Sensitization of sarcoma tumors with short chain sphingolipid liposomes

Introduction: Multidrug resistance (MDR) is one of the main challenges in cancer chemotherapy. The overexpression of multidrug transporters like P glycoprotein (Pgp) is a common cause of resistance1. Liposomes enriched in... [ view full abstract ]

Introduction: Multidrug resistance (MDR) is one of the main challenges in cancer chemotherapy. The overexpression of multidrug transporters like P glycoprotein (Pgp) is a common cause of resistance1. Liposomes enriched in short chain sphingolipids (SCS) may interact with cancer cell membranes improving permeability to encapsulated drugs2-4. Our aim is to evaluate the effect of SCS liposomes in resistant tumor cells with the aim of improve their chemo-sensitivity.

Methods: MES-SA/MX2 is a resistant human utero sarcoma cell line derived from MES-SA, with Pgp over-expression. Liposomes loaded with doxorubicin were enriched (SCS-LP) or not (LP) with SCS, characterized and incubated with both cell lines to evaluate drug internalization and cytotoxic effect. Biodistribution, pharmacokinetics and efficacy was evaluated in xenograft tumor bearing mice with the above mentioned sensitive and resistant cell lines.

Results: In vitro assays showed a higher effect of SCS-LP in MES-SA/MX2, which was related with an increase in the sensitivity to doxorubicin. Actually SCS-LP were able to revert their resistance compared to sensitive cell results. On the MES-SA cell line all liposomes had a similar effect under all conditions tested. A higher accumulation of doxorubicin in resistant tumors after SCS-LP administration was observed in mice bearing these tumors subcutaneously, compared to the sensitive tumor and LP. Besides, nuclear accumulation of doxorubicin was superior in resistant tumors under SCS-LP treatment. Finally, enriched liposomes showed a faster clearance but were able to control the tumor growth more efficiently than non SCS liposomes in resistant tumors, whereas in sensitive tumor no difference was found.

Discussion: Based on our in vitro and in vivo results we conclude that the use of doxorubicin-SCS-LP reverts the resistance of MES-SA/MX2. Our data indicates that sensitivity to the drug is improved through bypassing or compensation of Pgp activity. Although the formulation needs to be optimized, e.g. to avoid serum instability, these liposomes represent a very promising tool to treat cancer, especially MDR tumors.

1. Adv Drug Deliv Rev. 2013 Nov;65(13-14):1852-65.
2. J Biomed Nanotechnol. 2016 Apr;12(4):630-44.
3. Pharm Res. 2015 Apr;32(4):1354-67.
4. Pharm Res. 2013 Jul;30(7):1883-95.