Advancements in Cubosomes: A Promising Platform for Targeted Anticancer Drug Delivery
Keywords:
Cubosomes, Lipid nano carriers, Anticancer therapy, Targeted drug delivery, Amphiphilic lipids
Abstract
Nanosized particles are stabilised by polymers and made mostly of amphiphilic lipids known as cubosomes (CUBs). Encapsulating hydrophilic, hydrophobic, and amphiphilic pharmaceuticals is made effective by their internal bi-continuous cubic phase architecture, which gives a high surface area and partitioned aqueous domains. These self-assembled nanoparticles exhibit thermodynamic stability, biocompatibility, and mucoadhesive properties, making them ideal carriers for diverse multiple administration routes, including oral, transdermal, parenteral, and ocular. Problems with medication solubility, bioavailability, and non-specific toxicity are some of the most important ones that CUBs aim to solve. This review presents a comprehensive overview of CUB structure, types, formulation methods, and characterization techniques. The review emphasizes recent advancements in CUB-based delivery of chemotherapeutic agents, including paclitaxel and doxorubicin, cisplatin, methotrexate, and 5-fluorouracil, highlighting their improved pharmacokinetics and reduced systemic toxicity Despite manufacturing challenges, ongoing research into scalable production and novel excipients continues to support their translational promise. CUBs represent a versatile and potent platform in nanomedicine, offering substantial improvements in drug delivery and cancer treatment. Recent advancements in formulation strategies and surface modification is further strengthened their therapeutic potential. Cubosomes as a promising platform in precision oncology and next generation cancer therapeutics.
References
ABDELKADER, H., ALANI, A. W. & ALANY, R. G. 2014a. Recent advances in non-ionic surfactant vesicles (niosomes): self-assembly, fabrication, characterization, drug delivery applications and limitations. Drug delivery, 21, 87-100.
ABDELKADER, H., FARGHALY, U. & MOHARRAM, H. 2014b. Effects of surfactant type and cholesterol level on niosomes physical properties and in vivo ocular performance using timolol maleate as a model drug. Journal of pharmaceutical investigation, 44, 329-337.
ACHOURI, D., ALHANOUT, K., PICCERELLE, P. & ANDRIEU, V. 2013. Recent advances in ocular drug delivery. Drug development and industrial pharmacy, 39, 1599-1617.
ALI, M. A., NOGUCHI, S., IWAO, Y., OKA, T. & ITAI, S. 2016. Preparation and characterization of SN-38-encapsulated phytantriol cubosomes containing α-monoglyceride additives. Chemical and Pharmaceutical Bulletin, 64, 577-584.
ALMEIDA, J., EDWARDS, D. C., BRAND, C. & HEATH, T. 1975. Formation of virosomes from influenza subunits and liposomes. The Lancet, 306, 899-901.
ALMGREN, M., EDWARDS, K. & GUSTAFSSON, J. 1996. Cryotransmission electron microscopy of thin vitrified samples. Current opinion in colloid & interface science, 1, 270-278.
ANCY, T. & RAJU, S. 2018. Cubosomes-a novel drug delivery system. Int J of Pharmacy, 8, 10-18.
ANGELOV, B., ANGELOVA, A., DRECHSLER, M., GARAMUS, V. M., MUTAFCHIEVA, R. & LESIEUR, S. 2015. Identification of large channels in cationic PEGylated cubosome nanoparticles by synchrotron radiation SAXS and Cryo-TEM imaging. Soft Matter, 11, 3686-3692.
ARCHANA, A., VIJAYASRI, K., MADHURIM, M. & KUMAR, C. 2015. Curcumin loaded nano cubosomal hydrogel: preparation, in vitro characterization and antibacterial activity. Chem Sci Trans, 4, 75-80.
BARAUSKAS, J., JOHNSSON, M., JOABSSON, F. & TIBERG, F. 2005a. Cubic phase nanoparticles (cubosome): principles for controlling size, structure, and stability. Langmuir, 21, 2569-2577.
BARAUSKAS, J., JOHNSSON, M. & TIBERG, F. 2005b. Self-assembled lipid superstructures: beyond vesicles and liposomes. Nano letters, 5, 1615-1619.
BARAUSKAS, J. & LANDH, T. 2003. Phase behavior of the phytantriol/water system. Langmuir, 19, 9562-9565.
BARRIGA, H. M., CES, O., LAW, R. V., SEDDON, J. M. & BROOKS, N. J. 2019. Engineering swollen cubosomes using cholesterol and anionic lipids. Langmuir, 35, 16521-16527.
BEI, D., MENG, J. & YOUAN, B.-B. C. 2010a. Engineering nanomedicines for improved melanoma therapy: progress and promises. Nanomedicine, 5, 1385-1399.
BEI, D., ZHANG, T., MUROWCHICK, J. B. & YOUAN, B.-B. C. 2010b. Formulation of dacarbazine-loaded cubosomes. Part III. Physicochemical characterization. AAPS pharmscitech, 11, 1243-1249.
BOYD, B. J., WHITTAKER, D. V., KHOO, S.-M. & DAVEY, G. 2006. Lyotropic liquid crystalline phases formed from glycerate surfactants as sustained release drug delivery systems. International journal of pharmaceutics, 309, 218-226.
BRAY, F., LAVERSANNE, M., WEIDERPASS, E. & SOERJOMATARAM, I. 2021. The ever‐increasing importance of cancer as a leading cause of premature death worldwide. Cancer, 127, 3029-3030.
CHANG, C., MEIKLE, T. G., DRUMMOND, C. J., YANG, Y. & CONN, C. E. 2021. Comparison of cubosomes and liposomes for the encapsulation and delivery of curcumin. Soft Matter, 17, 3306-3313.
CHONG, J. Y., MULET, X., BOYD, B. J. & DRUMMOND, C. J. 2015. Steric stabilizers for cubic phase lyotropic liquid crystal nanodispersions (cubosomes). Advances in planar lipid bilayers and liposomes. Elsevier.
