Anti-cancer activity of doxorubicin-loaded liposomes co-modified with transferrin and folic acid

Abstract

Cancer-specific drug delivery represents an attractive approach to prevent undesirable side-effects and increase the accumulation of the drug in the tumor. Surface modification of nanoparticles such as liposomes with targeting moieties specific to the up-regulated receptors on the surface of tumor cells thus represents an effective strategy. Furthermore, since this receptor expression can be heterogeneous, using a dual-combination of targeting moieties may prove advantageous. With this in mind, the anti-cancer activity of PEGylated doxorubicin-loaded liposomes targeted with folic acid (F), transferrin (Tf) or both (F+Tf) was evaluated. The dual-targeted liposomes showed a 7-fold increase in cell association compared to either of the single-ligand targeted ones in human cervical carcinoma (HeLa) cell monolayers. The increased penetration and cell association of the dual-targeted liposomes was also demonstrated using HeLa cell spheroids. The in vitro cytotoxicity of the doxorubicin liposomes (LD) was then evaluated using HeLa and A2780-ADR ovarian carcinoma cell monolayers. In both these cell lines, the (F+Tf) LD showed significantly higher cytotoxic effects than the untargeted, or single-ligand targeted liposomes. Ina HeLa xenograft model in nude mice, compared to the untreated group, though the untargeted LD showed 42% tumor growth inhibition, both the (F) LD as well as (F+Tf) LD showed 75% and 79% tumor growth inhibition respectively. These results thus highlight that though the dual-targeted liposomes represent an effective cytotoxic formulation in the in vitro setting, they were equally effective as the folic acid-targeted liposomes in reducing tumor burden in the more complex in vivo setting in this particular model.

Multicellular Tumor Spheroids (MCTS) as a 3D In Vitro Evaluation Tool of Nanoparticles

“…Nanoparticles, decorated with Pep‐1 and CGKRK, were observed to enhance the delivery of paclitaxel into MCTS compared to nanoparticles with only one ligand . Similar observations were made by combining folic acid and transferrin as two targeting ligands on a liposome showing a significant increase in HeLa spheroid association compared to nanoparticles with single targeting ligands …”

Development of antiproliferative long-circulating liposomes co-encapsulating doxorubicin and curcumin, through the use of a quality-by-design approach

“…DOX can inhibit the replication of tumor cells by intercalating in the base pairs of DNA 9. Also, it induces apoptosis in cancerous cells as a result of oxidative damage to DNA 11. However, despite the fact that it is a very potent chemotherapeutic agent, its clinical use is limited by its induced toxicity and drug resistance 8.…”

Possible role of nanocarriers in drug delivery against cervical cancer

“…It was concluded that stealth liposomes are efficient carriers for drugs, genes, and vaccines and can be easily tailored with proteins, antibodies, and other suitable ligands, resulting in smart formulations for targeted drug delivery [47]. Furthermore, liposomes conjugated with folic acid and transferrin showed higher cell association, penetration, and efficacy of delivering doxorubicin in vitro in human cervical carcinoma cell line (HeLa) as compared with either of the single-ligand targeted liposomes, or non-targeted liposomes [48]. …”

“…No.Drug/antibodyType/composition of liposomesCell lines/animal/clinical modelsReference1.PaclitaxelStearyl amine-based positively charged multilayered liposomesHeLa cell lines[42]2.Cisplatin–ME-180 cervical cancer cell line, cisplatin-resistant clone R-ME-180 and HeLa cells[43]3.CisplatinHeat-activated thermosensitive liposome–[44]4.Doxorubicin–Cervical cancer patients[45]5.IL-2Anionic, cationic, and neutral liposomesINBL cells 6.DoxorubicinTransferrin (Tf)-conjugated stealth liposomes (Tf-SL-DOX)–[47]7.DoxorubicinLiposomes conjugated with folic acid and transferrinHeLa cells[48]8.IL-2Cationic liposome containingINBL cells induced tumor-containing immune-depressed CBA mice[49] …”