Cubosomes the pliant honeycombed nano-cargos in drug delivery applications

Document Type : Review Paper


1 College of Pharmacy, JSS Academy of Techhnical Education, Noida, India 201301

2 SRM Modinagar College of Pharmacy, SRM-IST, Delhi-NCR Campus, Ghaziabad, India 201204

3 Department of Civil Engineering, JSS Academy of Technical Education, Noida , India 201301



Cubosomes are the aqueous dispersions of lipid-based liquid-crystalline bi-continuous phases, with the inner structure comprised of triply periodic, non-intersecting, curved, bilayers folded in cubic symmetry, and are organized to form two disjoined continuous water channels on an infinite periodic minimal surface. This review emphasized the peer findings about history and origin of cubosomes, including preparation, characterization and evaluation techniques, along with its promising features as a bio-therapeutics biodegradable cargo nano-material in descriptive manner. The structures of cubosomes, e.g. Q223, Q227, Q212, Q230 etc. are discussed here reflecting their versatile applicability. The automated cubosome preparation method in addition to the general preparation methods and assessment of cubosomes with the aid of both, ordinary visual characterization as well as sophisticated instruments like cryo-TEM, Cryo-FESEM, SAXS, LUMiFuge® have been described. Physical parameter’s quantification approves the drug-carriers system fit in therapeutics, i.e stability analysis, permeation, entrapment efficiency (EE), loading capacity (LC), drug content of dispersions, in-vitro drug release studies, HPLC analysis, in-vivo studies, etc., which are framed here in detail. Cubosomes owes the versatility and desired characteristic of a nanoparticle for drug delivery and other biomedical applications. Therefore, we have described here the up to date wide area applications of cubosomes administered through various routes.


1.     Verma G, Hassan PA. Self assembled materials: Design strategies and drug delivery perspectives. Phys Chem Chem Phys. 2013;15(40): 17016-17028. 
2.     Caltagirone C, Falchi AM, Lampis S, Lippolis V, Meli V, Monduzzi M, et al. Cancer-cell-targeted theranostic cubosomes. Langmuir. 2014;30(21): 6228–6236. 
3.     Nagao M, Ranneh AH, Iwao Y, Yamamoto K, Ikeda Y. Preparation of Cubosomes with Improved Colloidal and Structural Stability Using a Gemini Surfactant. Mol Pharm. 2023;20(10):5066–5077. 
4.     Iqbal S, Zaman M, Waqar MA, Sarwar HS, Jamshaid M. Vesicular approach of cubosomes, its components, preparation techniques, evaluation and their appraisal for targeting cancer cells. J Liposome Res. 2023;1–17. 
5.     Leu JSL, Teoh JJX, Ling ALQ, Chong J, Loo YS, Mat Azmi ID, et al. Recent Advances in the Development of Liquid Crystalline Nanoparticles as Drug Delivery Systems. Pharmaceutics. 2023;15(5):1421. 
6.     Palma AS, Casadei BR, Lotierzo MC, de Castro RD, Barbosa LRS. A short review on the applicability and use of cubosomes as nanocarriers. Biophys Rev. 2023;15(4):553–567. 
7.     Huang Y, Chang Z, Xia X, Zhao Z, Zhang X, Huang Z, et al. Current and evolving knowledge domains of cubosome studies in the new millennium. J Nanopart Res. 2023;25(9):176. 
8.     Sivadasan D, Sultan MH, Alqahtani SS, Javed S. Cubosomes in drug delivery—A comprehensive review on its structural components, preparation techniques and therapeutic applications. Biomedicines. 2023;11(4):1114. 
9.     Zaborowska M, Bartkowiak A, Nazaruk E, Matyszewska D, Bilewicz R. Interfacial Behavior of Cubosomes: Combined Langmuir–Blodgett/Langmuir–Schaefer and AFM Investigations. Langmuir. 2023;39(22):7958–7967. 
10.     Hyde ST, Andersson S, Ericsson B, Larsson K. A cubic structure consisting of a lipid bilayer forming an infinite periodic minimum surface of the gyroid type in the glycerolmonooleat-water system. Z Kristallogr Cryst Mater. 1984;168(1–4):213–219. 
11.     Liu H, Wang Y, Wang Q, Li Z, Zhou Y, Zhang Y, et al. Protein-bearing cubosomes prepared by liquid precursor dilution: Inner ear delivery and pharmacokinetic study following intratympanic administration. J Biomed Nanotechnol. 2013;9(10):1784-1793. 
12.     Liu Q, Dong Y Da, Hanley TL, Boyd BJ. Sensitivity of nanostructure in charged cubosomes to phase changes triggered by ionic species in solution. Langmuir. 2013;29(46):14265-14273. 
13.     Singh S, Sachan K, Verma S, Singh N, Singh PK. Cubosomes: An Emerging and Promising Drug Delivery System for Enhancing Cancer Therapy. Curr Pharm Biotechnol. 2023;25. 
14.     Fong C, Le T, Drummond CJ. Lyotropic liquid crystal engineering–ordered nanostructured small molecule amphiphile self-assembly materials by design. Chem Soc Rev [Internet]. 2012;41(3):1297–1322. 
15.     Spicer PT. Cubosome Formation via Dilution: Kinetic Effects and Consumer Product Implications. In 2003. p. 346–59. 
16.     Spicer PT, Hayden KL, Lynch ML, Ofori-Boateng A, Burns JL. Novel process for producing cubic liquid crystalline nanoparticles (cubosomes). Langmuir. 2001;17(19): 5748–5756. 
17.     Hoffmann H. Mizellen: Micellization, Solubilization, and Microemulsions. 2 Bde. Hrsg. von K. L. Mittal. Plenum Press, New York 1978;26(3). 
18.     Luzzati V, Husson F. The structure of the liquid-crystalline phases of lipid-water systems. J Cell Biol. 1962 1;12(2):207–219. 