CHONG, J. Y., MULET, X., WADDINGTON, L. J., BOYD, B. J. & DRUMMOND, C. J. 2011. Steric stabilisation of self-assembled cubic lyotropic liquid crystalline nanoparticles: high throughput evaluation of triblock polyethylene oxide-polypropylene oxide-polyethylene oxide copolymers. Soft Matter, 7, 4768-4777.
CHUNG, H., KIM, J.-S., UM, J., KWON, I. & JEONG, S. 2002. Self-assembled “nanocubicle” as a carrier for peroral insulin delivery. Diabetologia, 45, 448-451.
CYTRYNIAK, A., NAZARUK, E., BILEWICZ, R., GóRZYńSKA, E., ŻELECHOWSKA-MATYSIAK, K., WALCZAK, R., MAMES, A., BILEWICZ, A. & MAJKOWSKA-PILIP, A. 2020. Lipidic cubic-phase nanoparticles (cubosomes) loaded with doxorubicin and labeled with 177Lu as a potential tool for combined chemo and internal radiotherapy for cancers. Nanomaterials, 10, 2272.
DAHARWAL, S., VERMA, E. & SAUDAGAR, R. 2014. Semi solid dosage forms. Farmavita Net, 13, 10.
DAWARE, S. & SAUDAGAR, R. 2017. Formulation and Development of Cubosome Loaded Emulgel-A Review. International Journal of ChemTech Research, 10, 918-924.
FLAK, D. K., ADAMSKI, V., NOWACZYK, G., SZUTKOWSKI, K., SYNOWITZ, M., JURGA, S. & HELD-FEINDT, J. 2020. AT101-loaded cubosomes as an alternative for improved glioblastoma therapy. International journal of nanomedicine, 7415-7431.
GARG, G., SARAF, S. & SARAF, S. 2007. Cubosomes: an overview. Biological and Pharmaceutical Bulletin, 30, 350-353.
GUILLOT, S., SALENTINIG, S., CHEMELLI, A., SAGALOWICZ, L., LESER, M. E. & GLATTER, O. 2010. Influence of the stabilizer concentration on the internal liquid crystalline order and the size of oil-loaded monolinolein-based dispersions. Langmuir, 26, 6222-6229.
GUO, Q. & JIANG, C. 2020. Delivery strategies for macromolecular drugs in cancer therapy. Acta Pharmaceutica Sinica B, 10, 979-986.
HAN, N., ZHANG, B., WEI, X. & YU, L. 2023. The inhibitory function of icariin in cell model of benign prostatic hyperplasia by upregulation of miR-7. Biofactors, 49.
HIMESH, S., SHARAN, P. S., MISHRA, K., GOVIND, N. & SINGHAI, A. 2011. Qualitative and quantitative profile of curcumin from ethanolic extract of Curcuma longa. Int Res J Pharm, 2, 180-184.
HUANG, C.-Y., JU, D.-T., CHANG, C.-F., REDDY, P. M. & VELMURUGAN, B. K. 2017. A review on the effects of current chemotherapy drugs and natural agents in treating non–small cell lung cancer. Biomedicine, 7, 23.
HYDE, S. T. 2001. Identification of lyotropic liquid crystalline mesophases. Handbook of applied surface and colloid chemistry, 2, 299-332.
ISRAELACHVILI, J. N., MITCHELL, D. J. & NINHAM, B. W. 1976. Theory of self-assembly of hydrocarbon amphiphiles into micelles and bilayers. Journal of the Chemical Society, Faraday Transactions 2: Molecular and Chemical Physics, 72, 1525-1568.
JANAKIRAMAN, K., KRISHNASWAMI, V., SETHURAMAN, V., RAJENDRAN, V. & KANDASAMY, R. 2019. Development of methotrexate-loaded cubosomes with improved skin permeation for the topical treatment of rheumatoid arthritis. Applied Nanoscience, 9, 1781-1796.
KAASGAARD, T. & DRUMMOND, C. J. 2006. Ordered 2-D and 3-D nanostructured amphiphile self-assembly materials stable in excess solvent. Physical Chemistry Chemical Physics, 8, 4957-4975.
KARAMI, Z. & HAMIDI, M. 2016. Cubosomes: remarkable drug delivery potential. Drug discovery today, 21, 789-801.
KULKARNI, C. V., WACHTER, W., IGLESIAS-SALTO, G., ENGELSKIRCHEN, S. & AHUALLI, S. 2011. Monoolein: a magic lipid? Physical Chemistry Chemical Physics, 13, 3004-3021.
LARSSON, K. 2000. Aqueous dispersions of cubic lipid–water phases. Current opinion in colloid & interface science, 5, 64-69.
LEUNG, S. S. & LEAL, C. 2019. The stabilization of primitive bicontinuous cubic phases with tunable swelling over a wide composition range. Soft Matter, 15, 1269-1277.
LI, C.-Y., LU, J.-T., WU, C.-P., DUAN, S.-M. & POO, M.-M. 2004. Bidirectional modification of presynaptic neuronal excitability accompanying spike timing-dependent synaptic plasticity. Neuron, 41, 257-268.
LIU, H., PAN, W.-S., NIE, S.-F., YANG, X.-G. & YAN, T.-X. 2008. Study on in vitro release empirical method and the release mechanism of budesonide colonic localization tablet. Yao xue xue bao= Acta Pharmaceutica Sinica, 43, 1147-1151.
LUZZATI, V. & HUSSON, F. 1962. The structure of the liquid-crystalline phases of lipid-water systems. The Journal of cell biology, 12, 207-219.
LUZZATI, V., TARDIEU, A., GULIK-KRZYWICKI, T., RIVAS, E. & REISS-HUSSON, F. 1968. Structure of the cubic phases of lipid–water systems. Nature, 220, 485-488.
