Complexes of Pentagamavunon-1 and Lactosylated Albumin for Enhancing the Cytotoxic Effect on Hepatocellular Carcinoma
Keywords:
PGV-1, albumin, glycoprotein, lactosylated, HCC
Abstract
PGV-1 exhibits potential as an anticancer drug for hepatocellular carcinoma (HCC), and this study focuses on enhancing its solubility and cytotoxicity against liver cancer cells. To achieve this, complexes were developed by combining Bovine Serum Albumin (BSA) with lactose, aiming to improve the bioavailability of PGV-1 as an anticancer agent. Subsequently, these complexes were further modified through lactosylation, resulting in PGV-1-loaded lactosylated BSA (PGV-1+BSA+Lac), with the purpose of increasing their cytotoxic effects on HCC cells. The glycation of BSA with d-lactose was conducted under dry-heat conditions at 60°C for various durations (0, 30, 60, 120, or 240 minutes). Monitoring the extent of BSA glycation involved assessing the availability of free peptide and examining the molecular weight profile. A straightforward formulation was proposed, involving the complexation of BSA lactosylated with PGV-1. The solubility of PGV-1 in aqueous solutions was assessed with varying amounts of BSA. Cytotoxicity was evaluated through an MTT assay using the HLF liver cancer cell line. The results revealed distinct variations in BSA conjugation depending on the duration of heating. Modified BSA exhibited reduced peptide availability and slower migration in SDS/PAGE. Notably, PGV-1 demonstrated significantly higher solubility when combined with BSA+Lac, as compared to PGV-1+BSA. The IC50 values for PGV-1+BSA+Lac in HLF cells (0.008±0.002 µM) were markedly lower than those for PGV-1 (0.437±0.002 µM) and PGV-1+BSA (0.631±0.002 µM), highlighting the potent inhibitory effect of PGV-1+BSA+Lac on HLF cell proliferation. These findings suggest that PGV-1+BSA+Lac complexes hold promise as potential candidates for targeted PGV-1 delivery in HCC therapy
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Weber, K., & Osborn, M. (1969). The reliability of molecular weight determinations by dodecyl sulfate-polyacrylamide gel electrophoresis. Journal of Biological Chemistry, 244(16), 4406–4412.
Zhang, J., Sun, H.-H., Zhang, Y.-Z., Yang, L.-Y., Dai, J., & Liu, Y. (2012). Interaction of human serum albumin with indomethacin: spectroscopic and molecular modeling studies. Journal of Solution Chemistry, 41, 422–435.
Zhang, L., Hou, S., Mao, S., Wei, D., Song, X., & Lu, Y. (2004). Uptake of folate-conjugated albumin nanoparticles to the SKOV3 cells. International Journal of Pharmaceutics, 287(1–2), 155–162.
Zu, Y., Zhang, Y., Zhao, X., Zhang, Q., Liu, Y., & Jiang, R. (2009). Optimization of the preparation process of vinblastine sulfate (VBLS)-loaded folateconjugated bovine serum albumin (BSA) nanoparticles for tumor-targeted drug delivery using response surface methodology (RSM). International Journal of Nanomedicine, 321–333.
Bellantone, R. A. (2014). Fundamentals of amorphous systems: thermodynamic aspects. Amorphous Solid Dispersions: Theory and Practice, 3–34.
Bogdan, M., Pirnau, A., Floare, C., & Bugeac, C. (2008). Binding interaction of indomethacin with human serum albumin. Journal of Pharmaceutical and Biomedical Analysis, 47(4–5), 981–984.
Bosselmann, S., & Williams, R. O. (2011). Route-specific challenges in the delivery of poorly water-soluble drugs. Formulating Poorly Water Soluble Drugs, 1–26.
Bu, G., Zhang, N., & Chen, F. (2015). The influence of glycosylation on the antigenicity, allergenicity, and structural properties of 11S-lactose conjugates. Food Research International, 76, 511–517.
Curry, S. (2002). Beyond expansion: structural studies on the transport roles of human serum albumin. Vox Sanguinis, 83, 315–319.
