PEG-100-stearate (Myrj®59)

4400

100

Phytantriol

1,3-Didodecyloxy-2-glycidyl-glycerolPEG (DDGG4-(EO)114)

5000

114

GMO (RYLO MG 90)

PEG6K10PHYT 40

6000

136

Phytantriol

PEG6K20PHYT 30

6000

136

PEG6K25PHYT 25

6000

PEG6K30PHYT 20


[202,206]

Pn3m (Q224)

[118,203]


[202,206]

Pn3m (Q224)

[201]

Phytantriol

Pn3m (Q224)

[201]

136

Phytantriol

Pn3m (Q224)

[201]

6000

136

Phytantriol

Pn3m (Q224)

[201]

PEG6K40PHYT 10

6000

136

Phytantriol

Pn3m (Q224)

[201]

1,3-Didodecyloxy-2-glycidyl-glycerolPEG-1,3-didodecyloxy-2glycidyl-glycerol (DDGG2-(EO)136DDGG2)

6000

136

GMO (RYLO MG 90)

PEG-150-stearate

6600

150

Phytantriol


[202,206]

Pn3m (Q224)

[118]

224

PEG8K10PHYT 40

8000

181

Phytantriol

Pn3m (Q

)

[201]

PEG8K20PHYT 30

8000

181

Phytantriol

Pn3m (Q224)

[201]

PEG8K25PHYT 25

8000

181

Phytantriol

Pn3m (Q224)

[201]

PEG8K30PHYT 20

8000

181

Phytantriol

Pn3m (Q224)

[201]

PEG8K40PHYT 10

8000

181

Phytantriol

Pn3m (Q224)

[201]

PEG10K10PHYT40

10,000 227

Phytantriol

Pn3m (Q224)

[201]

PEG10K20PHYT30

10,000 227

Phytantriol

Pn3m (Q224)

[201]

PEG10K25PHYT25

10,000 227

Phytantriol

Pn3m (Q224)

[201]

PEG10K30PHYT20

10,000 227

Phytantriol

Pn3m (Q224)

[201]

PEG10K40PHYT10

10,000 227

Phytantriol

Pn3m (Q224)

[201]

PEG14K10PHYT40

14,000 317

Phytantriol

Pn3m (Q224)

[201]

PEG14K20PHYT30

14,000 317

Phytantriol

Pn3m (Q224)

[201] Continued


PEG14K25PHYT25

14,000 317

Phytantriol

224

Pn3m (Q

)

References

[201]




[202,206]

Pn3m (Q224)

[118]

Pn3m (Q224)

[201]

1,3-Didodecyloxy-2-glycidyl-glycerolPEG-1,3-didodecyloxy-2glycidyl-glycerol (DDGG2-(EO)136DDGG2)

6000

136

GMO (RYLO MG 90)

PEG-150-stearate

6600

150

Phytantriol

PEG8K10PHYT 40

8000

181

Phytantriol

224

PEG8K20PHYT 30

8000

181

Phytantriol

Pn3m (Q

)

[201]

PEG8K25PHYT 25

8000

181

Phytantriol

Pn3m (Q224)

[201]


8000 8000

181 181


224

)

[201]

224

)

[201]

224

Pn3m (Q

Pn3m (Q

PEG10K10PHYT40

10,000 227

Phytantriol

Pn3m (Q

)

[201]

PEG10K20PHYT30

10,000 227

Phytantriol

Pn3m (Q224)

[201]

PEG10K25PHYT25

10,000 227

Phytantriol

Pn3m (Q224)

[201]

PEG10K30PHYT20

10,000 227

Phytantriol

Pn3m (Q224)

[201]

PEG10K40PHYT10

10,000 227

Phytantriol

Pn3m (Q224)

[201]

PEG14K10PHYT40

14,000 317

Phytantriol

Pn3m (Q224)

[201]

PEG14K20PHYT30

14,000 317

Phytantriol

Pn3m (Q224)

[201]


Continued


References

PEG14K25PHYT25

14,000 317

Phytantriol

Pn3m (Q

)

[201]

PEG14K30PHYT20

14,000 317

Phytantriol

Pn3m (Q224)

[201]

PEG14K40PHYT10

14,000 317

Phytantriol

Pn3m (Q224)

[201]

Phytantriol

Pn3m (Q224)

[207]

Im3m (Q229)

[207]

Pn3m (Q224)

[207]

Im3m (Q229)

[207]

Pn3m (Q224)

[207]

Im3m (Q229)

[207]

Pn3m (Q224)

[207]

Im3m (Q229)

[207]

Pn3m (Q224)

[207]

Im3m (Q229)

[207]

Pn3m (Q224)

[207]

Im3m (Q229)

[207]

P(ODA)6-b-P(PEGA-OMe)27

Glyceryl monooleate P(ODA)6-b-P(PEGA-OMe)35

Phytantriol


Phytantriol


Phytantriol


Phytantriol


Phytantriol Glyceryl monooleate

PEG-based copolymers bearing lipid-mimetic anchors

Glyceryl monooleate/sodium cholate

Cubosome (coexisting with [208] L3 phase)

Table 4 Additional miscellaneous steric stabilizers for cubosomes reported in the general literature Stabilizer

Lipid matrix constituent

Space group of inner structure

References



PEG14K25PHYT25 PEG14K30PHYT20 PEG14K40PHYT10 P(ODA)6-b-P(PEGA-OMe)27

14,000 317 14,000 317 14,000 317


Pn3m (Q224)

Phytantriol

Phytantriol


Phytantriol


Phytantriol


Phytantriol

Glyceryl monooleate PEG-based copolymers bearing lipid-mimetic anchors

)

