Appendix A: Literature search for specific toxicology studies with novel supplement formulations
In this guide
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Skip the menu of subheadings on this page.Searches for studies investigating the toxicity of vitamin C, CBD, and curcumin in novel formulations were conducted in PubMed using the search strings listed in table 1.
Table 1. Search strings and number of total and relevant results.
|
Search string |
Results |
Relevant |
|
“Vitamin C” AND “toxicity” AND “encapsulated” |
7 |
0 |
|
“Vitamin C” AND “toxicity” AND “liposomal” |
5 |
0 |
|
“Vitamin C” AND “toxicity” AND “micelles” |
6 |
0 |
|
“Vitamin C” AND “toxicity” AND “emulsion” |
3 |
0 |
|
“CBD” AND “toxicity” AND “encapsulated” |
1 |
0 |
|
“CBD” AND “toxicity” AND “liposomal” |
0 |
0 |
|
“CBD” AND “toxicity” AND “micelles” |
0 |
0 |
|
“CBD” AND “toxicity” AND “emulsion” |
0 |
0 |
|
“Curcumin” AND “toxicity” AND “encapsulated” |
121 |
7 |
|
“Curcumin” AND “toxicity” AND “liposomal” |
33 |
5 |
|
“Curcumin” AND “toxicity” AND “micelles” |
84 |
8 |
|
“Curcumin” AND “toxicity” AND “emulsion” |
27 |
3 |
PM = PubMed; WoS = Web of Science.
Relevant results were only retrieved for novel formulations of curcumin. A total of 23 studies were identified, 11 of which were in vitro studies and 11 of which were in vivo studies. Three studies were performed in human subjects and are reviewed in the main paper. A few of the relevant hits were retrieved by more than one search string and in these cases such results were omitted from the ‘relevant’ count in the subsequent strings such that all ‘relevant’ counts are unique. Publications investigating the toxicology of novel curcumin formulations in vitro and in vivo are briefly summarised table 2 and the full references are listed below table 2.
Table 2. Summary of studies investigating the toxicity of novel curcumin formulations.
|
Formulation - In Vitro |
System |
Key findings |
Study |
|
Curcumin nano-blisomes |
Non-cancer cell line (Wi-38l) |
Lower cytotoxicity vs unformulated curcumin |
Abbas et al. 2022 |
|
Micellar curcumin |
Immortalised fibroblasts Glioblastoma LN229 Human endothelial cell line Primary vascular endothelial cells Primary smooth muscle cells Primary pericytes |
Reduced cell viability. Reversible genotoxicity (comet assay). Similar efficacy of native vs. micellar curcumin. |
Beltzig et al. 2021 |
|
Liposomal curcumin |
Human lymphocytes EBV-transformed B-cells (LCL) |
Empty DMPC liposomes toxic. Liposomal curcumin inhibited LCL proliferation. |
Chen et al. 2009 |
|
Micellar curcumin |
Breast tumor cell line Human stromal cells Zebrafish embryotoxicity assay |
Induced apoptosis in tumour cells and spheroids. Reduced viability in stromal cells. Toxicity to zebrafish embryo development. Micellar curcumin more toxic. |
Do et al. 2022 |
|
Curcumin chitosan nanoparticles |
Cervical tumour cells VERO cells |
Cytotoxicity to tumour cells. Biocompatible with VERO cells. |
Facchi et al. 2019 |
|
Liposomal curcumin |
Human synovial fibroblasts Mouse macrophages |
Liposomal curcumin less toxic to cells. |
Kloesch et al. 2016 |
|
Curcumin microemulsion |
HepG2 cells |
Cytotoxicity to HepG2 cells, greater with smaller emulsion droplet size. |
Lin et al. 2014 |
|
Micellar curcumin |
HepG2 cells |
Cytotoxicity to HepG2 cells. |
Phan et al. 2016 |
|
Solid lipid curcumin nanoparticles |
3T3 fibroblasts |
Reduction in cell viability and alteration of lipid profile (dependent upon particle composition). |
Rosa et al. 2022 |
|
Liposomal curcumin |
Red blood cells in vitro |
Dose-dependent echinocyte formation and increases in mean cellular volume. |
Storka et al. 2013 |
|
Liposomal solid curcumin gels |
Huh7it cell line |
Non-cytotoxic. |
Yusuf et al. 2022 |
|
Formulation - In Vivo |
System |
Key findings |
Study |
|
Curcumin PLGA nanoparticles |
Mice RAW 264.7 cell line |
Increased lymphocytes. No changes in hepatotoxic biomarkers. Higher toxicity in RAW 264.7 cells at higher concentrations, but not at lower concentrations. |
Busari et al. 2017 |
|
Curcumin-loaded hydrogel nanoparticles |
“in vivo” [abstract only] |
Low toxicity. No genotoxicity observed. |
Dandekar et al. 2010 |
|
Hydrogenated curcumin |
Sprague Dawley rats |
No treatment related toxicity. |
Gopi et al. 2016 |
|
Alginate-curcumin conjugate; micelle forming |
Mouse tumour models. |
No toxicity observed in blood parameters, histology, comet assay, or cytokine levels. |
Karabasz et al. 2019 |
|
Nano-micelle curcumin |
Male Wistar rats |
Testicular toxicity observed; DNA damage.