LUZZATI, V., VARGAS, R., MARIANI, P., GULIK, A. & DELACROIX, H. 1993. Cubic phases of lipid-containing systems: elements of a theory and biological connotations. Journal of molecular biology, 229, 540-551.
MANSOORI, B., MOHAMMADI, A., DAVUDIAN, S., SHIRJANG, S. & BARADARAN, B. 2017. The different mechanisms of cancer drug resistance: a brief review. Advanced pharmaceutical bulletin, 7, 339.
MAYURI AHIRRAO, M. A. & SHILPA SHROTRIYA, S. S. 2017. In vitro and in vivo evaluation of cubosomal in situ nasal gel containing resveratrol for brain targeting.
MCMAHON, H. T. & GALLOP, J. L. 2005. Membrane curvature and mechanisms of dynamic cell membrane remodelling. Nature, 438, 590-596.
MEHNERT, W. & MäDER, K. 2012. Solid lipid nanoparticles: production, characterization and applications. Advanced drug delivery reviews, 64, 83-101.
MONTIS, C., CASTROFLORIO, B., MENDOZZA, M., SALVATORE, A., BERTI, D. & BAGLIONI, P. 2015. Magnetocubosomes for the delivery and controlled release of therapeutics. Journal of colloid and interface science, 449, 317-326.
MURPHY, W. K., FOSSELLA, F. V., WINN, R. J., SHIN, D. M., HYNES, H., GROSS, H. M., DAVILLA, E., LEIMERT, J., DHINGRA, H. & RABER, M. N. 1993. Phase II study of taxol in patients with untreated advanced non-small-cell lung cancer. JNCI: Journal of the National Cancer Institute, 85, 384-388.
NASR, M., GHORAB, M. K. & ABDELAZEM, A. 2015. In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting. Acta pharmaceutica sinica B, 5, 79-88.
PATIL, S. M., SAWANT, S. S. & KUNDA, N. K. 2021. Inhalable bedaquiline-loaded cubosomes for the treatment of non-small cell lung cancer (NSCLC). International Journal of Pharmaceutics, 607, 121046.
PATTA, A. C. F., MATHEWS, P. D., MADRID, R. R., RIGONI, V. L., SILVA, E. R. & MERTINS, O. 2020. Polyionic complexes of chitosan-N-arginine with alginate as pH responsive and mucoadhesive particles for oral drug delivery applications. International Journal of Biological Macromolecules, 148, 550-564.
PENG, X., WEN, X., PAN, X., WANG, R., CHEN, B. & WU, C. 2010a. Design and in vitro evaluation of capsaicin transdermal controlled release cubic phase gels. Aaps Pharmscitech, 11, 1405-1410.
PENG, X., YANG, Z., CHEN, M., HAN, K., XIAO, Y. & WU, C. 2010b. Preparation, characterization and content determination of cubic phase gel containing capsaicin. Zhongguo Zhong yao za zhi= Zhongguo Zhongyao Zazhi= China Journal of Chinese Materia Medica, 35, 3123-3126.
PENG, X.-S., ZHOU, Y.-F., HAN, K., QIN, L.-Z. & WU, C.-B. 2014. Preparation and in vitro study on diffusion of capsaicin cubosome. Zhongguo Zhong yao za zhi= Zhongguo Zhongyao Zazhi= China Journal of Chinese Materia Medica, 39, 644-647.
QI, B., WANG, C., DING, J. & TAO, W. 2019. Applications of nanobiotechnology in pharmacology. Frontiers Media SA.
RAROKAR, N. & KHEDEKAR, P. 2018. Cubosomes: A vehicle for delivery of various therapeutic agents. MOJ Toxicol, 4, 19-21.
RAROKAR, N. R., SAOJI, S. D., RAUT, N. A., TAKSANDE, J. B., KHEDEKAR, P. B. & DAVE, V. S. 2016. Nanostructured cubosomes in a thermoresponsive depot system: an alternative approach for the controlled delivery of docetaxel. AAPS pharmscitech, 17, 436-445.
RASHI, S., SINGH, D., CHANCHAL, D. K., SINGH, M., ANAND, S. & ALOK, S. 2015. Cubosomes: a bicontinuous cubic crystalline phase. International Journal of Life Sciences and Review, 1, 291-301.
RICHERT, S., SCHRADER, A. & SCHRADER, K. 2003. Transdermal delivery of two antioxidants from different cosmetic formulations. International journal of cosmetic science, 25, 5-13.
RIZWAN, S. B. & BOYD, B. J. 2014. Cubosomes: structure, preparation and use as an antigen delivery system. Subunit Vaccine Delivery. Springer.
SADHU, V., BERAM, N. & KANTAMNENI, P. 2018. A review on cubosome: the novel drug delivery system. GSC Biol Pharm Sci 5: 076–081.
SAGALOWICZ, L., LESER, M., WATZKE, H. & MICHEL, M. 2006. Monoglyceride self-assembly structures as delivery vehicles. Trends in Food Science & Technology, 17, 204-214.
SAGNELLA, S. & DRUMMOND, C. 2012. Drug delivery a nanomedicine approach. Aust Biochem, 43, 5-20.
SALA, M., DIAB, R., ELAISSARI, A. & FESSI, H. 2018. Lipid nanocarriers as skin drug delivery systems: Properties, mechanisms of skin interactions and medical applications. International journal of pharmaceutics, 535, 1-17.
SALENTINIG, S., YAGHMUR, A., GUILLOT, S. & GLATTER, O. 2008. Preparation of highly concentrated nanostructured dispersions of controlled size. Journal of Colloid and Interface Science, 326, 211-220.
SHAH, M. H., BIRADAR, S. V. & PARADKAR, A. R. 2006. Spray dried glyceryl monooleate–magnesium trisilicate dry powder as cubic phase precursor. International journal of pharmaceutics, 323, 18-26.
