A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells

Abstract

There is currently no effective long-term treatment for ovarian cancer (OC) resistant to poly-chemotherapy regimens based on platinum drugs. Preclinical and clinical studies have demonstrated a strong association between development of Pt-drug resistance and increased thymidylate synthase (hTS) expression, and the consequent cross-resistance to the hTS inhibitors 5-fluorouracil (5-FU) and raltitrexed (RTX). In the present work, we propose a new tool to combat drug resistance. We propose to treat OC cell lines, both Pt-sensitive and -resistant, with dual combinations of one of the four chemotherapeutic agents that are widely used in the clinic, and the new peptide, hTS inhibitor, [D-Gln4]LR. This binds hTS allosterically and, unlike classical inhibitors that bind at the catalytic pocket, causes cell growth inhibition without inducing hTS overexpression. The dual drug combinations showed schedule-dependent synergistic antiproliferative and apoptotic effects. We observed that the simultaneous treatment or 24h pre-treatment of OC cells with the peptide followed by either agent produced synergistic effects even in resistant cells. Similar synergistic or antagonistic effects were obtained by delivering the peptide into OC cells either by means of a commercial delivery system (SAINT-PhD) or by pH sensitive PEGylated liposomes. Relative to non-PEGylated liposomes, the latter had been previously characterized and found to allow macrophage escape, thus increasing their chance to reach the tumour tissue. The transition from the SAINT-PhD delivery system to the engineered liposomes represents an advancement towards a more drug-like delivery system and a further step towards the use of peptides for in vivo studies. Overall, the results suggest that the association of standard drugs, such as cDDP and/or 5-FU and/or RTX, with the novel peptidic TS inhibitor encapsulated into PEGylated pH-sensitive liposomes can represent a promising strategy for fighting resistance to cDDP and anti-hTS drugs.

A bioinformatic analysis: the overexpression and clinical significance of FCGBP in ovarian cancer

“…Tumor microenvironment immune cells constitute a key factor of tumor tissues with increasing evidence supporting their clinicopathological significance in predicting survival status and therapeutic efficacy of tumor patients [ 14 – 17 ]. Specifically, the infiltration level of TAM accelerates the progression of ovarian cancer [ 18 , 19 ]. TAM consist primarily of M2 macrophages, likely due to exposure to complex factors in the tumor microenvironment [ 20 , 21 ].…”

Folic Acid–Peptide Conjugates Combine Selective Cancer Cell Internalization with Thymidylate Synthase Dimer Interface Targeting

“…We have recently shown that the proper drug combination sequence of cDDP:LR, RTX:LR, and 5-FU:LR, where LR was wrapped into a specific peptide delivery system or encapsulated into PEGylated pH-sensitive liposomes, was able to counteract resistance to cDDP and anti-hTS drugs. In particular, we observed that the simultaneous treatment or 24 h pretreatment of cells with the peptide followed by either agent produced synergistic effects even in resistant cells …”

“…In particular, we observed that the simultaneous treatment or 24 h pretreatment of cells with the peptide followed by either agent produced synergistic effects even in resistant cells. 57 In the present study, FA−LR is combined with concentrations of RTX in the low nanomolar range ( 10…”

“…In particular, we observed that the simultaneous treatment or 24 h pretreatment of cells with the peptide followed by either agent produced synergistic effects even in resistant cells. 57 …”

The Formation of Chitosan-Coated Rhamnolipid Liposomes Containing Curcumin: Stability and In Vitro Digestion

“…Currently, a number of researchers have proposed liposomal surface modifications as a way to overcome these limitations. Various polymers were successfully applied to improve the surface properties of liposomes, including synthetic polymers (pluronics and polyethylene glycol) [ 8 , 9 , 10 ] and natural polymer (peptide, protein, and polysaccharides) [ 11 , 12 ]. Among them, polysaccharides are the most extensively used polymers for liposome modification owing to non-toxicity, non-immunogenicity, good biocompatibility and biodegradability.…”