Targeting Ovarian Cancer Cells Overexpressing CD44 with Immunoliposomes Encapsulating Glycosylated Paclitaxel.

Apriliana Cahya Khayrani,Juan Du,Yuhki Seno,Tsukasa Shigehiro,Maram H Zahra,Tadakatsu Mandai,Said M Afify,Miharu Oze,Aung Ko Ko Oo,Hagar A Abu Quora,Koki Fujita,Md Jahangir Alam,Hafizah Mahmud,Masaharu Seno,Anna Sanchez Calle,Nobuhiro Okada,Hiroki Hamada,Akimasa Seno

doi:10.3390/ijms20051042

Abstract

Paclitaxel (PTX) is one of the front-line drugs approved for the treatment of ovarian cancer. However, the application of PTX is limited due to the significant hydrophobicity and poor pharmacokinetics. We previously reported target-directed liposomes carrying tumor-selective conjugated antibody and encapsulated glycosylated PTX (gPTX-L) which successfully overcome the PTX limitation. The tubulin stabilizing activity of gPTX was equivalent to that of PTX while the cytotoxic activity of gPTX was reduced. In human ovarian cancer cell lines, SK-OV-3 and OVK18, the concentration at which cell growth was inhibited by 50% (IC50) for gPTX range from 15–20 nM, which was sensitive enough to address gPTX-L with tumor-selective antibody coupling for ovarian cancer therapy. The cell membrane receptor CD44 is associated with cancer progression and has been recognized as a cancer stem cell marker including ovarian cancer, becoming a suitable candidate to be targeted by gPTX-L therapy. In this study, gPTX-loading liposomes conjugated with anti-CD44 antibody (gPTX-IL) were assessed for the efficacy of targeting CD44-positive ovarian cancer cells. We successfully encapsulated gPTX into liposomes with the loading efficiency (LE) more than 80% in both of gPTX-L and gPTX-IL with a diameter of approximately 100 nm with efficacy of enhanced cytotoxicity in vitro and of convenient treatment in vivo. As the result, gPTX-IL efficiently suppressed tumor growth in vivo. Therefore gPTX-IL could be a promising formulation for effective ovarian cancer therapies.

Highlights

Ovarian cancer ranks the eighth cause of cancer death in women worldwide annually estimated to be 151,900 out of 238,700 new cases [1]
We successfully developed liposomes encapsulating glycosylated paclitaxel in the hydrophilic-core [11]. gPTX is a PTX derivative with a glucose moiety coupled at the 7-OH radical [12], and this modification enhanced the hydrophilicity of PTX allowing practically different solubility in the solvents mixed solvent of Cremophor EL®, ethanol, and phosphate buffered saline (PBS); in 12:12:76 ratio (CEP) and EG (40% ethylene glycol)
Since the overexpression of CD44 was only found in SK-OV-3 cells line, we considered it as representative of CD44-positive cells

Summary

Introduction

Ovarian cancer ranks the eighth cause of cancer death in women worldwide annually estimated to be 151,900 out of 238,700 new cases [1]. In the US as one of the typical developed countries, it ranks the fifth cause of lethal tumors among women, accounting for the seriousness in female gynecological cancers [2]. The standard treatment of progressive ovarian cancer is surgical resections followed by systemic chemotherapy [3,4]. Taxol treatment itself is followed by side effects such as hypersensitivity reactions, nephrotoxicity and neurotoxicity [8,9].

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Conclusion