SHARMA, R., KAUR, G. & KAPOOR, D. N. 2015. Fluconazole loaded cubosomal vesicles for topical delivery. Int. J. Drug Dev. Res, 7, 32-41.
SIEKMANN, B., BUNJES, H., KOCH, M. H. & WESTESEN, K. 2002. Preparation and structural investigations of colloidal dispersions prepared from cubic monoglyceride–water phases. International journal of pharmaceutics, 244, 33-43.
SPICER, P. 2005. Cubosome processing: industrial nanoparticle technology development. Chemical Engineering Research and Design, 83, 1283-1286.
SPICER, P. T., HAYDEN, K. L., LYNCH, M. L., OFORI-BOATENG, A. & BURNS, J. L. 2001. Novel process for producing cubic liquid crystalline nanoparticles (cubosomes). Langmuir, 17, 5748-5756.
SPICER, P. T., SMALL, W. B., SMALL, W. B., LYNCH, M. L. & BURNS, J. L. 2002. Dry powder precursors of cubic liquid crystalline nanoparticles (cubosomes). Journal of nanoparticle research, 4, 297-311.
SRI, V. R., REDDY, A. M., KARTHIKEYAN, R. & SRINIVASABABU, P. 2017. A review on: cubosomes drug delivery system. Indian Journal of Drugs, 5, 104-108.
TEAGARDEN, D. L., ANDERSON, B. D. & PETRE, W. J. 1988. Determination of the pH-dependent phase distribution of prostaglandin El in a lipid emulsion by ultrafiltration. Pharmaceutical research, 5, 482-487.
THADANKI, M., KUMARI, P. S. & PRABHA, K. S. 2011. Overview of cubosomes: a nano particle. Int J Res Pharm Chem, 1, 535-541.
THAPA, R. K., CHOI, J. Y., GUPTA, B., RAMASAMY, T., POUDEL, B. K., KU, S. K., YOUN, Y. S., CHOI, H. G., YONG, C. S. & KIM, J. O. 2016. Liquid crystalline nanoparticles encapsulating cisplatin and docetaxel combination for targeted therapy of breast cancer. Biomaterials science, 4, 1340-1350.
THORAT, Y. S., GONJARI, I. D. & HOSMANI, A. H. 2011. Solubility enhancement techniques: a review on conventional and novel approaches. International journal of pharmaceutical sciences and research, 2, 2501.
TIAN, Y., LI, J.-C., ZHU, J.-X., ZHU, N., ZHANG, H.-M., LIANG, L. & SUN, L. 2017. Folic acid-targeted etoposide cubosomes for theranostic application of cancer cell imaging and therapy. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 23, 2426.
TILEKAR, K., KHADE, P., KAKADE, S., KOTWAL, S. & PATIL, R. 2014. Cubosomes-a drug delivery system. International Journal of Pharmaceutical, Chemical & Biological Sciences, 4.
TU, Y., FU, J., SUN, D., ZHANG, J., YAO, N., HUANG, D. & SHI, Z. 2014. Preparation, characterisation and evaluation of curcumin with piperine-loaded cubosome nanoparticles. Journal of microencapsulation, 31, 551-559.
URVI, S., DHIREN, D., BHAVIN, P., PATEL, U. & SHAH, R. 2013. Overview of cubosomes: A nanoparticle. Int J of Pharmacy and Integrated Sci, 1, 36-47.
VADNERE, M., AMIDON, G., LINDENBAUM, S. & HASLAM, J. L. 1984. Thermodynamic studies on the gel-sol transition of some pluronic polyols. International journal of pharmaceutics, 22, 207-218.
VAN OSS, C., GOOD, R. & CHAUDHURY, M. 1986. The role of van der Waals forces and hydrogen bonds in “hydrophobic interactions” between biopolymers and low energy surfaces. Journal of colloid and Interface Science, 111, 378-390.
VARGHESE, R., SALVI, S., SOOD, P., KULKARNI, B. & KUMAR, D. 2022. Cubosomes in cancer drug delivery: A review. Colloid and Interface Science Communications, 46, 100561.
WADSTEN-HINDRICHSEN, P., BENDER, J., UNGA, J. & ENGSTRöM, S. 2007. Aqueous self-assembly of phytantriol in ternary systems: effect of monoolein, distearoylphosphatidylglycerol and three water-miscible solvents. Journal of colloid and interface science, 315, 701-713.
WIBROE, P. P., AZMI, I. D. M., NILSSON, C., YAGHMUR, A. & MOGHIMI, S. M. 2015. Citrem modulates internal nanostructure of glyceryl monooleate dispersions and bypasses complement activation: Towards development of safe tunable intravenous lipid nanocarriers. Nanomedicine: Nanotechnology, Biology and Medicine, 11, 1909-1914.
WöRLE, G., SIEKMANN, B., KOCH, M. H. & BUNJES, H. 2006. Transformation of vesicular into cubic nanoparticles by autoclaving of aqueous monoolein/poloxamer dispersions. European journal of pharmaceutical sciences, 27, 44-53.
ZHAI, J., LUWOR, R. B., AHMED, N., ESCALONA, R., TAN, F. H., FONG, C., RATCLIFFE, J., SCOBLE, J. A., DRUMMOND, C. J. & TRAN, N. 2018. Paclitaxel-loaded self-assembled lipid nanoparticles as targeted drug delivery systems for the treatment of aggressive ovarian cancer. ACS applied materials & interfaces, 10, 25174-25185.
ZHAI, J., WADDINGTON, L., WOOSTER, T. J., AGUILAR, M.-I. & BOYD, B. J. 2011. Revisiting β-casein as a stabilizer for lipid liquid crystalline nanostructured particles. Langmuir, 27, 14757-14766.