|
Moshari et al. 2017 |
|
Nano-micelle curcumin |
Male Wistar rats |
Testicular toxicity observed; suppression of spermatogenesis; DNA damage. |
Radmanesh et al. 2021 |
|
Nano-liposome curcumin with tetrandrine |
Zebrafish |
No developmental toxicity. |
Song et al. 2022 |
|
Chitosan solid lipid nanoparticle curcumin with sulforaphane |
BALB/c mice |
No toxicity in acute, subacute, or chronic tests. |
Thakkar et al. 2016 |
|
Micellar curcumin |
Male Wistar rats |
No haematopoietic or liver tissue toxicity. |
Tzankova et al. 2016 |
Full references
In vitro
Abbas, H., El-Feky, Y.A., Al-Sawahli, M.M., El-Deeb, N.M., El-Nassan, H.B., Zewail, M., 2022. Development and optimization of curcumin analog nano-bilosomes using 21.31 full factorial design for anti-tumor profiles improvement in human hepatocellular carcinoma: in-vitro evaluation, in-vivo safety assay. Drug Deliv 29, 714–727. https://doi.org/10.1080/10717544.2022.2044938
Beltzig, L., Frumkina, A., Schwarzenbach, C., Kaina, B., 2021. Cytotoxic, Genotoxic and Senolytic Potential of Native and Micellar Curcumin. Nutrients 13, 2385. https://doi.org/10.3390/nu13072385
Chen, C., Johnston, T.D., Jeon, H., Gedaly, R., McHugh, P.P., Burke, T.G., Ranjan, D., 2009. An in vitro study of liposomal curcumin: stability, toxicity and biological activity in human lymphocytes and Epstein-Barr virus-transformed human B-cells. Int J Pharm 366, 133–139. https://doi.org/10.1016/j.ijpharm.2008.09.009
Do, X.-H., Hoang, M.H.T., Vu, A.-T., Nguyen, L.-T., Bui, D.T.T., Dinh, D.-T., Nguyen, X.-H., Than, U.T.T., Mai, H.T., To, T.T., Nguyen, T.N.H., Hoang, N.T.M., 2022. Differential Cytotoxicity of Curcumin-Loaded Micelles on Human Tumor and Stromal Cells. Int J Mol Sci 23, 12362. https://doi.org/10.3390/ijms232012362
Facchi, S.P., Scariot, D.B., Bueno, P.V.A., Souza, P.R., Figueiredo, L.C., Follmann, H.D.M., Nunes, C.S., Monteiro, J.P., Bonafé, E.G., Nakamura, C.V., Muniz, E.C., Martins, A.F., 2016. Preparation and cytotoxicity of N-modified chitosan nanoparticles applied in curcumin delivery. Int J Biol Macromol 87, 237–245. https://doi.org/10.1016/j.ijbiomac.2016.02.063
Kloesch, B., Gober, L., Loebsch, S., Vcelar, B., Helson, L., Steiner, G., 2016. In Vitro Study of a Liposomal Curcumin Formulation (Lipocurc™): Toxicity and Biological Activity in Synovial Fibroblasts and Macrophages. In Vivo 30, 413–419.