19.     Luzzati V, Tardieu A, Gulik-Krzywicki T, Rivas E, Reiss-Husson F. Structure of the cubic phases of lipid-water systems. Nature. 1968;220(5166):485-488.
20.     Mariani P, Luzzati V, Delacroix H. Cubic phases of lipid-containing systems. Structure analysis and biological implications. J Mol Biol. 1988;204(1):165-189. 
21.     Shah JC, Sadhale Y, Chilukuri DM. Cubic phase gels as drug delivery systems. Adv Drug Deliv Rev. 2001;47(2–3):229-250. 
22.     Zhao XY, Zhang J, Zheng LQ, Li DH. Studies of cubosomes as a sustained drug delivery system. J Dispers Sci Technol. 2004;25(6):795-799. 
23.     Gowda BHJ, Ahmed MG, Alshehri SA, Wahab S, Vora LK, Singh TRR, et al. The cubosome-based nanoplatforms in cancer therapy: Seeking new paradigms for cancer theranostics. Environ Res. 2023;237:116894. 
24.     Garg G, Saraf S, Saraf S. Cubosomes: An Overview. Biol Pharm Bull. 2007;30(2):350–353. 
25.     Garg M, Goyal A, Kumari S. An Update on the Recent Advances in Cubosome: A Novel Drug Delivery System. Curr Drug Metab. 2021;22(6):441–450. 
26.     Tudose A, Celia C, Belu I, Borisova S, Paolino D. Effect of three monoglyceride based cubosomes systems on the viability of human keratinocytes. Farmacia. 2014;62(4):  777-790. 
27.     Larsson K. Cubic lipid-water phases: Structures and biomembrane aspects. J Phys Chem. 1989; 93(21):7304–7314. 
28.     Larsson K, Fontell K, Krog N. Structural relationships between lamellar, cubic and hexagonal phases in monoglyceride-water systems. possibility of cubic structures in biological systems. Chem Phys Lipids. 1980;27(4):321-328. 
29.     Gustafsson J, Ljusberg-Wahren H, Almgren M, Larsson K. Cubic Lipid−Water Phase Dispersed into Submicron Particles. Langmuir. 1996;12(20):4611–4613. 
30.     Gustafsson J, Ljusberg-Wahren H, Almgren M, Larsson K. Submicron particles of reversed lipid phases in water stabilized by a nonionic amphiphilic polymer. Langmuir. 1997;13(26):6964–6971. 
31.     Engström S, Alfons K, Rasmusson M, Ljusberg-Wahren H. Solvent-induced sponge (L3) phases in the solvent-monoolein-water system. Prog Colloid Polym Sci. 1998;108:93-98. 
32.     Spicer P. Cubosome processing: Industrial nanoparticle technology development. Chem Eng Res Des. 2005;83(11):  1283-1286. 
33.     Spicer PT. Progress in liquid crystalline dispersions: Cubosomes. Vol. 10, Curr Opin Colloid Interface Sci. 2005. 
34.     Spicer PT, Small WB, Lynch ML, Burns JL. Dry powder precursors of cubic liquid crystalline nanoparticles (cubosomes). J Nanopart Res. 2002;4(4):297-311. 
35.     Buchheim W, Larsson K. Cubic lipid-protein-water phases. J Colloid Interface Sci. 1987 Jun;117(2):582–583. 
36.     Neto C, Aloisi G, Baglioni P, Larsson K. Imaging soft matter with the atomic force microscope: Cubosomes and hexosomes. J Phys Chem B. 1999;103(19):3896–3899. 
37.     Almoshari Y. Development, Therapeutic Evaluation and Theranostic Applications of Cubosomes on Cancers: An Updated Review. Vol. 14, Pharmaceutics. 2022; 14(3):600. 
38.     Nylander T, Mattisson C, Razumas V, Miezis Y, Håkansson B. A study of entrapped enzyme stability and substrate diffusion in a monoglyceride-based cubic liquid crystalline phase. Colloids Surf A Physicochem Eng Asp. 1996;114:311–320. 
39.     Swarnakar NK, Thanki K, Jain S. Lyotropic liquid crystalline nanoparticles of CoQ10: Implication of lipase digestibility on oral bioavailability, in vivo antioxidant activity, and in vitro - In vivo relationships. Mol Pharm. 2014;11(5): 1435-1449. 
40.     Patrick T. Spicer. Cubosomes: Bicontinuous Liquid Crystalline Nanoparticles. In: Dekker Encyclopedia of Nanoscience and Nanotechnology, Seven Volume Set. 3rd ed. Boca Raton: CRC Press; 2011. 
41.     Patrick Thomas Spicer, William Broderick Small, Matthew Lawrence Lynch. Cubic liquid crystalline compositions and methods for their preparation. United States: United States Patent; US7008646B2, 2006. 
42.     Lee KWY, Nguyen TH, Hanley T, Boyd BJ. Nanostructure of liquid crystalline matrix determines in vitro sustained release and in vivo oral absorption kinetics for hydrophilic model drugs. Int J Pharm. 2009;365(1–2):190-199. 
43.     Alam MM, Ushiyama K, Aramaki K. Phase behavior, formation, and rheology of cubic phase and related gel emulsion in Tween80/water/oil systems. J Oleo Sci. 2009;58(7):361-367. 
44.     Varghese R, Salvi S, Sood P, Kulkarni B, Kumar D. Cubosomes in cancer drug delivery: A review. Colloid Interface Sci Commun. 2022 Jan;46:100561. 
45.     Chountoulesi M, Pispas S, Tseti IK, Demetzos C. Lyotropic Liquid Crystalline Nanostructures as Drug Delivery Systems 
and Vaccine Platforms. Pharmaceuticals. 2022;15(4):429. 
46. Sadhale Y, Shah JC. Stabilization of insulin against agitation-induced aggregation by the GMO cubic phase gel. Int J Pharm. 1999 Nov 25;191(1):51-64. 
