Nanoparticles of Metal-Organic Cages Overcoming Drug Resistance in Ovarian Cancer.

Han Wang,Yao-Rong Zheng,Zihan Qiu,Zhizhou Yue,Hala Daghlas,David J Bowers,Bansidhar Datta,Amarasooriya M D S Jayawardhana,He Liu

doi:10.3389/fchem.2019.00039

Abstract

A long-standing challenge in the treatment of ovarian cancer is drug resistance to standard platinum-based chemotherapy. Recently, increasing attention has been drawn to the use of self-assembled metal-organic complexes as novel therapeutics for cancer treatment. However, high hydrophobicity that is often associated with these structures lowers their solubility and hinders their clinical translation. In this article, we present a proof-of-concept study of using nanoprecipitation to formulate the hydrophobic metal-organic cages and facilitate their use in treating chemoresistant ovarian cancer. The Pt6L4 Cage 1 is an octahedral cage formed by self-assembly of six 1,10-phenanthroline-Pt(II) centers and four 2,4,6-tris(4-pyridyl)-1,3,5-triazine ligands (L). Cage 1 is able to trigger DNA damage and exhibits promising in vitro potency against a panel of human ovarian cancer cell lines. However, due to the large portion of aromatic components, this cage structure has very limited solubility in cell culture media (<20μM). Notably, upon nanoformulation by using fluorescein (2) and a pegylated anionic polymer (3), the concentration of Cage 1 can reach up to 0.4 mM. Production of the nanoparticles of metal-organic cages (nMOC) is driven by the formation of the 1:1 host-guest complex of 1 and 2 in aqueous solution, which then form nanoprecipitation in presence of poly glutamic acid-b-poly ethylene glycol (3). The resulted nMOC are about 100 nm in diameter, and they serve as a delivery platform that slowly releases the therapeutic content. The use of fluorescein facilitates monitoring cell entry of nMOC and drug release using flow cytometry. Finally, comparing to cisplatin, the nMOC exhibit comparable in vitro efficacy against a panel of human cancer cell lines, and notably, it shows a much lower resistance factor against chemoresistant ovarian cancer cell lines.

Highlights

Ovarian cancer is the most lethal gynecologic cancer and ranks as the fifth leading cause of death for women in the US
We have presented a novel design of formulating cytotoxic hydrophobic metal-organic cages to facilitate their use in treating chemoresistant ovarian cancer
We demonstrated that Cage 1, a cytotoxic hydrophobic metalorganic cage with low solubility, can be formulated into pegylated nanoparticles in presence of fluorescein (2) and MPEG5k-PGA50 (3)

Summary

Introduction

The FDA-approved platinum drugs, cisplatin and carboplatin, are widely used as the first line treatment for ovarian cancer patients in the US and worldwide (Kelland, 2007). The patients show good responses to these compounds, but after about 12–24 months, patients commonly develop cancer relapse with drug resistance. There are very few alternative treatment options after the development of drug resistance to these platinum compounds. The search of new drug candidates has largely focused on mononuclear metal complexes similar to structure of cisplatin, but there are rarely any clinically relevant breakthroughs (Wilson and Lippard, 2014; Zheng et al, 2014). Macromolecular polynuclear metal complexes emerges as a new type of therapeutic candidates to widen the spectrum of activity of current FDA-approved platinum drugs, studies of the therapeutic effects of such compounds are still limited (Farrell, 2015)

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Conclusion