ZHANG, L., LI, J., TIAN, D., SUN, L., WANG, X. & TIAN, M. 2020a. Theranostic combinatorial drug-loaded coated cubosomes for enhanced targeting and efficacy against cancer cells. Cell death & disease, 11, 1.
ZHANG, Z., ZHOU, L., XIE, N., NICE, E. C., ZHANG, T., CUI, Y. & HUANG, C. 2020b. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal transduction and targeted therapy, 5, 113.
ZHOU, Y., CHEN, X., CAO, J. & GAO, H. 2020. Overcoming the biological barriers in the tumor microenvironment for improving drug delivery and efficacy. Journal of Materials Chemistry B, 8, 6765-6781.
ABDELKADER, H., FARGHALY, U. & MOHARRAM, H. 2014b. Effects of surfactant type and cholesterol level on niosomes physical properties and in vivo ocular performance using timolol maleate as a model drug. Journal of pharmaceutical investigation, 44, 329-337.
ACHOURI, D., ALHANOUT, K., PICCERELLE, P. & ANDRIEU, V. 2013. Recent advances in ocular drug delivery. Drug development and industrial pharmacy, 39, 1599-1617.
ALI, M. A., NOGUCHI, S., IWAO, Y., OKA, T. & ITAI, S. 2016. Preparation and characterization of SN-38-encapsulated phytantriol cubosomes containing α-monoglyceride additives. Chemical and Pharmaceutical Bulletin, 64, 577-584.
ALMEIDA, J., EDWARDS, D. C., BRAND, C. & HEATH, T. 1975. Formation of virosomes from influenza subunits and liposomes. The Lancet, 306, 899-901.
ALMGREN, M., EDWARDS, K. & GUSTAFSSON, J. 1996. Cryotransmission electron microscopy of thin vitrified samples. Current opinion in colloid & interface science, 1, 270-278.
ANCY, T. & RAJU, S. 2018. Cubosomes-a novel drug delivery system. Int J of Pharmacy, 8, 10-18.
ANGELOV, B., ANGELOVA, A., DRECHSLER, M., GARAMUS, V. M., MUTAFCHIEVA, R. & LESIEUR, S. 2015. Identification of large channels in cationic PEGylated cubosome nanoparticles by synchrotron radiation SAXS and Cryo-TEM imaging. Soft Matter, 11, 3686-3692.
ARCHANA, A., VIJAYASRI, K., MADHURIM, M. & KUMAR, C. 2015. Curcumin loaded nano cubosomal hydrogel: preparation, in vitro characterization and antibacterial activity. Chem Sci Trans, 4, 75-80.
BARAUSKAS, J., JOHNSSON, M., JOABSSON, F. & TIBERG, F. 2005a. Cubic phase nanoparticles (cubosome): principles for controlling size, structure, and stability. Langmuir, 21, 2569-2577.
BARAUSKAS, J., JOHNSSON, M. & TIBERG, F. 2005b. Self-assembled lipid superstructures: beyond vesicles and liposomes. Nano letters, 5, 1615-1619.
BARAUSKAS, J. & LANDH, T. 2003. Phase behavior of the phytantriol/water system. Langmuir, 19, 9562-9565.
BARRIGA, H. M., CES, O., LAW, R. V., SEDDON, J. M. & BROOKS, N. J. 2019. Engineering swollen cubosomes using cholesterol and anionic lipids. Langmuir, 35, 16521-16527.
BEI, D., MENG, J. & YOUAN, B.-B. C. 2010a. Engineering nanomedicines for improved melanoma therapy: progress and promises. Nanomedicine, 5, 1385-1399.
BEI, D., ZHANG, T., MUROWCHICK, J. B. & YOUAN, B.-B. C. 2010b. Formulation of dacarbazine-loaded cubosomes. Part III. Physicochemical characterization. AAPS pharmscitech, 11, 1243-1249.
BOYD, B. J., WHITTAKER, D. V., KHOO, S.-M. & DAVEY, G. 2006. Lyotropic liquid crystalline phases formed from glycerate surfactants as sustained release drug delivery systems. International journal of pharmaceutics, 309, 218-226.
BRAY, F., LAVERSANNE, M., WEIDERPASS, E. & SOERJOMATARAM, I. 2021. The ever‐increasing importance of cancer as a leading cause of premature death worldwide. Cancer, 127, 3029-3030.
CHANG, C., MEIKLE, T. G., DRUMMOND, C. J., YANG, Y. & CONN, C. E. 2021. Comparison of cubosomes and liposomes for the encapsulation and delivery of curcumin. Soft Matter, 17, 3306-3313.
CHONG, J. Y., MULET, X., BOYD, B. J. & DRUMMOND, C. J. 2015. Steric stabilizers for cubic phase lyotropic liquid crystal nanodispersions (cubosomes). Advances in planar lipid bilayers and liposomes. Elsevier.
CHONG, J. Y., MULET, X., WADDINGTON, L. J., BOYD, B. J. & DRUMMOND, C. J. 2011. Steric stabilisation of self-assembled cubic lyotropic liquid crystalline nanoparticles: high throughput evaluation of triblock polyethylene oxide-polypropylene oxide-polyethylene oxide copolymers. Soft Matter, 7, 4768-4777.
CHUNG, H., KIM, J.-S., UM, J., KWON, I. & JEONG, S. 2002. Self-assembled “nanocubicle” as a carrier for peroral insulin delivery. Diabetologia, 45, 448-451.
CYTRYNIAK, A., NAZARUK, E., BILEWICZ, R., GóRZYńSKA, E., ŻELECHOWSKA-MATYSIAK, K., WALCZAK, R., MAMES, A., BILEWICZ, A. & MAJKOWSKA-PILIP, A. 2020. Lipidic cubic-phase nanoparticles (cubosomes) loaded with doxorubicin and labeled with 177Lu as a potential tool for combined chemo and internal radiotherapy for cancers. Nanomaterials, 10, 2272.