[201]

)

[201]

)

[207]

)

[207]

Pn3m (Q224)

[207]

Im3m (Q229)

[207]

Pn3m (Q224)

[207]

Im3m (Q229)

[207]

Pn3m (Q224)

[207]

Im3m (Q229)

[207]

Pn3m (Q224)

[207]

Im3m (Q229)

[207]

Pn3m (Q224)

[207]

Im3m (Q229)

[207]

224 224

Pn3m (Q


[201]

Pn3m (Q


224

Pn3m (Q

Glyceryl monooleate/sodium cholate

References

229

Im3m (Q


Cubosome (coexisting with [208] L3 phase)




References

Casein

β-Casein

Glyceryl monooleate

Casein

Myverol™ 18-99K

Pn3m (Q224)

Cubosome

[152]

[113]

Albumin

Albumin

Myverol™ 18-99K

Cubosome

[113]

Lecithin

Partially hydrolyzed emulsifier lecithin Dimodan U/J (96% monoglycerides: 62% linoleate (Emultop®EP) and 25% oleate)

Im3m (Q229)

[195]

Modified cellulose

Pn3m (Q224)

[161]


Pn3m (Q224)

[161]

1-O -(5,9,13,17-tetramethyloctadecyl)-β-D-xylopyranoside (β-XP)

Pn3m (Q224)

[161]

Glyceryl monooleate

Cubosome

Hydroxypropyl methyl cellulose acetate succinate (HPMCAS)

Glyceryl monooleate

Hydroxypropyl methyl cellulose acetate succinate (HPMCAS) Hydroxypropyl methyl cellulose acetate succinate (HPMCAS)

Modified starch

HI-CAP100 (hydrophobically modified with octenyl succinate groups)

[209]

Continued

Table 4 Additional miscellaneous steric stabilizers for cubosomes reported in the general literature —cont'd Space group of Stabilizer Lipid matrix constituent inner structure

CAPSUL-E (hydrophobically modified with octenyl succinate

Glyceryl monooleate

Cubosome

References

[209]





References

Casein

β-Casein

Glyceryl monooleate

Casein

Myverol™ 18-99K

Pn3m (Q224)

Cubosome

[152]

[113] A R T I C L E I N

Albumin

Albumin

Myverol™ 18-99K

Cubosome

[113]

Lecithin

Partially hydrolyzed emulsifier lecithin Dimodan U/J (96% monoglycerides: 62% linoleate (Emultop®EP) and 25% oleate)

Im3m (Q229)

[195]

P R E S S

Modified cellulose

Pn3m (Q224)

[161]


Pn3m (Q224)

[161]

1-O -(5,9,13,17-tetramethyloctadecyl)-β-D-xylopyranoside (β-XP)

Pn3m (Q224)

[161]

Glyceryl monooleate

Cubosome

Hydroxypropyl methyl cellulose acetate succinate (HPMCAS)

Glyceryl monooleate

Hydroxypropyl methyl cellulose acetate succinate (HPMCAS) Hydroxypropyl methyl cellulose acetate succinate (HPMCAS)

Modified starch

HI-CAP100 (hydrophobically modified with octenyl succinate groups)

[209]

Continued


References

CAPSUL-E (hydrophobically modified with octenyl succinate groups)

Glyceryl monooleate

Cubosome

[209]

Dextran

Glyceryl monooleate

Cubosome

[209]

Laponite

A R T I C L E I N

Pn3m (Q224) [151]

Laponite XLG

Phytantriol

Laponite XLG


Pn3m (Q224) [193]

Laponite XLG


Pn3m (Q224) [192]

Phytantriol/tetradecane (oil)

Pn3m (Q224) [210]

P R E S S

Silica nanoparticles


No stabilizer

1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)

Im3m (Q229)

Glyceryl monooleate/cis-5,8,11,14,17-eicosapentaenoic acid/1,2-dioleyl-sn-glycero-3-phosphoethanolamine-N [methoxy(poly(ethylene glycol))-2000] (DOPE-PEG 2000)

Cubosome

[101]

[204]


4.1.1.1 Poloxamer™

31


References

CAPSUL-E (hydrophobically modified with octenyl succinate groups)

Glyceryl monooleate

Cubosome

[209]

Dextran

Glyceryl monooleate

Cubosome

[209]

Laponite

A R T I C L E I N

Pn3m (Q224) [151]

Laponite XLG

Phytantriol

Laponite XLG


Pn3m (Q224) [193]

Laponite XLG


Pn3m (Q224) [192]

Phytantriol/tetradecane (oil)

Pn3m (Q224) [210]

P R E S S



No stabilizer

1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)

Im3m (Q229)

Glyceryl monooleate/cis-5,8,11,14,17-eicosapentaenoic acid/1,2-dioleyl-sn-glycero-3-phosphoethanolamine-N [methoxy(poly(ethylene glycol))-2000] (DOPE-PEG 2000)

Cubosome

[101]

[204]


