Multipronged, strategic delivery of paclitaxel-topotecan using engineered liposomes to ovarian cancer

Abstract

Context: Synergistically active combinations have been used to enhance therapeutic efficacy for ovarian cancer chemotherapy.

Objective: The synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) were loaded into folate-anchored PEGylated liposomes (FPL-Pac-Top) for safe and effective treatment of ovarian cancer.

Materials and methods: Coupling reactions were carried out using carbodiimide chemistry and confirmed by infrared spectral analysis. These liposomes were studied for shape and physical interaction (and integrity), in vitro drug release kinetics, hemolytic toxicity, ex vivo pharmacodynamics in OVCAR-3 cell lines, and pharmacokinetics in ovarian tumor-bearing mice.

Results: The differential scanning calorimeter studies exhibited melting of liposomes (∼150 nm) at ∼41 °C. The drug(s) release from liposomes followed Fickian diffusion model. The hematological studies revealed insignificant toxicity to blood cells. In vivo studies showed long circulatory behavior (increased AUC_0–t and AUMC_0–t and MRT) and selective accumulation of FPL-Pac-Top in the ovaries. FPL-Pac-Top showed less necrosis and more apoptosis in flow cytometry. Kaplan–Meier survival analysis revealed the doubling of the survival time with FPL-Pac-Top in comparison to Pac-Top solution.

Discussion and conclusion: Potentiated anti-cancer activity of FPL-Pac-Top was attributed to multiple features viz. thermosensitivity, long circulatory nature and targetability. Such approach could be a paradigm chemotherapeutic approach for safe and effective targeting of cancer.

• Ovarian cancer
• ovcar-3
• paclitaxel
• thermo-sensitive liposomes
• topotecan

Acknowledgements

We are highly thankful to Dr. Dhiraj Khattar (Director, Formulation Development & Delivery Systems), Fresenius Kabi Oncology Ltd.; Haryana (India) for providing the gift samples of Pac and Top. We are also gratified to Mr. Prakash Arora (GE Healthcare, India) for gifting Hi-Trap® columns.

Declaration of interest

Financial support (A. J.) was obtained from University Grant Commission (UGC), Delhi as Junior Research Fellowship (JRF) to Mr. Ankit Jain. The authors declare no competing financial interest, direct or indirect, in the subject matter or materials discussed in the article.

Supplementary material available online

Supplementary Figure S1