DAHARWAL, S., VERMA, E. & SAUDAGAR, R. 2014. Semi solid dosage forms. Farmavita Net, 13, 10.
DAWARE, S. & SAUDAGAR, R. 2017. Formulation and Development of Cubosome Loaded Emulgel-A Review. International Journal of ChemTech Research, 10, 918-924.
FLAK, D. K., ADAMSKI, V., NOWACZYK, G., SZUTKOWSKI, K., SYNOWITZ, M., JURGA, S. & HELD-FEINDT, J. 2020. AT101-loaded cubosomes as an alternative for improved glioblastoma therapy. International journal of nanomedicine, 7415-7431.
GARG, G., SARAF, S. & SARAF, S. 2007. Cubosomes: an overview. Biological and Pharmaceutical Bulletin, 30, 350-353.
GUILLOT, S., SALENTINIG, S., CHEMELLI, A., SAGALOWICZ, L., LESER, M. E. & GLATTER, O. 2010. Influence of the stabilizer concentration on the internal liquid crystalline order and the size of oil-loaded monolinolein-based dispersions. Langmuir, 26, 6222-6229.
GUO, Q. & JIANG, C. 2020. Delivery strategies for macromolecular drugs in cancer therapy. Acta Pharmaceutica Sinica B, 10, 979-986.
HAN, N., ZHANG, B., WEI, X. & YU, L. 2023. The inhibitory function of icariin in cell model of benign prostatic hyperplasia by upregulation of miR-7. Biofactors, 49.
HIMESH, S., SHARAN, P. S., MISHRA, K., GOVIND, N. & SINGHAI, A. 2011. Qualitative and quantitative profile of curcumin from ethanolic extract of Curcuma longa. Int Res J Pharm, 2, 180-184.
HUANG, C.-Y., JU, D.-T., CHANG, C.-F., REDDY, P. M. & VELMURUGAN, B. K. 2017. A review on the effects of current chemotherapy drugs and natural agents in treating non–small cell lung cancer. Biomedicine, 7, 23.
HYDE, S. T. 2001. Identification of lyotropic liquid crystalline mesophases. Handbook of applied surface and colloid chemistry, 2, 299-332.
ISRAELACHVILI, J. N., MITCHELL, D. J. & NINHAM, B. W. 1976. Theory of self-assembly of hydrocarbon amphiphiles into micelles and bilayers. Journal of the Chemical Society, Faraday Transactions 2: Molecular and Chemical Physics, 72, 1525-1568.
JANAKIRAMAN, K., KRISHNASWAMI, V., SETHURAMAN, V., RAJENDRAN, V. & KANDASAMY, R. 2019. Development of methotrexate-loaded cubosomes with improved skin permeation for the topical treatment of rheumatoid arthritis. Applied Nanoscience, 9, 1781-1796.
KAASGAARD, T. & DRUMMOND, C. J. 2006. Ordered 2-D and 3-D nanostructured amphiphile self-assembly materials stable in excess solvent. Physical Chemistry Chemical Physics, 8, 4957-4975.
KARAMI, Z. & HAMIDI, M. 2016. Cubosomes: remarkable drug delivery potential. Drug discovery today, 21, 789-801.
KULKARNI, C. V., WACHTER, W., IGLESIAS-SALTO, G., ENGELSKIRCHEN, S. & AHUALLI, S. 2011. Monoolein: a magic lipid? Physical Chemistry Chemical Physics, 13, 3004-3021.
LARSSON, K. 2000. Aqueous dispersions of cubic lipid–water phases. Current opinion in colloid & interface science, 5, 64-69.
LEUNG, S. S. & LEAL, C. 2019. The stabilization of primitive bicontinuous cubic phases with tunable swelling over a wide composition range. Soft Matter, 15, 1269-1277.
LI, C.-Y., LU, J.-T., WU, C.-P., DUAN, S.-M. & POO, M.-M. 2004. Bidirectional modification of presynaptic neuronal excitability accompanying spike timing-dependent synaptic plasticity. Neuron, 41, 257-268.
LIU, H., PAN, W.-S., NIE, S.-F., YANG, X.-G. & YAN, T.-X. 2008. Study on in vitro release empirical method and the release mechanism of budesonide colonic localization tablet. Yao xue xue bao= Acta Pharmaceutica Sinica, 43, 1147-1151.
LUZZATI, V. & HUSSON, F. 1962. The structure of the liquid-crystalline phases of lipid-water systems. The Journal of cell biology, 12, 207-219.
LUZZATI, V., TARDIEU, A., GULIK-KRZYWICKI, T., RIVAS, E. & REISS-HUSSON, F. 1968. Structure of the cubic phases of lipid–water systems. Nature, 220, 485-488.
LUZZATI, V., VARGAS, R., MARIANI, P., GULIK, A. & DELACROIX, H. 1993. Cubic phases of lipid-containing systems: elements of a theory and biological connotations. Journal of molecular biology, 229, 540-551.
MANSOORI, B., MOHAMMADI, A., DAVUDIAN, S., SHIRJANG, S. & BARADARAN, B. 2017. The different mechanisms of cancer drug resistance: a brief review. Advanced pharmaceutical bulletin, 7, 339.
MAYURI AHIRRAO, M. A. & SHILPA SHROTRIYA, S. S. 2017. In vitro and in vivo evaluation of cubosomal in situ nasal gel containing resveratrol for brain targeting.
MCMAHON, H. T. & GALLOP, J. L. 2005. Membrane curvature and mechanisms of dynamic cell membrane remodelling. Nature, 438, 590-596.
MEHNERT, W. & MäDER, K. 2012. Solid lipid nanoparticles: production, characterization and applications. Advanced drug delivery reviews, 64, 83-101.