31


4.1.1.1.1 Poloxamer™ 407/Pluronic ® F127 By far the most widely and frequently used steric stabilizer for cubosomes is Poloxamer ™ 407 (also known as Pluronic®F127), a nonionic triblock copolymer composed of PEG and polypropylene oxide (PPO): PEG100PPO65PEG100, with a molecular weight of approximately 12,600 Da (Figs. 6 and 7). Pluronic®F127 is a nonionic macromolecule that is used widely in pharmaceutical formulations and personal care products. In lyotropic liquid crystalline dispersions, Pluronic®F127 acts as a steric stabilizer through the incorporation or adsorption of its hydrophobic PPO block onto the surface of the nanostructured particle. Whilst the PPO domain/block acts as an “anchor” to the particle, the hydrophilic PEG chains extend to cover the surface, providing steric shielding and stabilizing the colloidal particles in aqueous solutions [211]. Pluronic®F127 has been employed to stabilize cubosome dispersions in various lipid systems, including GMO, glycerol monolinoleate, and phytantriol. The GMO system has been the most extensively studied. At low stabilizer concentrations ( <4%, w/w, vs. GMO), Pluronic®F127 stabilized GMO dispersions form Q224 cubosomes with Pn3m space group symmetry, whilst at higher stabilizer concentrations (i.e., 7.4 or 10%, w/w, vs. GMO), Q229 cubosomes with Im3m space group symmetry are formed [173]. Although using low stabilizer concentrations of Pluronic ®F127 can

ARTICLE IN PRESS 31



4.1.1.1.1 Poloxamer™ 407/Pluronic ® F127 By far the most widely and frequently used steric stabilizer for cubosomes is Poloxamer ™ 407 (also known as Pluronic®F127), a nonionic triblock copolymer composed of PEG and polypropylene oxide (PPO): PEG100PPO65PEG100, with a molecular weight of approximately 12,600 Da (Figs. 6 and 7). Pluronic®F127 is a nonionic macromolecule that is used widely in pharmaceutical formulations and personal care products. In lyotropic liquid crystalline dispersions, Pluronic®F127 acts as a steric stabilizer through the incorporation or adsorption of its hydrophobic PPO block onto the surface of the nanostructured particle. Whilst the PPO domain/block acts as an “anchor” to the particle, the hydrophilic PEG chains extend to cover the surface, providing steric shielding and stabilizing the colloidal particles in aqueous solutions [211]. Pluronic®F127 has been employed to stabilize cubosome dispersions in various lipid systems, including GMO, glycerol monolinoleate, and phytantriol. The GMO system has been the most extensively studied. At low stabilizer concentrations ( <4%, w/w, vs. GMO), Pluronic®F127 stabilized GMO dispersions form Q224 cubosomes with Pn3m space group symmetry, whilst at higher stabilizer concentrations (i.e., 7.4 or 10%, w/w, vs. GMO), Q229 cubosomes with Im3m space group symmetry are formed [173]. Although using low stabilizer concentrations of Pluronic ®F127 can

A

B

4000

) O P P f o W M ( e b o h p o r d y H

L121

P123

F127

L101

P103 P104 P105

F108 ) O P P f o F87 W M ( e b o h F68 p o r d y H

L92 L81

L61

P84

L62

P85

L64

4000

L121

P123

L101

P103 P104 P105

L81

L61

P84

L62

L35 20

30

P85

F87

L64

F68

L43

950 10

F108

L92

L43

0

F127

40

50

F38 60

70

80

L35

950 0

10

Hydrophile (% of PEG)

20

30

40

50

F38 60

70

80

Hydrophile (% of PEG) Key:

Not assessed

Im3m

Pn3m

Figure 6 Lyotropic liquid crystalline phases obtained from (A) phytantriol and (B) monoolein dispersions using the Poloxamers™ /Pluronic® surfactants. Image reproduced from [160] with permission from The Royal Society of Chemistry.

ARTICLE IN PRESS 32


Figure 7 The chemical structures of stabilizers Pluronic® and Tetronic® . The blue (gray in the print version) shading indicates the hydrophilic domain, whilst the yellow (light gray in the print version) shading indicates the hydrophobic domain. A graphic illustration of the stabilizer structure is shown on the left hand side, with the dashed line representative of the surface of a nanostructured particle.

produce Q224 cubosomes, the overall quality of the dispersed sample is typically poor, with visual aggregates present. Therefore, higher stabilizer concentrations (i.e., 10% w/w vs. lipid) are typically employed in cubosome preparation, as they establish dispersions that are aggregate-free. It is important to preserve the Pn3m space group symmetry within GMO cubosomes because not only does the change to an Im3m space group symmetry indicate a disruption and destabilization of the lyotropic liquid crystal system, but also the release rate of encapsulated drugs from a cubic phase system with an Im3m space group symmetry is much faster than it is for one with a Pn3m space group symmetry [41]. In contrast to the case of GMO, the use of high Pluronic®F127 concentrations with either glycerol monolinoleate [164] or phytantriol [149], as the main lipid, results in retention of the Pn3m diamond (D) bicontinuous cubic phase within their dispersions. The Pluronic ®F127 content was as high as 33% relative to lipid in some of the phytantriol dispersions in water [149]. Mixed phase (Q229 and Q224) cubosome dispersions can also be obtained from the cubic phase-forming lipid, 1-O -(5,9,13,17tetramethyloctadecyl)-β-D-xylopyranoside (β-XP), system when dispersed with 5.1% (w/w) Pluronic®F127 [162]. Mixed phases were also observed


33

from a ternary system composed of pine needle oil monoglycerides (89.5 wt % GMO), Pluronic®F127, and water, whereby an extended inverted cubic phase was observed in which four different cubic structures (Q230 (G periodic minimal surface), Q224 (D periodic minimal surface), Q229 (P periodic minimal surface), and Q229 (Neovius’s periodic minimal surface) were detected by X-ray diffraction [187].