Curvale, R. A. (2009). Buffer capacity of bovine serum albumin (BSA). J. Argent. Chem. Soc, 97(1), 174–180.
Da’i M, UA, J., AM, S., M, K., & E., M. (2012). The effect of PGV-1, PGV-0 and curcumin on protein involve in G2-M phase of cell cycle and apoptosis on T47D breast cancer cell line. Jurnal Ilmu Kefarmasian Indonesia, 10(2), 99–110.
Evans, T. W. (2002). albumin as a drug—biological effects of albumin unrelated to oncotic pressure. Alimentary Pharmacology & Therapeutics, 16, 6–11.
Fu, Ling, Sun, Y., Ding, L., Wang, Y., Gao, Z., Wu, Z., Wang, S., Li, W., & Bi, Y. (2016). Mechanism evaluation of the interactions between flavonoids and bovine serum albumin based on multi-spectroscopy, molecular docking and Q-TOF HR-MS analyses. Food Chemistry, 203, 150–157.
Fu, Liyi, Sun, C., & Yan, L. (2015). Galactose targeted pH-responsive copolymer conjugated with near infrared fluorescence probe for imaging of intelligent drug delivery. ACS Applied Materials & Interfaces, 7(3), 2104–2115.
Ghuman, J., Zunszain, P. A., Petitpas, I., Bhattacharya, A. A., Otagiri, M., & Curry, S. (2005). Structural basis of the drug-binding specificity of human serum albumin. Journal of Molecular Biology, 353(1), 38–52.
Jithan, A. V, Madhavi, K., Madhavi, M., & Prabhakar, K. (2011). Preparation and characterization of albumin nanoparticles encapsulating curcumin intended for the treatment of breast cancer. International Journal of Pharmaceutical Investigation, 1(2), 119.
Kańska, U., & Boratyński, J. (2002). Thermal glycation of proteins by D-glucose and D-fructose. Archivum Immunologiae et Therapiae Experimentalis, 50(1), 61–66.
Khoder, M., Abdelkader, H., ElShaer, A., Karam, A., Najlah, M., & Alany, R. G. (2016). Efficient approach to enhance drug solubility by particle engineering of bovine serum albumin. International Journal of Pharmaceutics, 515(1–2), 740–748.
Kim, J.-H., Kim, Y.-K., Arash, M.-T., Hong, S.-H., Lee, J.-H., Kang, B. N., Bang, Y.-B., Cho, C.-S., Yu, D.-Y., & Jiang, H.-L. (2012). Galactosylation of chitosan-graft-spermine as a gene carrier for hepatocyte targeting in vitro and in vivo. Journal of Nanoscience and Nanotechnology, 12(7), 5178–5184.
Laemmli, U. K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227(5259), 680–685.
Lagemaat, J. Vande, Silván, J. M., Moreno, F. J., Olano, A., & Del Castillo, M. D. (2007). In vitro glycation and antigenicity of soy proteins. Food Research International, 40(1), 153–160.
Ledesma-Osuna, A., Ramos-Clamont, G., & Vázquez-Moreno, L. (2008). Characterization of bovine serum albumin glycated with glucose, galactose and lactose. Acta Biochimica Polonica, 55(3), 491–497.
Lestari, B., Nakamae, I., Yoneda-Kato, N., Morimoto, T., Kanaya, S., Yokoyama, T., Shionyu, M., Shirai, T., Meiyanto, E., & Kato, J. (2019). Pentagamavunon-1 (PGV-1) inhibits ROS metabolic enzymes and suppresses tumor cell growth by inducing M phase (prometaphase) arrest and cell senescence. Scientific Reports, 9(1), 1–12.
Lou, J., Hu, W., Tian, R., Zhang, H., Jia, Y., Zhang, J., & Zhang, L. (2014). Optimization and evaluation of a thermoresponsive ophthalmic in situ gel containing curcumin-loaded albumin nanoparticles. International Journal of Nanomedicine, 2517–2525.