47.     Sadhale Y, Shah JC. Glyceryl monooleate cubic phase gel as chemical stability enhancer of cefazolin and cefuroxime. Pharm Dev Technol. 1998;3(4):549-556.
48.     Lutton ES. Phase behavior of aqueous systems of monoglycerides. J Am Oil Chem Soc. 1965;42(12):1068-1070 .
49.     Fontell K, Mandell L, Ekwall P, Smidsrød O. Some Isotropic Mesophases in Systems Containing Amphiphilic Compounds. Acta Chem Scand. 1968;22: 3209. 
50.     Lindblom G, Larsson K, Johansson L, Fontell K, Forsén S. The Cubic Phase of Monoglyceride-Water Systems. Arguments for a Structure Based upon Lamellar Bilayer Units. J Am Chem Soc. 1979;101(19):5465-5470. 
51.     Ljusberg-Wahren H, Nyberg L, Larsson K. Dispersion of the cubic liquid crystalline phase - Structure, preparation and functionality aspects. Chim Oggi. 1996;14(6):40-43. 
52.     Landh T. Phase behavior in the system pine oil monoglycerides-poloxamer 407-water at 20°C. J Phys Chem. 1994;98(34): 8453–8467. 
53.     Tomas Landh, Kare Larsson. Particles, method of preparing said particles and uses thereof. United States: United States; US5531925A, 1996. 
54.     Nakano M, Sugita A, Matsuoka H, Handa T. Small-angle X-ray scattering and 13C NMR investigation on the internal structure of “cubosomes.” Langmuir. 2001;17(13):3917-3922. 
55.     Uyama M, Nakano M, Yamashita J, Handa T. Useful modified cellulose polymers as new emulsifiers of cubosomes. Langmuir. 2009;25(8):4336-4338.
56.     Siekmann B, Bunjes H, Koch MH, Westesen K. Preparation and structural investigations of colloidal dispersions prepared from cubic monoglyceride-water phases. Int J Pharm. 2002;244(1-2):33-43. 
57.     Wörle G, Siekmann B, Bunjes H. Effect of drug loading on the transformation of vesicular into cubic nanoparticles during heat treatment of aqueous monoolein/poloxamer dispersions. Eur J Pharm Biopharm. 2006;63(2):128-133. 
58.     Abourehab MAS, Ansari MJ, Singh A, Hassan A, Abdelgawad MA, Shrivastav P, et al. Cubosomes as an emerging platform for drug delivery: A review of the state of the art. J Mater Chem B. 2022;10(15):2781–2819. 
59.     Zakaria F, Ashari SE, Mat Azmi ID, Abdul-Rahman MB. Recent advances in encapsulation of drug delivery (active substance) in cubosomes for skin diseases. J Drug Deliv Sci Technol. 2022;68:103097. 
60.     Contescu CI, editor. Dekker Encyclopedia of Nanoscience and Nanotechnology, Second Edition - Six Volume Set (Print Version). CRC Press; 2008. 1018–1028. 
61.     Chong JYT, Mulet X, Boyd BJ, Drummond CJ. Accelerated Stability Assay (ASA) for Colloidal Systems. ACS Comb Sci. 2014;16(5):205–210. 
62.     Chong JY, Mulet X, Waddington LJ, Boyd BJ, Drummond CJ. High-throughput discovery of novel steric stabilizers for cubic lyotropic liquid crystal nanoparticle dispersions. Langmuir. 2012;28(25):9223-9232. 
63.     Zeng N, Gao X, Hu Q, Song Q, Xia H, Liu Z, et al. Lipid-based liquid crystalline nanoparticles as oral drug delivery vehicles for poorly water-soluble drugs: Cellular interaction and in vivo absorption. Int J Nanomedicine. 2012;7:3703-3718.
64.     Mosgaard LD, Jackson AD, Heimburg T. Advances in Planar Lipid Bilayers and Liposomes Volume 16. Adv Planar Lipid Bilayers Liposomes. 2012;16. 
65.     Nanjwade BK, Hundekar YR, Kamble MS, Srichana T. Development of Cuboidal Nanomedicine by. Nanotechnology Austin J Nanomed Nanotechnol. 2014;2(4) 1023. 
66.     Hundekar YR, Saboji JK, Patil SM, Nanjwade BK. Preparation and evaluation of Diclofenac sodium Cubosomes for percutaneous administration. World J Pharm Pharm Sci. 2014;3(5) 523-539. 
67.     Góźdź WT. Cubosome Topologies at Various Particle Sizes and Crystallographic Symmetries. Langmuir. 2015;31(49):13321-13326. 
68.     Triggle DJ. Topics in Pharmaceutical Sciences. J Pharm Sci. 1986;75(8):822. 
69.     Lakshmi N, Yalavarthi P, Vadlamudi H, Thanniru J, Yaga G, K H. Cubosomes as Targeted Drug Delivery Systems - A Biopharmaceutical Approach. Curr Drug Discov Technol. 2014;11(3) 181-188. 
70.     Lippacher A, Müller RH, Mäder K. Semisolid SLNTM dispersions for topical application: Influence of formulation and production parameters on viscoelastic properties. Eur J Pharm Biopharm. 2002;53(2) 155-160. 
71.     Jain S, Jain V, Mahajan SC. Lipid Based Vesicular Drug Delivery Systems. Advances in Pharmaceutics 2014(7):1-12. 
72.     Mehnert W, Mäder K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev. 2001;47(2-3):165-196. 
73.     Schwarz C, Mehnert W, Lucks JS, Müller RH. Solid lipid nanoparticles (SLN) for controlled drug delivery. I. Production, characterization and sterilization. J Control Release. 1994;30(1) 83-96. 
74.     J. Sjoblom, P. Stenius, I. Danielsson. Nonionic Surfactants: Physical Chemistry. Martin J. Schick, editor. New York: Marcel Dekker; 1987. 369–434. 