4.1.1.1.2 Poloxamer™ 338/Pluronic ® F108 Pluronic®F108, with the structure PEG132PPO50PEG132, is another Poloxamer ™ class amphiphile which has recently been successfully used to sterically stabilize cubosomes. It has longer hydrophilic arms than Pluronic ®F127 with a molecular weight of 14,600 Da. Chong et al. reported its ability to conserve the native Pn3m space group symmetry of the bulk phase in both GMO and phytantriol cubosome dispersions (Fig. 6) in 2011 [118,160]. Since then, Swarnakar et al., Murgia et al., and Caltagirone et al. have used Pluronic®F108 to stabilize drug-loaded cubic nanostructured particles from aqueous dispersions based on GMO (GMO–Pluronic®F108–water system) [74,92,93]. Swarnakar et al. also reported cubic nanostructured particles from aqueous dispersions based on phytantriol (phytantriol–Pluronic ®F108–water system) [74]. 4.1.1.1.3 Other Poloxamers™/Pluronics ® Other Poloxamers™/ Pluronics® which have been used for the stabilization of cubosome dispersions of GMO and/or phytantriol are summarized in Table 2. Chong et al. reported the use of Pluronics® with lower molecular weights than Pluronic®F127 (i.e., Pluronic®F87, F68, P123, P105, P104, P84) as steric stabilizers (Fig. 6) [160]. Pluronics® with PEG chains greater or equal to 37 PEG units were reported to stabilize phytantriol cubosome dispersions, which had Pn3m space group symmetry. In contrast, all the Pluronics® that were able to produce cubosome dispersions based on GMO were reported to have Im3m space group symmetry. Tamayo-Esquivel et al., Swarnakar et al., and Boyd et al. also reported cubic nanostructured particles from aqueous dispersions based on GMO (GMO–Pluronic®F68–water system) [73,74,113] and phytantriol (phytantriol–Pluronic®F68–water system) [74], employing Pluronic®F68 as a steric stabilizing agent. 4.1.1.2 Poloxamine™

4.1.1.2.1 Poloxamine™ 908/Tetronic ® 908 Poloxamine™ 908, also known as Tetronic®908, is a tetrafunctional PEG–PPO ethylenediamine block copolymer (Fig. 7). Boyd et al. reported stabilizing aqueous dispersions of Myverol™ 18-99K in Poloxamine™ 908 solution [113]. Aqueous

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dispersions of Myverol™ 18-99K in water were also achieved using a combination of Poloxamer ™ 407 and Poloxamine™ 908, as stabilizing agents [113]. 4.1.2 PEGylated lipids In addition to commercially available block copolymer stabilizers, PEGylated lipids (i.e., PEG-lipids) have also been reported to sterically stabilize inverse bicontinuous cubic phase particles. To date only a few PEGylated lipids have been published as effective stabilizers for cubosomes (Fig. 8) [38,88,197–200,202,204–206,208]. The lipid anchors of these PEGylated lipids are explored in greater detail below. 4.1.2.1 Glyceryl monooleate

Johnsson et al. reported cubic nanostructured particles prepared from the dispersion of DOPE with PEGylated monoolein (MO-PEG 660) as a steric stabilizing agent [199]. These cubosomes were identified with the mixed cubic phases Ia3d and Pn3m space groups (Q230 and Q224). Angelov et al. reported cubic nanostructured particles from aqueous dispersions of GMO in water using a PEGylated monoolein with a longer PEG chain (MO-PEG2000) as the steric stabilizing agent [88]. These cubosomes had mixed Im3m and Pn3m space group symmetry. 4.1.2.2 Sorbitan monooleate and sorbitan monopalmitate

Polyoxyethylene (20) sorbitan monooleate, otherwise known as polysorbate 80 or Tween®80, is a commercially available PEGylated lipid which has been reported to stabilize cubosomes (Fig. 8). Polysorbate 80 is a solubilizing agent ubiquitously used in nutritives, creams, ointments, lotions, and multiple medical preparations (e.g., vitamin oils, vaccines, and anticancer agents) and as an additive in tablets. Barauskas et al. reported cubic nanostructured particles from aqueous dispersions of GMO (GMO–Tween®80–water system) with Tween®80, as a steric stabilizing agent [102]. Cubosomes have also been prepared using soy phosphatidyl choline (SPC) and glycerol dioleate (GDO) in water, sterically stabilized with Tween®80 [75,84,85]. Barauskas et al. have also stabilized cubic nanostructured particles from aqueous dispersions of soy PE (L-α-phosphatidylethanolamine) (Soy PE– Tween®80–water system) using Tween®80 [38]. It is interesting to note that Boyd et al. observed immediate phase separation when using polysorbate 80 to stabilize dispersions of Myverol ™ 18-99K, using 10% w/w solution in lipid [113]. Although polysorbate

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Figure 8 The chemical structures of some of the PEGylated lipid stabilizers used in the literature for the preparation of cubosome dispersions. The blue (gray in the print version) shading indicates the hydrophilic domain and the yellow (light gray in the print version) shading indicates the hydrophobic domain. A graphic illustration of the stabilizer structure is shown on the left hand side, with the dashed line representative of the nanostructured particle's surface.

