LDL-conjugated to GM1 micelles incorporating anticancer drugs to improve tumor cell uptake

Document Type : Research Paper


1 Centro de Excelencia en Productos y Procesos de Córdoba (CEPROCOR), Córdoba, Argentina

2 Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina

3 Cátedra de Biotecnología, Facultad de Ciencias Químicas, Universidad Católica de Córdoba, Córdoba, Argentina


Objective(s): The role of lipoproteins (LDL) as active molecules with preferential tumor interaction, but limited drug delivery capacity, has been previously reported. On the other hand, in a previous report, we demonstrated the high capacity of monosialogangliosides (GM1) micelles as drug transporters.
Materials and Methods: In this work, GM1 was loaded with high doses of oncologic drugs such Paclitaxel or Doxorubicin and binded to LDL lipoproteins to form GM1-drug-LDLwater soluble complex. Evidence suggests that both, hydrophobic and electrostatic forces, participate in the interaction, regulated by conditions such as pH, temperature and ionic strength.
Results: Results of DLS and TEM show that GM1-LDL complexes are considerably larger than the sum of their individual compounds, with a high charge of electronegative surface (-55.9 mV). In addition, the cytotoxic effect on cell cultures is greater when drugs are contained in GM1-LDL complexes than when loaded in GM1 micelles.
Conclusion: The results suggest the participation of active energy-dependent mechanism in the uptake of GM1-LDL drug, probably linked to the LDL receptor by the tumor cells. However, we could not confirm that the transport through LDL receptors is the only one that participates in the cellular uptake of the micelles.