75.     Hartnett TE, O’Connor AJ, Ladewig K. Cubosomes and other potential ocular drug delivery vehicles for macromolecular therapeutics. Expert Opin Drug Deliv. 2015;12(9):1513–1526. 
76.     Barauskas J, Johnsson M, Joabsson F, Tiberg F. Cubic phase nanoparticles (Cubosome): principles for controlling size, structure, and stability. Langmuir. 2005;21(6):2569-2577. 
77.     Barauskas J, Cervin C, Jankunec M, Špandyreva M, Ribokaitė K, Tiberg F, et al. Interactions of lipid-based liquid crystalline nanoparticles with model and cell membranes. Int J Pharm. 2010;391(1–2):284–291. 
78.     Schwarz, Hermann Amandus. Gesammelte mathematische abhandlungen. Vol. 260. American Mathematical Soc., 1972. 
79.     Ahuja M, Dhake AS, Sharma SK, Majumdar DK. Topical Ocular Delivery of NSAIDs. AAPS J. 2008 Jun 25;10(2):229. 
80.     Schoen, Alan H. Infinite periodic minimal surfaces without self-intersections. No. C-98. 1970. 
81.     Scriven, L. E. “Equilibrium bicontinuous structure.” Nature 263.5573 (1976): 123-125. 
82.     Balmbra R, Clunie J, Goodman J. Cubic Mesomorphic Phases. Nature 222, (1969) 1159–1160. 
83.     Delacroix H, Gulik-Krzywicki T, Seddon JM. Freeze fracture electron microscopy of lyotropic lipid systems: quantitative analysis of the inverse micellar cubic phase of space group Fd3m (Q227). J Mol Biol. 1996 ;258(1):88-103. 
84.     Diat O, Porte G, Berret JF. Orientation and twins separation in a micellar cubic crystal under oscillating shear. Phys Rev B Condens Matter. 1996;54(21):14869-14872.
85.     Shearman GC, Tyler AI, Brooks NJ, Templer RH, Ces O, Law RV, Seddon JM. A 3-D hexagonal inverse micellar lyotropic phase. J Am Chem Soc. 2009;131(5):1678-1679. 
86.     Yaghmur A, Glatter O. Characterization and potential applications of nanostructured aqueous dispersions. Adv Colloid Interface Sci. 2009;147-148:333-342. 
87.     Amar-Yuli I, Libster D, Aserin A, Garti N. Solubilization of food bioactives within lyotropic liquid crystalline mesophases. Curr Opin Colloid Interface Sci. 14(1):21-32. 
88.     Rosen MR. Delivery System Handbook for Personal Care and Cosmetic Products: Technology, Applications and Formulations. Delivery System Handbook for Personal Care and Cosmetic Products: Technology, Applications and Formulations. 2005. 
89.     Umar H, Wahab HA, Gazzali AM, Tahir H, Ahmad W. Cubosomes: Design, Development, and Tumor-Targeted Drug Delivery Applications. Polymers (Basel). 2022;14(15):3118. 
90.     Patond VB, Ghonge AB, Narkhede MB. Cubosome-Review. Int J Trend Sci Res. 2020;4:1116–1120. 
91.     Johnsson M, Barauskas J, Norlin A, Tiberg F. Physicochemical and drug delivery aspects of lipid-based liquid crystalline nanoparticles: A case study of intravenously administered propofol. J Nanosci Nanotechnol. 2006 6(9-10):3017-3024. 
92.     Mezzenga R, Meyer C, Servais C, Romoscanu AI, Sagalowicz L, Hayward RC. Shear rheology of lyotropic liquid crystals: A case study. Langmuir. 2005;21(8):3322-3333. 
93.    Boyd BJ. Characterisation of drug release from cubosomes using the pressure ultrafiltration method. Int J Pharm. 2003;260(2):239-247.
94.     Boyd BJ, Dong Y Da, Rades T. Nonlamellar liquid crystalline nanostructured particles: Advances in materials and structure determination. J Liposome Res. 2009;19(1):12-28. 
95.     Guo C, Wang J, Cao F, Lee RJ, Zhai G. Lyotropic liquid crystal systems in drug delivery. Drug Discov Today. 2010;15(23-24):1032-1040. 
96.     Chong JYT, Mulet X, Postma A, Keddie DJ, Waddington LJ, Boyd BJ, et al. Novel RAFT amphiphilic brush copolymer steric stabilisers for cubosomes: Poly(octadecyl acrylate)-block-poly(polyethylene glycol methyl ether acrylate). Soft Matter. 2014;10(35):6666-6676. 
97.     Dong Y Da, Larson I, Hanley T, Boyd BJ. Bulk and dispersed aqueous phase behavior of phytantriol: Effect of vitamin E acetate and F127 polymer on liquid crystal nanostructure. Langmuir. 2006;22(23):9512-9518. 
98.     Sagalowicz L, Mezzenga R, Leser ME. Investigating reversed liquid crystalline mesophases. Curr Opin Colloid Interface Sci. 2006; 11(4):224-229. 
99.     Sagalowicz L, Leser ME, Watzke HJ, Michel M. Monoglyceride self-assembly structures as delivery vehicles. Trends Food Sci Technol. 2006; 17 (5): 204-214. 
100.     Patel PV, Patel JB, Dangar RD, Patel KS, Chauhan KN. Liquid crystal drug delivery system. Int J Appl Biol Pharm. 2010;1(1):118–123. 
101.     Kaur SD, Singh G, Singh G, Singhal K, Kant S, Bedi N. Cubosomes as Potential Nanocarrier for Drug Delivery: A Comprehensive Review. J Pharm Res Int. 2021; 33 (31): 118-135. 
102.     Barriga HMG, Holme MN, Stevens MM. Cubosomes: The Next Generation of Smart Lipid Nanoparticles? Angew Chem Int Ed Engl. 2019;58(10):2958–2978. 