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80 was successfully used to stabilize GMO cubosomes, Myverol ™ is a mixture of monoglycerides, and it is possible the impurities influence the effect of the polysorbate stabilizer. Boyd et al. have also assessed other polysorbates for their effectiveness at stabilizing Myverol™ dispersions. These were polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), and polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), which are commercially known as Tween®20, 40, and 60, respectively [113]. Similar to polysorbate 80, it was found that polysorbates 20 and 60 stabilized Myverol™ systems in water displayed immediate phase separation. Only polysorbate 40 (Fig. 8) was found to produce a coarse dispersion of Myverol™ in water. This indicates the importance of the lipophilic domain length of a polysorbate stabilizer and that an optimal hydrocarbon chain length is apparently required to sufficiently anchor the stabilizer to the nanostructured particles and effectively stabilize these systems. 4.1.2.3 D-alpha-tocopheryl (vitamin E)

Barauskas et al. reported cubic nanostructured particles from aqueous dispersions of phytantriol in water, with D-alpha-tocopheryl PEO1000 succinate (vitamin E TPGS) as the steric stabilizer [38]. Cubosomes were identified with cubic phase Q229, with Im3m space group symmetry. 4.1.2.4 Phospholipids (DOPE, DSPE, and DMPE)

The use of PEGylated phospholipids as a steric stabilizer for cubic nanostructured particles was reported by Angelov et al. [204], Johnsson and Edwards [200], Zeng et al. [205], and Koynova et al. [197,198]. Angelov et al. reported cubic nanostructured particles from aqueous dispersions of GMO and cis-5,8,11,14,17-eicosapentaenoic acid (20:5, EPA) in water, with 1,2dioleoylphosphatidylethanolamine-PEG (DOPE-PEG2000) as the steric stabilizer [204]. Johnsson and Edwards reported cubic nanostructured particles from aqueous dispersions of DOPE-PEG-derivatized phospholipids (PEG lipid +water systems) with PEG lipids (DSPE-PEG (DSPE-PEG750 or DSPEPEG2000)) as a steric stabilizing agent [200]. Zeng et al. also used DSPEPEG2000 as a stabilizing agent for forming cubic nanostructured particles from aqueous dispersions of SPC and GDO [205]. Koynova et al. reported cubic nanostructured particles from aqueous dispersions of dielaidoylphosphatidylethanolamine (DEPE) with PEGylated lipid, PEGylated DMPE (DMPE-PEG550) as a steric stabilizing agent


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[197,198]. Cubosomes were identified with cubic phase Q229, with Im3m space group symmetry. 4.1.2.5 1,3-Didodecyloxy-propane-2-ol and 1,3-didodecyloxy-2-glycidyl-glycerol

Rangelov and Almgren reported cubosomes with Ia3d space group from aqueous dispersions of GMO (RYLO MG 90) in water, using 1,3didodecyloxy-propane-2-ol (DDP)-PEG (DDP(EO) 30) as the steric stabilizer [202]. These findings were further supported by Almgren and Rangelov who reported cubic nanostructured particles from aqueous dispersions of GMO (RYLO MG 90) in water, using DDP-PEG (DDP(EO)52 or DDP(EO)92) as the steric stabilizer [206]. However, cubosomes were also identified with an additional cubic phase Q229, with Im3m space group. Almgren and Rangelov [202,206] also reported cubic nanostructured particles from aqueous dispersions of GMO (RYLO MG 90) in water, with 1,3-didodecyloxy-2-glycidyl-glycerol (DDGG)-PEG (DDGG4-(EO)114) as the steric stabilizer. They also tested a PEGylated lipid with a triblock copol ymer structure, with the lipids located on both terminal ends of the PEG domain (DDGG2-(EO)136-DDGG2) [202,206]. Cubosomes formed were identified with cubic phase Q230, with Ia3d space group and cubic phase Q229, with Im3m space group symmetry. 4.1.2.6 Octadecanoic acid (stearic acid)

Chong et al. reported cubic nanostructured particles from aqueous dispersions of phytantriol in water, using PEG-stearates (Myrj®) as steric stabilizers [118,203]. From the series of PEG-stearates assessed (i.e., PEG-stearates with 10, 20, 25, 40, 45, 50, 55, 100, and 150 PEG units), only those with 40 or greater PEG units were able to form aqueous dispersions of phytantriol in water (Fig. 9) [203]. Furthermore, the PEG-stearates that were able to retain the Pn3m space group of phytantriol, had 100 or greater PEG units (i.e., PEG-100-stearate (Myrj®59) and PEG-150-stearate) [118,203]. It is also interesting to note that the addition of an additional stearate chain to the PEG-150-stearate stabilizer disabled its effectiveness as a steric stabilizer, as PEG-150-distearate was unable to provide stable dispersions of phytantriol in water [118]. This reinforces the importance of the position of hydrophilic moieties within an amphiphilic polymer, for its application as a steric stabilizer. Chong et al. also reported that PEG-stearates were unsuccessful in stabilizing monoolein dispersions. Although several PEGylated lipid stabilizers with different PEG lengths have been identified, the most frequently used PEG length in PEGylated lipid

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Figure 9 Illustration of PEG-100-stearate (Myrj® 59), the SAXS-scattering profile when used to stabilize phytantriol-based cubosomes, and the visual assessment results for dispersions using commercially available stabilizers, including the PEG-stearate copolymer series. Images reproduced with permission from [203].

stabilizers is 45 PEG units (i.e., PEG2000) [88,200,204,205]. The use of PEG2000 was initiated for liposome stabilization, whereby the use of PEG2000 hindered aggregation of lipid nanostructured particles under physiological conditions [88,212–214]. The shortest and the longest chain lengths for PEGylated lipid stabilizers that have been reported are 10 PEG units on average [197,198,203] and 150 PEG units on average [118], respectively. These PEGylated lipids have mainly been used to stabilize dispersions of GMO, resulting in Q229 cubic phase dispersions, with an Im3m space group. However, other lipid dispersions stabilized using PEGylated lipids as steric stabilizers include DEPE, DOPE, and a mixture of SPC and GDO. The first PEGylated lipid that had been reported to stabilize phytantriol dispersions in water was D-alpha-tocopheryl poly(ethylene glycol) 1000 succinate (vitamin E TPGS), which was used at around 10% w/w stabilizer concentration. This resulted in a cubosome with the P-type cubic phase internal structure ( Im3m space group) [38]. Since, PEG-100-stearate (Myrj®59) [118,203] and PEG150-stearate [118] were reported to successfully stabilize phytantriol dispersions in water, with stabilizer concentrations as low as 1% w/w. In contrast to vitamin E TPGS stabilized dispersions, these cubosome dispersions had Pn3m space group symmetry [118,203]. 4.1.3 Designer/customized lipid –copolymer series 4.1.3.1 PEGylated-phytanyl copolymer series

