Conveying a newly designed hydrophilic anti-human thymidylate synthase peptide to cisplatin resistant cancer cells: are pH-sensitive liposomes more effective than conventional ones?

Abstract

Context: LR-peptide, a novel hydrophilic peptide synthetized and characterized in previous work, is able to reduce the multi-drug resistance response in cisplatin (cDPP) resistant cancer cells by inhibiting human thymidylate synthase (hTS) overexpressed in several tumors, including ovarian and colon-rectal cancers, but it is unable to enter the cells spontaneously.

Objective: The aim of this work was to design and characterize liposomal vesicles as drug delivery systems for the LR peptide, evaluating the possible benefits of the pH-responsive feature in improving intracellular delivery.

Materials and methods: For this purpose, conventional and pH-sensitive liposomes were formulated, compared regarding their physical-chemical properties (size, PDI, morphology, in vitro stability and drug release) and studied for in vitro cytotoxicity against a cDDP-resistant cancer cells.

Results and discussion: Results indicated that LR peptide was successfully encapsulated in both liposomal formulations but at short incubation time only LR loaded pH-sensitive liposomes showed cell inhibition activity while for long incubation time the two kinds of liposomes demonstrated the same efficacy.

Conclusions: Data provide evidence that acidic pH-triggered liposomal delivery is able to significantly reduce the time required by the systems to deliver the drug to the cells without inducing an enhancement of the efficacy of the drug.

Keywords:

• Hydrophilic peptide
• pH sensitive liposomes
• cancer cells
• human thymidylate synthase
• endosomal escape

Acknowledgments

The authors are grateful to Dr. D. Pinetti and Dr. M. Tonelli (Centro Interdipartimentale Grandi Strumenti, University of Modena and Reggio Emilia) for their valuable technical support. The authors acknowledge the Fondazione Cassa di Risparmio di Modena for funding the HPLC-ESI-TQ system at the Centro Interdipartimentale Grandi Strumenti (CIGS).

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This work was financially supported by Fondazione di Vignola (Vignola, Italy) grant to E. Leo. This work is also supported in part by AIRC-2010, IG 10474 and AIRC-2015, IG 16977 grants to M.P. Costi.