103.     Tamayo-Esquivel D, Ganem-Quintanar A, Martínez AL, Navarrete-Rodríguez M, Rodríguez-Romo S, Quintanar-Guerrero D. Evaluation of the enhanced oral effect of omapatrilat-monolein nanoparticles prepared by the emulsification-diffusion method. J Nanosci Nanotechnol. 2006;6(9-10):3134-3138. 
104.     Sanjana A, Ahmed MG, Gowda JBH. Development and evaluation of dexamethasone loaded cubosomes for the treatment of vitiligo. Mater Today Proc. 2022;50:197–205. 
105.     Dubey A, Chauhan A, Kaur A, AlamMdA, Yadav S, Rao GSNK. CUBOSOME-A Novel Drug Delivery for Anticancer Drugs. Curr Nanosci. 2024;20(2):206–223. 
106.     Oliveira C, Ferreira CJO, Sousa M, Paris JL, Gaspar R, Silva B, et al. A Versatile Nanocarrier—Cubosomes, Characterization, and Applications. Nanomaterials (Basel). 2022;12(13):2224.
107.     La Y, Park C, Shin TJ, Joo SH, Kang S, Kim KT. Colloidal inverse bicontinuous cubic membranes of block copolymers with tunable surface functional groups. Nat Chem. 2014;6(6):534-541. 
108.     Makai M, Csányi E, Németh Z, Pálinkás J, Eros I. Structure and drug release of lamellar liquid crystals containing glycerol. Int J Pharm. 2003;256(1-2):95-107. 
109.     Fraser SJ, Mulet X, Martin L, Praporski S, Mechler A, Hartley PG, et al. Surface immobilization of bio-functionalized cubosomes: Sensing of proteins by quartz crystal microbalance. Langmuir. 2012;28(1):620-627. 
110.     Fraser SJ, Dawson RM, Waddington LJ, Muir BW, Mulet X, Hartley PG, et al. Development of cubosomes as a cell-free biosensing platform. Aust J Chem. 2011. 
111.     Kuntsche J, Horst JC, Bunjes H. Cryogenic transmission electron microscopy (cryo-TEM) for studying the morphology of colloidal drug delivery systems. Int J Pharm. 2011; 64(1) 46-53. 
112.     Rizwan SB, Dong YD, Boyd BJ, Rades T, Hook S. Characterisation of bicontinuous cubic liquid crystalline systems of phytantriol and water using cryo field emission scanning electron microscopy (cryo FESEM). Micron. 2007;38(5):478-485. 
113.     Rizwan SB, Assmus D, Boehnke A, Hanley T, Boyd BJ, Rades T, et al. Preparation of phytantriol cubosomes by solvent precursor dilution for the delivery of protein vaccines. Eur J Pharm Biopharm. 2011;79(1):15-22. 
114.     Rizwan SB, McBurney WT, Young K, Hanley T, Boyd BJ, Rades T, et al. Cubosomes containing the adjuvants imiquimod and monophosphoryl lipid A stimulate robust cellular and humoral immune responses. J Control Release. 2013;165(1):16-21. 
115.     Angelov B, Angelova A, Garamus VM, Drechsler M, Willumeit R, Mutafchieva R, et al. Earliest stage of the tetrahedral nanochannel formation in cubosome particles from unilamellar nanovesicles. Langmuir. 2012;28(48):16647-16655. 
116.     Angelov B, Angelova A, Papahadjopoulos-Sternberg B, Hoffmann S V., Nicolas V, Lesieur S. Protein-containing PEGylated cubosomic particles: Freeze-fracture electron microscopy and synchrotron radiation circular dichroism study. J Phys Chem B. 2012;116(26):7676-7686. 
117.     Rattanapak T, Young K, Rades T, Hook S. Comparative study of liposomes, transfersomes, ethosomes and cubosomes for transcutaneous immunisation: Characterisation and in vitro skin penetration. J Pharm Pharmacol. 2012;64(11):1560-1569. 
118.     Rattanapak T, Birchall J, Young K, Ishii M, Meglinski I, Rades T, et al. Transcutaneous immunization using microneedles and cubosomes: Mechanistic investigations using Optical Coherence Tomography and Two-Photon Microscopy. J Control Release. 2013;172(3):894-903. 
119.     Chang CM, Bodmeier R. Swelling of and drug release from monoglyceride-based drug delivery systems. J Pharm Sci. 1997;86(6):747-752. 
120.     Chang CM, Bodmeier R. Effect of dissolution media and additives on the drug release from cubic phase delivery systems. J Control Release. 1997;46(3):215-222. 
121.     Aleandri S, Bandera D, Mezzenga R, Landau EM. Biotinylated Cubosomes: A Versatile Tool for Active Targeting and Codelivery of Paclitaxel and a Fluorescein-Based Lipid Dye. Langmuir. 2015;31(46):12770-12776. 
122.     Polyzos A, Alderton MR, Dawson RM, Hartley PG. Biofunctionalized surfactant mesophases as polyvalent inhibitors of cholera toxin. Bioconjug Chem. 2007;18(5): 1442-1449. 
123.     Zheng M, Wang Z, Liu F, Mi Q, Wu J. Study on the microstructure and rheological property of fish oil lyotropic liquid crystal. Colloids Surf A PhysicochemEng Asp. 2011;385(1–3):47–54. 
124.     Murgia S, Bonacchi S, Falchi AM, Lampis S, Lippolis V, Meli V, et al. Drug-loaded fluorescent cubosomes: Versatile nanoparticles for potential theranostic applications. Langmuir. 2013;29(22):6673-6679. 
125.     Murgia S, Falchi AM, Mano M, Lampis S, Angius R, Carnerup AM, et al. Nanoparticles from lipid-based liquid crystals: Emulsifier influence on morphology and cytotoxicity. J Phys Chem B. 2010;114(10):3518-3525. 