Chong et al. reported cubosomes with Pn3m and Im3m space groups, from aqueous dispersions of phytantriol, using random copolymers from a series


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of PEGylated-phytanyl copolymers, as the steric stabilizing agent [201]. The molecular weight of the PEG used in the preparation of the copolymers and the ratio of the PEG-to-lipid within the copolymer composition were varied to enable structure–performance relationships to be established to guide further work on rationally designed systems (Fig. 10). The important relationships established were that an asymmetric amphiphilic structure with a larger hydrophilic domain (e.g., high hydrophilic lipophilic balance (HLB)) and adequate PEG length were essential for establishing an effective steric stabilizer. Copolymers with PEG lengths between 68 and 136 PEG units on average, with HLB > 17, were found to be effective steric stabilizers for phytantriol cubosome dispersions. Chong et al. also reported a maximum hydrophilic threshold, whereby the effectiveness of the copolymer at providing effective long-term steric stability diminishes when the hydrophilic domain exceeds 60% of the copolymer’s total amphiphilic structure. 4.1.3.2 Polymeric PEGylated lipid copolymer series

In addition to PEGylated lipids, a recently developed customized polymeric PEGylated lipid system, P(ODA)-b-P(PEGA-OMe) was reported by Chong et al. to successfully sterically stabilize aqueous dispersions of both phytantriol and monoolein cubosomes in water [207]. Cubosomes with Pn3m space group symmetry were prepared, from aqueous dispersions of phytantriol, using the P(ODA)- b-P(PEGA-OMe) copolymers as the steric stabilizing agents [207]. Similar to Pluronic®F127, the P(ODA)-b-P(PEGAOMe) copolymers also sterically stabilized monoolein cubosomes, with Im3m space group symmetry (Fig. 11) [207]. The effectiveness of the designer copolymers was equivalent to Pluronic®F127, highlighting the potential of developing custom steric stabilizers for cubosomes [207]. Specifically, these custom polymeric PEGylated lipid copolymers were designed to allow functionalization at the terminal end of the hydrophilic moiety (i.e., P(PEGA-OMe)), to enable the addition of active targeting functionalities for targeting in vivo delivery applications. 4.1.4 Alternative steric stabilizers In addition to amphiphilic block copolymers, PEGylated lipids, and customized lipid copolymers, other amphiphilic stabilizing agents have been reported for cubosomes, including bile salts, amphiphilic proteins (i.e.,

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Figure 10 Accelerated stability assay results for (A) F127 (control stabilizer) at 0.3, 0.5, 0.7, 1, and 1.2 wt% stabilizer concentration, (B) PEG 20PHYT 30 copolymer series, where PEG MW: 2–14K, (C) PEG4K-PHYT copolymer (from 20, 25, 30 and 40 PEG mol% copolymer series), and (D) PEG6K-PHYT copolymer (from 20, 30 and 40 PEG mol% copolymer series). ASA results after first spin 1800 rpm are represented in black columns, whilst ASA results after second spin 2000 rpm are represented in blue (gray in the print version) columns. Steric stabilizer concentration for ASA results presented in (B)–(D) is 1 wt%, with control standard steric stabilizer F127 at 1 wt% presented to the right. Image reproduced with permission from [201].

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A

B 600

√2

500

) U400 A ( y t i s 300 n e t n I

√4

√6 √12

200

√10

√14

100

0.05

0.1

0.15 −1

q (Å

)

0.2

500 nm

Figure 11 (A) SAXS diffraction pattern showing an Im3m space group symmetry and (B) cryo-TEM image of monoolein dispersion stabilized using reduced P(ODA) 10-b-P (PEGA-OMe) 34 copolymer at 25 C. Images reproduced from [207] with permission from The Royal Society of Chemistry. °

casein and albumin), modified polysaccharide polymers (i.e., modified cellulose and starch), poly(vinyl) alcohol, and nanoparticles (i.e., silica and clay nanoparticles). 4.1.4.1 Bile salts

The first fragmented bilayer cubic phase structure was observed in 1979 [215]. The cubic phase formed from a monoglyceride–water mixture was dispersed in the presence of micellar solutions of bile salts [119,208,216]. The cubic phase was stabilized by the formation of a lamellar envelope composed of bile salt and monoglycerides shielding the inner cubic structure. 4.1.4.2 Amphiphilic protein

4.1.4.2.1 β-Casein β-Casein is an amphiphilic protein and a very effective emulsifier and so was employed as a stabilizer in a disperse monoglyceride–water cubic phase. Here, the protein is believed to partition into the outer layer of the lipid particle, yielding a hydrophilic coating and therefore easy to disperse [152,217]. 4.1.4.2.2 Albumin Albumin is a ubiquitous protein which is soluble in water and can be found in egg white, milk, and blood serum. Boyd et al. briefly reported coarse dispersions of Myverol™ 18-99K in water using albumin as a steric stabilizer [113].