1.Kader A, Davis PJ, Kara M, Liu H. Drug targeting using low density lipoprotein (LDL): physicochemical factors affecting drug loading into LDL particles. J Control Release. 1998; 55: 231–243.
2. Abdul Kader, Alan Pater. Loading anticancer drugs into HDL as well as LDL has little effect on properties of complexes and enhances cytotoxicity to human carcinoma cells. J Control Release. 2002; 80: 29–44.
3.Amin AR, Amin HK. Lipoprotein nanoparticles in diagnosis and treatment of cancer. MOJ Drug Des Develop Ther. 2018; 2(1):15‒18.
4.Raut S, Dasseux JL, Sabnis NA, Mooberry L, Lacko A. Lipoproteins for therapeutic delivery: recent advances and future opportunities. Ther Deliv. 2018; 9, 4: 257-268.
5.Upadhyay RK. Lipoproteins as drug delivery vehicles for cancer and tumor therapeutics. J Stem Cell Res Ther.2018; 4(3):53‒63.
6.Filipowska D, Filipowski T, Morelowska B, Kazanowska W, Laudanski T, Lapinjoki S, Akerlund M, Breeze A. Treatment of cancer patients with a low-density-lipoprotein delivery vehicle containing a cytotoxic drug. Cancer Chemother Pharmacol. 1992; 29: 396-400.
7. Firestone RA. Low-density lipoprotein as a vehicle for targeting antitumor compounds to cancer cells. Bioconjugate Chem. 1994; 5(2): 105-113.
8.Ng KK, Lovell JF, Zheng G. Lipoprotein-Inspired Nanoparticles for Cancer Theranostics. Acc Chem Res. 2011; 44(10): 1105–1113.
9.Glickson JD, Lund-Katz S, Zhou R, Choi H, Chen IW, Li H, Corbin I, Popov AV, Cao W, Song L, Qi C, Marotta D, Nelson DS, Chen J, Chance B, Zheng G. Lipoprotein Nanoplatform for Targeted Delivery of Diagnostic and Therapeutic Agents. Adv Exp Med Biol. 2009;645:227-239 .
10.Gal D, Ohashi M, MacDonald PC, Buchsbaum HJ, Simpson ER. Low-density lipoprotein as a potential vehicle for chemotherapeutic agents and radionuclides in the management of gynecologic neoplasms. Am J Obstet Gynecol. 1981; 139: 877–885.
11.Prokazova NV, Mikhailenko IA, Preobrazhensky SN, Ivanov VO, Pokrovsky SN, Timofeeva NG, Martinova MA, Repin VS & Bergelson LD. Interaction gangliosides with plasma low density proteins. Glycoconj J. 1986; 3, 273-286.
12.Rebbaa A and Portoukalian J. Distribution of exogenously added gangliosides in serum proteins depends on the relative affinity of albumin and lipoproteins. J Lipid Res. 1995; 36: 564-572.
13. Filipovic I, Schwarzmann G, Mraz W, Wiegandt H, Buddecke E. Sialic-Acid Content of Low-Density Lipoproteins Controls Their Binding and Uptake by Cultured Cells. Eur J Biochem. 1979; 93: 51 -55.
14.Mikhailenko IA, Dubrovskaya SA, Korepanova OB, Timofeeva NG, Morozkin AD, Prokazova NV, Bergelson LD. Interaction of low-density lipoproteins with gangliosides. Biochim Biophys Acta. 1991; 1085(3): 299-305.
15.Leonhard V, Alasino RV, Bianco, ID, Garro AG, Heredia V, Beltramo DM. Self-assembled micelles of monosialogangliosides as nano delivery vehicles for taxanes. J Control Release. 2012; 162: 619–627.
16.Leonhard V, Alasino RV, Bianco ID, Garro AG, Heredia V, Beltramo DM. Biochemical characterization of the interactions between doxorubicin and lipidic GM1 micelles with or without paclitaxel loading. Int J Nanomedicine. 2015; 10: 3377–3388.
17.Burstein M, Scholnick HR, Morfin R. Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions. J Lipid Res. 1970; 11(6): 583-595.
18.Abraham SA, Edwards K, Karlsson G, MacIntosh S, Mayer,LD, McKenzie C, Bally MB. Formation of transition metal-doxorubicin complexes inside liposomes. Biochim Biophys Acta. 2002; 1565(1): 41–54.
19.Gallagher EJ, Zelenko Z, Neel BA, Antoniou IM , Rajan L, Kase N, LeRoith D. Elevated tumor LDLR expression accelerates LDL cholesterol-mediated breast cancer growth in mouse models of hyperlipidemia. Oncogene. 2017; 36 (46): 6462-6471.
20.Vasseur S, Guillaumond F. LDL Receptor: An open route to feed pancreatic tumor cells. Mol Cell Oncol. 2015; 3(1):e1033586.
21. Brown MS and Goldstein JL. Regulation of the Activity of the Low Density Lipoprotein Receptor in Human Fibroblasts. Cell. 1975; 6: 307-316.
22.Havekes LM, Verboom H, de Wit E, Yap SH, Princen HM.. Regulation of Low Density Lipoprotein Receptor Activity in Primary Cultures of Human Hepatocytes by Serum Lipoproteins. Hepatology. 1986; 6 (6): 1356-1360.
23.Versluis AJ, van Geel PJ, Oppelaar H, van Berkel TJ, Bijsterbosch MK. Receptor-mediated uptake of low-density lipoprotein by B16 melanoma cells in vitro and in vivo in mice. Br J Cancer. 1996; 74: 525-532.
24.Lombardi P, Mulder M, de Wit E, van Berkel TJ, Frants RR, Havekes LM. Low-density lipoproteins are degraded in HepG2 cells with low efficiency. Biochem J. 1993; 1; 290 (2):509-514.
25.Schouten D, van der Kooij M, Muller J, Pieters MN, Bijsterbosch MK, van Berkel TJ. Development of lipoprotein-like lipid particles for drug targeting: neo-high density lipoproteins. Mol Pharmacol. 1993; 44(2):486-492.
26. Counsell RE and Pohland RC. Lipoproteins as Potential Site-Specific Delivery Systems for Diagnostic and Therapeutic Agents. J Med Chem. 1982; 25: 1115–1120.
27.Edge SB, Hoeg JM, Triche T, Schneider PD, Brewer HB Jr.Cultured Human Hepatocytes. Evidence for Metabolism of Low Density Lipoproteins by a Pathway Independent of the Classical Low Density Lipoprotein Receptor. J Biol Chem. 1986; 261(8): 3800-3806.
28.Shaw JM, Shaw KV, Yanovich S, Iwanik M, Futch WS, Rosowsky A, Schook LB. Delivery of lipophilic drugs using lipoproteins, Ann N Y Acad Sci. 1987; 507: 252–271.