126.     Murgia S, Falchi AM, Meli V, Schillén K, Lippolis V, Monduzzi M, et al. Cubosome formulations stabilized by a dansyl-conjugated block copolymer for possible nanomedicine applications. Colloids Surf B Biointerfaces. 2015;129:87–94. 
127.     Falchi AM, Rosa A, Atzeri A, Incani A, Lampis S, Meli V, et al. Effects of monoolein-based cubosome formulations on lipid droplets and mitochondria of HeLa cells. Toxicol Res (Camb). 2015;4(4):1025-1036. 
128.     Angelov B, Ollivon M, Angelova A. X-ray diffraction study of the effect of the detergent octyl glucoside on the structure of lamellar and nonlamellar lipid/water phases of use for membrane protein reconstitution. Langmuir. 1999;15(23):8225–8234. 
129.     Bei D, Zhang T, Murowchick JB, Youan BBC. Formulation of dacarbazine-loaded cubosomes. Part III. physicochemical characterization. AAPS PharmSciTech. 2010;11(3). 
130.     Meli V, Caltagirone C, Falchi AM, Hyde ST, Lippolis V, Monduzzi M, et al. Docetaxel-Loaded Fluorescent Liquid-Crystalline Nanoparticles for Cancer Theranostics. Langmuir. 2015;31(35):9566-9575. 
131.     Bazylińska U, Wawrzyńczyk D, Kulbacka J, Picci G, Manni LS, Handschin S, et al. Hybrid Theranostic Cubosomes for Efficient NIR-Induced Photodynamic Therapy. ACS Nano. 2022;16(4):5427–5438. 
132.     Wu C, Yang Z, Peng X, Tan Y, Chen M, Zhu X, et al. Optimization of the preparation process for an oral phytantriol-based Amphotericin B cubosomes. J Nanomater. 2011;2011:1-10. 
133.     Wu H, Li J, Zhang Q, Yan X, Guo L, Gao X, et al. A novel small Odorranalectin-bearing cubosomes: Preparation, brain delivery and pharmacodynamic study on amyloid-β 25-35-treated rats following intranasal administration. Eur J Pharm Biopharm. 2012;80(2):368-378. 
134.     Kojarunchitt T, Hook S, Rizwan S, Rades T, Baldursdottir S. Development and characterisation of modified poloxamer 407 thermoresponsive depot systems containing cubosomes. Int J Pharm. 2011;408(1–2):20-26. 
135.     Shen HH, Hartley PG, James M, Nelson A, Defendi H, McLean KM. The interaction of cubosomes with supported phospholipid bilayers using neutron reflectometry and QCM-D. Soft Matter. 2011;7(18):8041-8049. 
136.     Han S, Shen JQ, Gan Y, Geng HM, Zhang XX, Zhu CL, et al. Novel vehicle based on cubosomes for ophthalmic delivery of flurbiprofen with low irritancy and high bioavailability. Acta Pharmacol Sin. 2010;31(8):990-998. 
137.     Shen HH, Lake V, Le Brun AP, James M, Duff AP, Peng Y, et al. Targeted detection of phosphatidylserine in biomimetic membranes and invitro cell systems using annexin V-containing cubosomes. Biomaterials. 2013;34(33): 8361-8369. 
138.     Thomas RK, Lu JR, Penfold J. Applications of neutron reflectometry in surface science. Materials Science Forum. 1994;154:153-162. 
139.     Vandoolaeghe P, Rennie AR, Campbell RA, Thomas RK, Höök F, Fragneto G, et al. Adsorption of cubic liquid crystalline nanoparticles on model membranes. Soft Matter. 2008;4(11):2267--2277. 
140.     Vandoolaeghe P, Campbell RA, Rennie AR, Nylander T. Adsorption of Intact Cubic Liquid Crystalline Nanoparticles on Hydrophilic Surfaces: Lateral Organization, Interfacial Stability, Layer Structure, and Interaction Mechanism. J Phys Chem C. 2009;113(11):4483–4494. 
141.     Vandoolaeghe P, Rennie AR, Campbell RA, Nylander T. Neutron reflectivity studies of the interaction of cubic-phase nanoparticles with phospholipid bilayers of different coverage. Langmuir. 2009;25(7):4009-4020. 
142.     Cervin C, Vandoolaeghe P, Nistor C, Tiberg F, Johnsson M. A combined in vitro and in vivo study on the interactions between somatostatin and lipid-based liquid crystalline drug carriers and bilayers. Eur J Pharm Sci. 2009;36(4–5):377-385. 
143.     Elnaggar Y, Etman S, Abdelmonsif D, Abdallah O. Novel piperine-loaded Tween-integrated monoolein cubosomes as brain-targeted oral nanomedicine in Alzheimer’s disease: pharmaceutical, biological, and toxicological studies. Int J Nanomedicine. 2015;10:5459-5473.  
144.     Tu YS, Fu JW, Sun DM, Zhang JJ, Yao N, Huang DE, et al. Preparation, characterisation and evaluation of curcumin with piperine-loaded cubosome nanoparticles. J Microencapsul. 2014;31(6):551-559. 
145.     Rarokar NR, Saoji SD, Raut NA, Taksande JB, Khedekar PB, Dave VS. Nanostructured Cubosomes in a Thermoresponsive Depot System: An Alternative Approach for the Controlled Delivery of Docetaxel. AAPS PharmSciTech. 2016;17(2):436–445. 
146.     Luo Q, Lin T, Zhang CY, Zhu T, Wang L, Ji Z, et al. A novel glyceryl monoolein-bearing cubosomes for gambogenic acid: Preparation, cytotoxicity and intracellular uptake. Int J Pharm. 2015;493(1–2):30-39. 
147.     Wang D, Luo L, Zheng S, Niu Y, Bo R, Huang Y, et al. Cubosome nanoparticles potentiate immune properties of immunostimulants. Int J Nanomedicine. 2016; 11:3571–3583. 