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4.1.4.3 Partially hydrolyzed lecithin (Emultop® EP)

Emultop®EP, a partially hydrolyzed lecithin, is a well-accepted food grade emulsifier and contains a relatively large quantity of lysophospholipids. It was thought to be a good emulsifying/stabilizing agent as it was able to stabilize O/W emulsions. Sagalowicz et al. reported cubic nanostructured particles, with Im3m space group symmetry, from aqueous dispersions of Dimodan U/J (a lipid containing 96% monoglycerides: 62% linoleate and 25% oleate) in water, using Emultop®EP as the steric stabilizer [195]. 4.1.4.4 Modified polysaccharide polymers

4.1.4.4.1 Hydrophobically modified ethyl hydroxyethyl cellulose (modified cellulose) Almgren et al. applied hydrophobically modified ethyl hydroxyethyl cellulose (HMEHEC) to the GMO-based cubic phase [218]. Although cubosomes were formed, HMEHEC polymers do not make successful cubosome stabilizers as they were observed to have interacted so strongly with lipids that shortly after dispersion of the sample, the internal nanostructure of the cubosome transformed into lamellar and reversed hexagonal phase. 4.1.4.4.2 Hydroxypropyl methyl cellulose acetate succinate (modified cellulose) Uyama et al. reported cubic nanostructured particles from aqueous dispersions of three lipids: (i) GMO, (ii) 1-O -(5,9,13,17tetramethyloctadecanoyl)erythritol (EROCO C22), and (iii) 1-O (5,9,13,17-tetramethyloctadecyl)-β-D-xylopyranoside (β-XP), using hydroxypropyl methyl cellulose acetate succinate (HPMCAS) as a stabilizing agent [161]. The cubosomes formed were identified to have cubic phase Q224, with Pn3m space group symmetry. The motivation for using modified cellulose was because cellulose products are widely used in the cosmetics, food, and pharmaceutical industries, such as in eye drops and inhalants. HPMCAS is a commercially available generic coating agent and widely used in dry coating or solid dispersion systems [219–221] and demonstrated by Uyama et al., to be applicable as a stabilizer for cubosomes, which allows for sufficient dispersion stability without any internal structure modification [161]. 4.1.4.4.3 HI-CAP100, CAPSUL-E, dextran (modified starch) Spicer et al. presented a pseudoternary phase diagram of GMO with hydrophobically modified starch in water and prepared cubosomes by the rehydration of spray-dried starch–GMO mixtures [209]. In that system,


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starch was mixed threefold higher than the weight of GMO, and the particle size was 600 nm on average. 4.1.4.5 Amphiphilic poly(vinyl) alcohol

Poly(vinyl) alcohol is a water-soluble synthetic polymer, which has been used in papermaking and textiles. Tamayo-Esquivel et al. has reported using poly(vinyl) alcohol to stabilize aqueous GMO dispersions, resulting in sub200 nm particles [73]. 4.1.4.6 Nanoparticles

4.1.4.6.1 Laponite XLG (clay nanoparticles) Muller et al. and Salonen et al. have reported cubic nanostructured particles from aqueous dispersions of two lipids: (i) phytantriol [151] and (ii) Dimodan U/J (consisting of 96% monoglycerides, which contain 62% linoleate and 25% oleate), with [192] and without [193] tetradecane (oil) in water, using Laponite XLG (clay nanoparticles) as the steric stabilizer. The cubosomes formed were identified with cubic phase Q224, with Pn3m space group symmetry. 4.1.4.6.2 Silica (silica nanoparticles) Salonen et al. have reported cubic nanostructured particles from aqueous dispersions of phytantriol and tetradecane (oil) in water, using silica nanoparticles as the steric stabilizing agent [210]. The cubosomes formed were identified with cubic phase Q224, with Pn3m space group symmetry.

5. FUTURE DEVELOPMENTS IN THE STABILIZATION OF CUBOSOMES

Although advancements in high-throughput technology have accelerated the rate of screening for steric stabilizers for cubosomes, the current list of steric stabilizers for cubosomes is still relatively small and limited to a few classes of primarily steric stabilizers. This limits potential progression of these materials into viable products by reducing the available formulation space. Despite the applicability of the possible classes of steric stabilizers for cubosomes, there is an overwhelming reliance and frequency of use with one particular steric stabilizer, Pluronic®F127. Pluronic®F127 is still currently the main steric stabilizer for cubosome preparation of drugencapsulated cubosomes for drug delivery applications. This may be in part due to only recent attempts to establish an understanding of the