MONTIS, C., CASTROFLORIO, B., MENDOZZA, M., SALVATORE, A., BERTI, D. & BAGLIONI, P. 2015. Magnetocubosomes for the delivery and controlled release of therapeutics. Journal of colloid and interface science, 449, 317-326.
MURPHY, W. K., FOSSELLA, F. V., WINN, R. J., SHIN, D. M., HYNES, H., GROSS, H. M., DAVILLA, E., LEIMERT, J., DHINGRA, H. & RABER, M. N. 1993. Phase II study of taxol in patients with untreated advanced non-small-cell lung cancer. JNCI: Journal of the National Cancer Institute, 85, 384-388.
NASR, M., GHORAB, M. K. & ABDELAZEM, A. 2015. In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting. Acta pharmaceutica sinica B, 5, 79-88.
PATIL, S. M., SAWANT, S. S. & KUNDA, N. K. 2021. Inhalable bedaquiline-loaded cubosomes for the treatment of non-small cell lung cancer (NSCLC). International Journal of Pharmaceutics, 607, 121046.
PATTA, A. C. F., MATHEWS, P. D., MADRID, R. R., RIGONI, V. L., SILVA, E. R. & MERTINS, O. 2020. Polyionic complexes of chitosan-N-arginine with alginate as pH responsive and mucoadhesive particles for oral drug delivery applications. International Journal of Biological Macromolecules, 148, 550-564.
PENG, X., WEN, X., PAN, X., WANG, R., CHEN, B. & WU, C. 2010a. Design and in vitro evaluation of capsaicin transdermal controlled release cubic phase gels. Aaps Pharmscitech, 11, 1405-1410.
PENG, X., YANG, Z., CHEN, M., HAN, K., XIAO, Y. & WU, C. 2010b. Preparation, characterization and content determination of cubic phase gel containing capsaicin. Zhongguo Zhong yao za zhi= Zhongguo Zhongyao Zazhi= China Journal of Chinese Materia Medica, 35, 3123-3126.
PENG, X.-S., ZHOU, Y.-F., HAN, K., QIN, L.-Z. & WU, C.-B. 2014. Preparation and in vitro study on diffusion of capsaicin cubosome. Zhongguo Zhong yao za zhi= Zhongguo Zhongyao Zazhi= China Journal of Chinese Materia Medica, 39, 644-647.
QI, B., WANG, C., DING, J. & TAO, W. 2019. Applications of nanobiotechnology in pharmacology. Frontiers Media SA.
RAROKAR, N. & KHEDEKAR, P. 2018. Cubosomes: A vehicle for delivery of various therapeutic agents. MOJ Toxicol, 4, 19-21.
RAROKAR, N. R., SAOJI, S. D., RAUT, N. A., TAKSANDE, J. B., KHEDEKAR, P. B. & DAVE, V. S. 2016. Nanostructured cubosomes in a thermoresponsive depot system: an alternative approach for the controlled delivery of docetaxel. AAPS pharmscitech, 17, 436-445.
RASHI, S., SINGH, D., CHANCHAL, D. K., SINGH, M., ANAND, S. & ALOK, S. 2015. Cubosomes: a bicontinuous cubic crystalline phase. International Journal of Life Sciences and Review, 1, 291-301.
RICHERT, S., SCHRADER, A. & SCHRADER, K. 2003. Transdermal delivery of two antioxidants from different cosmetic formulations. International journal of cosmetic science, 25, 5-13.
RIZWAN, S. B. & BOYD, B. J. 2014. Cubosomes: structure, preparation and use as an antigen delivery system. Subunit Vaccine Delivery. Springer.
SADHU, V., BERAM, N. & KANTAMNENI, P. 2018. A review on cubosome: the novel drug delivery system. GSC Biol Pharm Sci 5: 076–081.
SAGALOWICZ, L., LESER, M., WATZKE, H. & MICHEL, M. 2006. Monoglyceride self-assembly structures as delivery vehicles. Trends in Food Science & Technology, 17, 204-214.
SAGNELLA, S. & DRUMMOND, C. 2012. Drug delivery a nanomedicine approach. Aust Biochem, 43, 5-20.
SALA, M., DIAB, R., ELAISSARI, A. & FESSI, H. 2018. Lipid nanocarriers as skin drug delivery systems: Properties, mechanisms of skin interactions and medical applications. International journal of pharmaceutics, 535, 1-17.
SALENTINIG, S., YAGHMUR, A., GUILLOT, S. & GLATTER, O. 2008. Preparation of highly concentrated nanostructured dispersions of controlled size. Journal of Colloid and Interface Science, 326, 211-220.
SHAH, M. H., BIRADAR, S. V. & PARADKAR, A. R. 2006. Spray dried glyceryl monooleate–magnesium trisilicate dry powder as cubic phase precursor. International journal of pharmaceutics, 323, 18-26.
SHARMA, R., KAUR, G. & KAPOOR, D. N. 2015. Fluconazole loaded cubosomal vesicles for topical delivery. Int. J. Drug Dev. Res, 7, 32-41.
SIEKMANN, B., BUNJES, H., KOCH, M. H. & WESTESEN, K. 2002. Preparation and structural investigations of colloidal dispersions prepared from cubic monoglyceride–water phases. International journal of pharmaceutics, 244, 33-43.
SPICER, P. 2005. Cubosome processing: industrial nanoparticle technology development. Chemical Engineering Research and Design, 83, 1283-1286.
SPICER, P. T., HAYDEN, K. L., LYNCH, M. L., OFORI-BOATENG, A. & BURNS, J. L. 2001. Novel process for producing cubic liquid crystalline nanoparticles (cubosomes). Langmuir, 17, 5748-5756.
SPICER, P. T., SMALL, W. B., SMALL, W. B., LYNCH, M. L. & BURNS, J. L. 2002. Dry powder precursors of cubic liquid crystalline nanoparticles (cubosomes). Journal of nanoparticle research, 4, 297-311.