148.     Peng X, Zhou Y, Han K, Qin L, Dian L, Li G, et al. Characterization of cubosomes as a targeted and sustained transdermal delivery system for capsaicin. Drug Des Devel Ther. 2015;9:4209–4218. 
149.     Pan X, Han K, Peng X, Yang Z, Qin L, Zhu C, et al. Nanostructed Cubosomes as Advanced Drug Delivery System. Curr Pharm Des. 2013;19(35):6290-6297. 
150.     Zhou Y, Guo C, Chen H, Zhang Y, Peng X, Zhu P. Determination of sinomenine in cubosome nanoparticles by HPLC technique. J Anal Methods Chem. 2015;2015:931687.
151.     Boyd BJ, Khoo SM, Whittaker D V., Davey G, Porter CJH. A lipid-based liquid crystalline matrix that provides sustained release and enhanced oral bioavailability for a model poorly water soluble drug in rats. Int J Pharm. 2007;340(1–2):52-60. 
152.     Akhlaghi SP, Ribeiro IR, Boyd BJ, Loh W. Impact of preparation method and variables on the internal structure, morphology, and presence of liposomes in phytantriol-Pluronic® F127 cubosomes. Colloids Surf B Biointerfaces. 2016;145:845–853. 
153.     Geraghty PB, Attwood D, Collett JH, Dandiker Y. The in vitro release of some antimuscarinic drugs from monoolein/water lyotropic liquid crystalline gels. Pharm Res. 1996;13(8):1265-1271. 
154.     Lai J, Chen J, Lu Y, Sun J, Hu F, Yin Z, et al. Glyceryl Monooleate/Poloxamer 407 Cubic Nanoparticles as Oral Drug Delivery Systems: I. In Vitro Evaluation and Enhanced Oral Bioavailability of the Poorly Water-Soluble Drug Simvastatin. AAPS PharmSciTech. 2009;10(3):960. 
155.     Lara MG, Bentley MVLB, Collett JH. In vitro drug release mechanism and drug loading studies of cubic phase gels. Int J Pharm. 2005;293(1–2):241-250. 
156.     Kwon TK, Hong SK, Kim JC. In vitro skin permeation of cubosomes containing triclosan. J Ind Eng Chem. 2012;18(1): 563-567.
 157.     Kwon TK, Lee HY, Kim JD, Shin WC, Park SK, Kim JC. In vitro skin permeation of cubosomes containing water soluble extracts of Korean barberry. Colloid J. 2010;72(2):205–210. 
158.     Dian L, Yang Z, Li F, Wang Z, Pan X, Peng X, et al. Cubic phase nanoparticles for sustained release of ibuprofen: Formulation, characterization, and enhanced bioavailability study. Int J Nanomedicine. 2013;8: 8:845-854. 
159.     Yang Z, Tan Y, Chen M, Dian L, Shan Z, Peng X, et al. Development of amphotericin B-loaded cubosomes through the SolEmuls technology for enhancing the oral bioavailability. AAPS PharmSciTech. 2012;13(4):1483–1491. 
160.     Hong SK, Ma JY, Kim JC. Preparation and Characterization of Cubosomal KIOM-C Suspension and Investigation on In Vitro Small Intestinal Absorption of Baicalin. J Dispers Sci Technol. 2013;34(2):252-258. 
161.     Nasr M, Ghorab MK, Abdelazem A. In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting. Acta Pharm Sin B. 2015;5(1):79-88. 
162.     Yaghmur A, Mu H. Recent advances in drug delivery applications of cubosomes, hexosomes, and solid lipid nanoparticles. Acta Pharm Sin B. 2021;11(4):871-885.
163.     Mangiapia G, Vaccaro M, D’Errico G, Frielinghaus H, Radulescu A, Pipich V, Carnerup AM, et al. Cubosomes for ruthenium complex delivery: Formulation and characterization. Soft Matter. 2011;7(22):10577-10580. 
164.     Thapa RK, Baskaran R, Madheswaran T, Kim JO, Yong CS, Yoo BK. Preparation, Characterization, and Release Study of Tacrolimus-Loaded Liquid Crystalline Nanoparticles. J Dispers Sci Technol. 2013;34(1):72–77. 
165.     Deshpande S, Venugopal E, Ramagiri S, Bellare JR, Kumaraswamy G, Singh N. Enhancing cubosome functionality by coating with a single layer of poly-ε-lysine. ACS Appl Mater Interfaces. 2014;6(19):17126-33. 
166.     Tan C, Hosseini SF, Jafari SM. Cubosomes and Hexosomes as Novel Nanocarriers for Bioactive Compounds. J Agric Food Chem. 2022;70(5):1423–1437. 
167.     Nguyen TH, Hanley T, Porter CJH, Boyd BJ. Nanostructured liquid crystalline particles provide long duration sustained-release effect for a poorly water soluble drug after oral administration. J Control Release. 2011;153(2):180-186. 
168.     Mat Azmi ID, Wu L, Wibroe PP, Nilsson C, Østergaard J, Stürup S, et al. Modulatory effect of human plasma on the internal nanostructure and size characteristics of liquid-crystalline nanocarriers. Langmuir. 2015;31(18):5042-5049. 
169.     Chung H, Kim J, Um JY, Kwon IC, Jeong SY. Self-assembled “nanocubicle” as a carrier for peroral insulin delivery. Diabetologia. 2002;45(3):448-451. 
170.     Esposito E, Ravani L, Contado C, Costenaro A, Drechsler M, Rossi D, et al. Clotrimazole nanoparticle gel for mucosal administration. Mater Sci Eng C. 2013;33(1): 411-418. 
171.     Esposito E, Mariani P, Ravani L, Contado C, Volta M, Bido S, et al. Nanoparticulate lipid dispersions for bromocriptine delivery: Characterization and in vivo study. Eur J Pharm Biopharm. 2012;80(2):306-314. 