Lin, C.-C., Lin, H.-Y., Chi, M.-H., Shen, C.-M., Chen, H.-W., Yang, W.-J., Lee, M.-H., 2014. Preparation of curcumin microemulsions with food-grade soybean oil/lecithin and their cytotoxicity on the HepG2 cell line. Food Chem 154, 282–290. https://doi.org/10.1016/j.foodchem.2014.01.012
Phan, Q.T., Le, M.H., Le, T.T.H., Tran, T.H.H., Xuan, P.N., Ha, P.T., 2016. Characteristics and cytotoxicity of folate-modified curcumin-loaded PLA-PEG micellar nano systems with various PLA:PEG ratios. Int J Pharm 507, 32–40. https://doi.org/10.1016/j.ijpharm.2016.05.003
Rosa, A., Nieddu, M., Pitzanti, G., Pireddu, R., Lai, F., Cardia, M.C., 2023. Impact of solid lipid nanoparticles on 3T3 fibroblasts viability and lipid profile: The effect of curcumin and resveratrol loading. J Appl Toxicol 43, 272–286. https://doi.org/10.1002/jat.4379
Storka, A., Vcelar, B., Klickovic, U., Gouya, G., Weisshaar, S., Aschauer, S., Helson, L., Wolzt, M., 2013. Effect of liposomal curcumin on red blood cells in vitro. Anticancer Res 33, 3629–3634.
In vivo
Busari, Z.A., Dauda, K.A., Morenikeji, O.A., Afolayan, F., Oyeyemi, O.T., Meena, J., Sahu, D., Panda, A.K., 2017. Antiplasmodial Activity and Toxicological Assessment of Curcumin PLGA-Encapsulated Nanoparticles. Front Pharmacol 8, 622. https://doi.org/10.3389/fphar.2017.00622
Dandekar, P.P., Jain, R., Patil, S., Dhumal, R., Tiwari, D., Sharma, S., Vanage, G., Patravale, V., 2010. Curcumin-loaded hydrogel nanoparticles: application in anti-malarial therapy and toxicological evaluation. J Pharm Sci 99, 4992–5010. https://doi.org/10.1002/jps.22191
Gopi, S., Jacob, J., Mathur, K.Y., 2016. Acute and subchronic oral toxicity studies of hydrogenated curcuminoid formulation “CuroWhite” in rats. Toxicol Rep 3, 817–825. https://doi.org/10.1016/j.toxrep.2016.10.007
Karabasz, A., Lachowicz, D., Karewicz, A., Mezyk-Kopec, R., Stalińska, K., Werner, E., Cierniak, A., Dyduch, G., Bereta, J., Bzowska, M., 2019. Analysis of toxicity and anticancer activity of micelles of sodium alginate-curcumin. Int J Nanomedicine 14, 7249–7262. https://doi.org/10.2147/IJN.S213942
Moshari, S., Nejati, V., Najafi, G., Razi, M., 2017. Nanomicelle curcumin-induced DNA fragmentation in testicular tissue; Correlation between mitochondria dependent apoptosis and failed PCNA-related hemostasis. Acta Histochem 119, 372–381. https://doi.org/10.1016/j.acthis.2017.03.007
Radmanesh, F., Razi, M., Shalizar-Jalali, A., 2021. Curcumin nano-micelle induced testicular toxicity in healthy rats; evidence for oxidative stress and failed homeostatic response by heat shock proteins 70-2a and 90. Biomed Pharmacother 142, 111945. https://doi.org/10.1016/j.biopha.2021.111945
Song, J.-W., Liu, Y.-S., Guo, Y.-R., Zhong, W.-X., Guo, Y.-P., Guo, L., 2022. Nano-Liposomes Double Loaded with Curcumin and Tetrandrine: Preparation, Characterization, Hepatotoxicity and Anti-Tumor Effects. Int J Mol Sci 23, 6858. https://doi.org/10.3390/ijms23126858
Thakkar, A., Chenreddy, S., Thio, A., Khamas, W., Wang, J., Prabhu, S., 2016. Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticle-encapsulated aspirin and curcumin in combination with free sulforaphane in BALB/c mice. Int J Nanomedicine 11, 3265–3276. https://doi.org/10.2147/IJN.S106736
Tzankova, V., Gorinova, C., Kondeva-Burdina, M., Simeonova, R., Philipov, S., Konstantinov, S., Petrov, P., Galabov, D., Yoncheva, K., 2016. In vitro and in vivo toxicity evaluation of cationic PDMAEMA-PCL-PDMAEMA micelles as a carrier of curcumin. Food Chem Toxicol 97, 1–10. https://doi.org/10.1016/j.fct.2016.08.026
Yusuf, H., Novitasari, E.K.D.D., Purnami, N.L.W., Mahbub, A.W., Sari, R., Setyawan, D., 2022. Formulation Design and Cell Cytotoxicity of Curcumin-Loaded Liposomal Solid Gels for Anti-Hepatitis C Virus. Adv Pharmacol Pharm Sci 2022, 3336837. https://doi.org/10.1155/2022/3336837
