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A novel microfluidic liposomal formulation for the delivery of the SN-38 camptothecin: characterization and in vitro assessment of its cytotoxic effect on two tumor cell lines

Authors Casadó A, Sagristá ML, Mora M

Received 23 March 2018

Accepted for publication 5 May 2018

Published 11 September 2018 Volume 2018:13 Pages 5301—5320

DOI https://doi.org/10.2147/IJN.S166219

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Alexander Kharlamov

Peer reviewer comments 3

Editor who approved publication: Dr Thomas Webster


Ana Casadó,1,2 M Lluïsa Sagristá,1 Margarita Mora1

1Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain; 2Communication and CSR Department, Hospital Clinic of Barcelona, Barcelona, Spain

Purpose: Irinotecan (CPT-11) and SN-38 – its active metabolite – are alkaloid-derived topoisomerase I interactive compounds widely used in various cancer therapy protocols. To solve the problems associated with the instability of their lactone ring at physiological pH and with the extreme insolubility of SN-38, the development of delivery carriers (eg, liposomes) has been considered a subject of unquestionable medical interest. This article focuses on the development of an alternative protocol to the classical lipid-film hydration procedures to obtain a pharmaceutical formulation for SN-38.
Methods: SN-38-loaded liposomes (SN-38lip) were produced by microemulsification, without a prior lipid-film preparation step, and characterized by different methods. Formulation parameters were determined by photon correlation spectroscopy, and the SN-38 entrapment efficiency was evaluated by absorbance spectroscopy. SN-38lip was obtained as a dry, white powder by lyophilization. MTT and LDH assays were conducted to assess the cytotoxic effect of SN-38, both in liposomal (SN-38lip) and solubilized form (SN-38sol); flow cytometry was used to quantify SN-38 uptake and to analyze cell-cycle phase distribution after drug exposure.
Results: Microfluidic, stable, and controlled sized, negatively charged liposomes, with high SN-38 incorporation efficiency into egg yolk phosphatidylcholine (EPC)/L-α-dioleoyl-phospathidylserine (DOPS) (9:1) vesicles (SN-38lip), were prepared. A lyophilized powder of SN-38lip, easily reconstitutable while retaining physicochemical parameters, was finally obtained. The efficacy of SN-38lip was assessed by in vitro studies with two tumor cell lines (HeLa and Caco-2) and compared with that of SN-38sol. It demonstrated the highest uptake of SN-38lip, in accordance with its highest cytotoxicity effect, in comparison with that of SN-38sol. In addition, different cell-cycle alterations were induced in both cell lines by the liposomal formulation.
Conclusion: The results highlight the potential usefulness of the procured SN-38 liposomal formulation and provide the basis for conducting in vivo studies that allow the development of alternative strategies for colorectal cancer treatment.

Keywords: microfluidic liposomes, drug delivery, SN-38, cytotoxicity, drug uptake, cell-cycle analysis

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