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structure–performance relationships dictating the colloidal stability for these relatively complex self-assembled particles. Although Pluronic®F127 is an established and effective steric stabilizer for cubosomes, some issues have been raised regarding its use. Physicochemically, Pluronic®F127 is thought to adsorb onto the particle surface [120]; however, this polymer has been shown to affect the internal structure of GMO-based cubosomes, inducing a transition from the parent Pn3m to Im3m space group [172,173,181,187]. In addition, the cubic phase is transformed to a lamellar phase (vesicles) at high Pluronic ®F127 concentrations [187]. Thus, there is generally a need to identify more alternative steric stabilizers, both commercially available and custom-synthesized stabilizers. Designing effective customized steric stabilizers generally requires identifying intelligent/smart design properties, which can only be established after screening many different stabilizers, and under different conditions. The structure–property relationships currently identified to be important in optimizing colloidal stability include PEG length in PEGylated stabilizers, and having multiple PEG chains (e.g., triblock and brush copolymers). For example, stabilizers Pluronic ®F127 and Myrj®59 both have approximately 100 PEG units and were successfully able to sterically stabilize phytantriol cubosome dispersions, which retained the native Pn3m space group symmetry [203]. However, Pluronic®F127 out-performs Myrj®59 when comparing colloidal stability of their stabilized dispersions using the accelerated stability assay, which may possibly be due to Pluronic ® stabilizers having two PEG arms compared with Myrj® stabilizers having just one PEG arm [118]. As increased PEGylation enhances the colloidal stability, polymers which are more effective steric stabilizers tend to have higher water solubility (e.g., high HLB value). It is also important to ensure that when designing and synthesizing a steric stabilizer, the hydrophilic moiety is not surrounded by hydrophobic groups. For example, PEG-150-distearate and nonreduced P(ODA)- b-P(PEGAOMe) copolymers were not as successful in maintaining stable dispersions as their single hydrophobic block counterparts, namely PEG-150-stearate and the reduced P(ODA)-b-P(PEGA-OMe) copolymers [118,207]. This is likely caused by the aggregation of the hydrophobic ends and increased interparticle bridging. With reverse addition-fragmentation chain transfer (RAFT) polymerization being a popular technique for synthesizing exciting, novel polymer architectures, it is also important to note that some RAFT end-groups can be hydrophobic and can impact the performance of the polymer as a steric stabilizer.


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The future developments for the stabilization of cubosomes involve adding functionalization (i.e., targeting and MRI imaging agent) to the stabilizer, for active targeting capabilities [92,93,106,108,188]. An extensive review of cubosome targeting, drug delivery, and medical imaging was recently written by Mulet et al. [106]. A recent study by Caltagirone et al. reported the functionalization of Pluronic ®F108 with folate, for targeting cubosomes to cancer cells. The targeted monoolein cubosomes were loaded with camptothecin, an anticancer therapeutic, and provided active drug targeting [93]. Although this is the first report of active targeting activity in cubosomes, there are a vast array of opportunities to be explored. With possible exploration of functionalizing and development of more customized steric stabilizers (e.g., P(ODA)-b-P(PEGA-OMe) copolymers), improvements in stealth behavior and colloidal stability, in addition to a targeting capability, are likely to result. Regardless, exceptional colloidal stability is essential for these systems to be eventually developed into clinical products/therapeutics. In addition to steric stabilization, there are other stabilizers (e.g., charged stabilizers), which have not been covered in detail in this chapter but have the potential to be explored further for the advancement of the stabilization of lyotropic liquid crystalline nanostructured particles. Other directions of research in the stabilization of lyotropic liquid crystalline nanostructured particles may include using charged polymers to stabilize dispersions [158,159,222,223]. In particular, Angelov et al. stabilized a dispersion of fusogenic monoolein, using cationic lipid dioctadecyldimethylammonium bromide and PEGylated lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N -(methoxy-(polyethyleneglycol)-2000) ammonium salt (DOPE-PEG2000) [223]. These nanostructured particles were able to encapsulate neurotropic plasmid DNA, for the study of using lyotropic liquid crystalline nanostructured particles as nanocarriers for DNA complexes for the development of prospective nanoparticle-based gene therapies. Lastly, it may be that the future developments in lyotropic liquid crystalline nanostructured particles may not require addition of a separate stabilizer. Studies investigating stimuli responsiveness of lyotropic liquid crystalline nanostructured particles, such as inducing a stable vesicle to unstable cubosome transformation in situ as reported recently by Du et al., have highlighted the possibility of maintaining stable lyotropic liquid crystalline nanostructured particle dispersions in the absence of a stabilizer, by maintaining a specific pH (e.g., pH 8 in Du’s study) [224]. Therefore, one of the future directions for maintaining stable lyotropic liquid crystalline

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nanostructured particle dispersions may depend on investigating different solvent conditions, such as temperature and pH.

6. CONCLUSION

We have discussed the stabilization of cubosomes. Due to their small size and ordered 3D mesoporous internal structure, with a high surface area for substance loading, cubosomes are being widely investigated as drug delivery systems, to encapsulate hydrophilic, lipophilic, or amphiphilic therapeutics, and/or imaging agents. However, these bicontinuous cubic lyotropic liquid crystalline nanostructured particles require the presence of a stabilizer for their colloidal stability. This review covers stabilizers which come from amphiphilic block copolymers, PEGylated lipids, designer/customized copolymer series, and alternative stabilizers. Although these few groups of stabilizers have been identified and reported as suitable stabilizers for these systems, researchers still rely quite heavily on commercially available stabilizers, such as Pluronic ®F127. However, advances in polymer synthesis techniques (e.g., RAFT polymerization) allow for new polymer structures (e.g., PEGylated brush copol ymers) to be investigated for their use as customized steric stabilizers for cubosome systems. An important molecular design feature for creating an effective customized stabilizer for cubosomes is having an asymmetric amphiphilic polymer structure with a larger hydrophilic domain/moiety (e.g., high HLB value). This can be achieved through the use of longer PEG chains (e.g., high PEG MW) and/or multiple PEG chains (e.g., brush or comb-like design). Designing and synthesizing new stabilizers for lyotropic liquid crystalline nanostructured particles enable these stabilizers to eventually be functionalized with a targeting moiety. This will enable active targeting of these systems, which may be important for certain clinical applications for different therapeutics. Future studies will focus on investigating and screening for more effective stabilizers (e.g., both commercial and customized) and/or solvent conditions for maintaining cubosome dispersions.

ACKNOWLEDGMENTS This work was supported by CSIRO and RMIT funding.


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Steric Stabilizers for Cubic Phase Lyotropic Liquid Crystal Nanodispersions (Cubosomas)

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