172.     Gan L, Han S, Shen J, Zhu J, Zhu C, Zhang X, et al. Self-assembled liquid crystalline nanoparticles as a novel ophthalmic delivery system for dexamethasone: Improving preocular retention and ocular bioavailability. Int J Pharm. 2010;396(1–2):179-187. 
173.     Bender J, Ericson MB, Merclin N, Iani V, Rosén A, Engström S, et al. Lipid cubic phases for improved topical drug delivery in photodynamic therapy. J Control Release. 2005;106(3):350-360. 
174.     Bender J, Simonsson C, Smedh M, Engström S, Ericson MB. Lipid cubic phases in topical drug delivery: Visualization of skin distribution using two-photon microscopy. J Control Release. 2008;129(3): :163-169. 
175.     Lopes LB, Lopes JLC, Oliveira DCR, Thomazini JA, Garcia MTJ, Fantini MCA, et al. Liquid crystalline phases of monoolein and water for topical delivery of cyclosporin A: Characterization and study of in vitro and in vivo delivery. Eur J Pharm Biopharm. 2006;63(2):146-155. 
176.     Vitoria-PupoSilvestrini A, WenderDebiasi B, Garcia-Praça F, Vitoria-Lopes BM. Progress and challenges of lyotropic liquid crystalline nanoparticles for innovative therapies. Int J Pharm. 2022;628:122299. 
177.     Esposito E, Cortesi R, Drechsler M, Paccamiccio L, Mariani P, Contado C, et al. Cubosome dispersions as delivery systems for percutaneous administration of indomethacin. Pharm Res. 2005;22(12):2163-2173. 
178.     Helledi LS, Schubert L. Release kinetics of acyclovir from a suspension of acyclovir incorporated in a cubic phase delivery system. Drug Dev Ind Pharm. 2001;27(10): ):1073-1081. 
179.     Morsi NM, Abdelbary GA, Ahmed MA. Silver sulfadiazine based cubosome hydrogels for topical treatment of burns: Development and in vitro/in vivo characterization. Eur J Pharm Biopharm. 2014;86(2):178-189. 
180.     Chen Y, Ma P, Gui S. Cubic and hexagonal liquid crystals as drug delivery systems. Biomed Res Int. 2014;2014:815981. 
181.     Chen Y, Lu Y, Zhong Y, Wang Q, Wu W, Gao S. Ocular delivery of cyclosporine A based on glyceryl monooleate/poloxamer 407 liquid crystalline nanoparticles: Preparation, characterization, in vitro corneal penetration and ocular irritation. J Drug Target. 2012;20(10):856-863. 
182.     Prajapati V, Jain A, Jain R, Sahu S, Kohli DV. Treatment of cutaneous candidiasis through fluconazole encapsulated cubosomes. Drug Deliv Transl Res. 2014;4(5-6):400-408.
183.     Teba HE, Khalil IA, El Sorogy HM. Novel cubosome based system for ocular delivery of acetazolamide. Drug Deliv. 2021;28(1):2177–2186. 
184.     Eldeeb AE, Salah S, Ghorab M. Formulation and evaluation of cubosomes drug delivery system for treatment of glaucoma: Ex-vivo permeation and in-vivo pharmacodynamic study. J Drug Deliv Sci Technol. 2019;52:236–247. 
185.     BizhanMalaekeh-Nikouei, Farzad Vafaei, Malihe Karimi. Preparation and in-vitro evaluation of fluorometholone cubosomes for ocular delivery. Nanomed J [Internet]. 2023;10(4):304–312. 
186.     Chavda VP, Dawre S, Pandya A, Vora LK, Modh DH, Shah V, et al. Lyotropic liquid crystals for parenteral drug delivery. J Control Release. 2022;349:533–549. 
187.     Seo SR, Kang G, Ha JW, Kim JC. In vivo hair growth-promoting efficacies of herbal extracts and their cubosomal suspensions. J Ind Eng Chem. 2013;19(4):1331-1339. 
188.     Sherif S, Bendas ER, Badawy S. The clinical efficacy of cosmeceutical application of liquid crystalline nanostructured dispersions of alpha lipoic acid as anti-wrinkle. Eur J Pharm Biopharm. 2014;86(2):251-259. 
189.     Norling T, Lading P, Engström S, Larsson K, Krog N, Nissen SS. Formulation of a drug delivery system based on a mixture of monoglycerides and triglycerides for use in the treatment of periodontal disease. J Clin Periodontol. 1992;19(9):687-692 
190.     Wiseman H, Halliwell B. Damage to DNA by reactive oxygen and nitrogen species: Role in inflammatory disease and progression to cancer. Biochem J. 1996;313(Pt 1)(Pt 1):17-29.
191.     Kim H, Leal C. Cuboplexes: Topologically Active siRNA Delivery. ACS Nano. 2015;9(10):10214–10226. 
192.     Karami Z, Hamidi M. Cubosomes: remarkable drug delivery potential. Drug Discov Today. 2016;21(5):789–801. 
193.     Jain V, Swarnakar NK, Mishra PR, Verma A, Kaul A, Mishra AK, et al. Paclitaxel loaded PEGylated gleceryl monooleate based nanoparticulate carriers in chemotherapy. Biomaterials. 2012;33(29):7206-7220. 
194.     Tajik-Ahmadabad B, Chollet L, White J, Separovic F, Polyzos A. Metallo-Cubosomes: Zinc-Functionalized Cubic Nanoparticles for Therapeutic Nucleotide Delivery. Mol Pharm. 2019;16(3):978–986. 
195.     Zhang L, Li J, Tian D, Sun L, Wang X, Tian M. Theranostic combinatorial drug-loaded coated cubosomes for enhanced targeting and efficacy against cancer cells. Cell Death Dis. 2020;11(1):1.