SRI, V. R., REDDY, A. M., KARTHIKEYAN, R. & SRINIVASABABU, P. 2017. A review on: cubosomes drug delivery system. Indian Journal of Drugs, 5, 104-108.
TEAGARDEN, D. L., ANDERSON, B. D. & PETRE, W. J. 1988. Determination of the pH-dependent phase distribution of prostaglandin El in a lipid emulsion by ultrafiltration. Pharmaceutical research, 5, 482-487.
THADANKI, M., KUMARI, P. S. & PRABHA, K. S. 2011. Overview of cubosomes: a nano particle. Int J Res Pharm Chem, 1, 535-541.
THAPA, R. K., CHOI, J. Y., GUPTA, B., RAMASAMY, T., POUDEL, B. K., KU, S. K., YOUN, Y. S., CHOI, H. G., YONG, C. S. & KIM, J. O. 2016. Liquid crystalline nanoparticles encapsulating cisplatin and docetaxel combination for targeted therapy of breast cancer. Biomaterials science, 4, 1340-1350.
THORAT, Y. S., GONJARI, I. D. & HOSMANI, A. H. 2011. Solubility enhancement techniques: a review on conventional and novel approaches. International journal of pharmaceutical sciences and research, 2, 2501.
TIAN, Y., LI, J.-C., ZHU, J.-X., ZHU, N., ZHANG, H.-M., LIANG, L. & SUN, L. 2017. Folic acid-targeted etoposide cubosomes for theranostic application of cancer cell imaging and therapy. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 23, 2426.
TILEKAR, K., KHADE, P., KAKADE, S., KOTWAL, S. & PATIL, R. 2014. Cubosomes-a drug delivery system. International Journal of Pharmaceutical, Chemical & Biological Sciences, 4.
TU, Y., FU, J., SUN, D., ZHANG, J., YAO, N., HUANG, D. & SHI, Z. 2014. Preparation, characterisation and evaluation of curcumin with piperine-loaded cubosome nanoparticles. Journal of microencapsulation, 31, 551-559.
URVI, S., DHIREN, D., BHAVIN, P., PATEL, U. & SHAH, R. 2013. Overview of cubosomes: A nanoparticle. Int J of Pharmacy and Integrated Sci, 1, 36-47.
VADNERE, M., AMIDON, G., LINDENBAUM, S. & HASLAM, J. L. 1984. Thermodynamic studies on the gel-sol transition of some pluronic polyols. International journal of pharmaceutics, 22, 207-218.
VAN OSS, C., GOOD, R. & CHAUDHURY, M. 1986. The role of van der Waals forces and hydrogen bonds in “hydrophobic interactions” between biopolymers and low energy surfaces. Journal of colloid and Interface Science, 111, 378-390.
VARGHESE, R., SALVI, S., SOOD, P., KULKARNI, B. & KUMAR, D. 2022. Cubosomes in cancer drug delivery: A review. Colloid and Interface Science Communications, 46, 100561.
WADSTEN-HINDRICHSEN, P., BENDER, J., UNGA, J. & ENGSTRöM, S. 2007. Aqueous self-assembly of phytantriol in ternary systems: effect of monoolein, distearoylphosphatidylglycerol and three water-miscible solvents. Journal of colloid and interface science, 315, 701-713.
WIBROE, P. P., AZMI, I. D. M., NILSSON, C., YAGHMUR, A. & MOGHIMI, S. M. 2015. Citrem modulates internal nanostructure of glyceryl monooleate dispersions and bypasses complement activation: Towards development of safe tunable intravenous lipid nanocarriers. Nanomedicine: Nanotechnology, Biology and Medicine, 11, 1909-1914.
WöRLE, G., SIEKMANN, B., KOCH, M. H. & BUNJES, H. 2006. Transformation of vesicular into cubic nanoparticles by autoclaving of aqueous monoolein/poloxamer dispersions. European journal of pharmaceutical sciences, 27, 44-53.
ZHAI, J., LUWOR, R. B., AHMED, N., ESCALONA, R., TAN, F. H., FONG, C., RATCLIFFE, J., SCOBLE, J. A., DRUMMOND, C. J. & TRAN, N. 2018. Paclitaxel-loaded self-assembled lipid nanoparticles as targeted drug delivery systems for the treatment of aggressive ovarian cancer. ACS applied materials & interfaces, 10, 25174-25185.
ZHAI, J., WADDINGTON, L., WOOSTER, T. J., AGUILAR, M.-I. & BOYD, B. J. 2011. Revisiting β-casein as a stabilizer for lipid liquid crystalline nanostructured particles. Langmuir, 27, 14757-14766.
ZHANG, L., LI, J., TIAN, D., SUN, L., WANG, X. & TIAN, M. 2020a. Theranostic combinatorial drug-loaded coated cubosomes for enhanced targeting and efficacy against cancer cells. Cell death & disease, 11, 1.
ZHANG, Z., ZHOU, L., XIE, N., NICE, E. C., ZHANG, T., CUI, Y. & HUANG, C. 2020b. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal transduction and targeted therapy, 5, 113.
ZHOU, Y., CHEN, X., CAO, J. & GAO, H. 2020. Overcoming the biological barriers in the tumor microenvironment for improving drug delivery and efficacy. Journal of Materials Chemistry B, 8, 6765-6781.
Published
2026-05-04
How to Cite
Patil, H. D., Bhagwat, D. A., Mali, S. S., Suprit D Saoji, Dipali A Nawadkar, Sonali A Chikhalwale, Vijay R Chidrawar, Pooja V Nagime, Chuda Chitasupho, & Singh, S. (2026). Advancements in Cubosomes: A Promising Platform for Targeted Anticancer Drug Delivery. Indonesian Journal of Pharmacy, 37(2), 238-256. https://doi.org/10.22146/ijp.28745
Issue
Section
Review Article