Meiyanto, E., Putri, H., Larasati, Y. A., Utomo, R. Y., Jenie, R. I., Ikawati, M., Lestari, B., Yoneda-Kato, N., Nakamae, I., & Kawaichi, M. (2019). Anti-proliferative and anti-metastatic potential of curcumin analogue, pentagamavunon-1 (PGV-1), toward highly metastatic breast cancer cells in correlation with ROS generation. Advanced Pharmaceutical Bulletin, 9(3), 445.
Meiyanto, E., Septisetyani, E. P., Larasati, Y. A., & Kawaichi, M. (2018). Curcumin analog pentagamavunon-1 (PGV-1) sensitizes Widr cells to 5-fluorouracil through inhibition of NF-κB activation. Asian Pacific Journal of Cancer Prevention: APJCP, 19(1), 49.
Nosrati, H., Sefidi, N., Sharafi, A., Danafar, H., & Manjili, H. K. (2018). Bovine Serum Albumin (BSA) coated iron oxide magnetic nanoparticles as biocompatible carriers for curcumin-anticancer drug. Bioorganic Chemistry, 76, 501–509.
Perales, J. C., Ferkol, T., Beegen, H., Ratnoff, O. D., & Hanson, R. W. (1994). Gene transfer in vivo: sustained expression and regulation of genes introduced into the liver by receptor-targeted uptake. Proceedings of the National Academy of Sciences, 91(9), 4086–4090.
Pertiwi, D., Martien, R., & Ismail, H. (2018). Formulation of nanoparticles ribosome inactivating proteins from Mirabilis jalapa L.(RIP MJ) conjugated AntiEpCAM antibody using low chain chitosan-pectin and cytotoxic activity against breast cancer cell line. Pakistan Journal of Pharmaceutical Sciences, 31(2), 379–385.
Singh, B., Jang, Y., Maharjan, S., Kim, H.-J., Lee, A. Y., Kim, S., Gankhuyag, N., Yang, M.-S., Choi, Y.-J., & Cho, M.-H. (2017). Combination therapy with doxorubicin-loaded galactosylated poly (ethyleneglycol)-lithocholic acid to suppress the tumor growth in an orthotopic mouse model of liver cancer. Biomaterials, 116, 130–144.
Urien, S., Tillement, J., & Barré, J. (2001). The significance of plasma‐protein binding in drug research. Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical, and Computational Strategies, 189–197.
Utomo, R. Y., Wulandari, F., Novitasari, D., Lestari, B., Susidarti, R. A., Jenie, R. I., Kato, J., Sardjiman, S., & Meiyanto, E. (2022). Preparation and cytotoxic evaluation of PGV-1 derivative, CCA-1.1, as a new curcumin analog with improved-physicochemical and pharmacological properties. Advanced Pharmaceutical Bulletin, 12(3), 603.
Weber, K., & Osborn, M. (1969). The reliability of molecular weight determinations by dodecyl sulfate-polyacrylamide gel electrophoresis. Journal of Biological Chemistry, 244(16), 4406–4412.
Zhang, J., Sun, H.-H., Zhang, Y.-Z., Yang, L.-Y., Dai, J., & Liu, Y. (2012). Interaction of human serum albumin with indomethacin: spectroscopic and molecular modeling studies. Journal of Solution Chemistry, 41, 422–435.
Zhang, L., Hou, S., Mao, S., Wei, D., Song, X., & Lu, Y. (2004). Uptake of folate-conjugated albumin nanoparticles to the SKOV3 cells. International Journal of Pharmaceutics, 287(1–2), 155–162.
Zu, Y., Zhang, Y., Zhao, X., Zhang, Q., Liu, Y., & Jiang, R. (2009). Optimization of the preparation process of vinblastine sulfate (VBLS)-loaded folateconjugated bovine serum albumin (BSA) nanoparticles for tumor-targeted drug delivery using response surface methodology (RSM). International Journal of Nanomedicine, 321–333.
Published
2025-04-10
How to Cite
Prihapsara, F., Khadijah, K., Hermawan, A., & Meiyanto, E. (2025). Complexes of Pentagamavunon-1 and Lactosylated Albumin for Enhancing the Cytotoxic Effect on Hepatocellular Carcinoma. Indonesian Journal of Pharmacy. https://doi.org/10.22146/ijp.10474
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Research Article
