PhD thesis of Daiva Vozgirdaitė (Immunoliposomes with 2 API against TNBC)

Objectives - v2

Summary

In this work antidiabetic drug metformin (Met), recently associated with reduced cancer risks, and chemotherapeutic drug doxorubicin (Dox) were entrapped in lipid-based nanocarriers – liposomes (LPs) to achieve enhanced therapy of Triple-Negative Breast Cancer.

First, Met was entrapped in LPs resulting in LPs < 200 nm, low polydispersity index (0.1) and negatively charged surface (-20 mV). Met-LPs showed lover Adenosine Triphosphate (ATP) levels (IC50 of 1 mM after 72 h for MDA-MB-468 cells), causing an arrest in TNBC cell proliferation.

Second, TROP 2 targeting single-chain variable fragments (scFvs) were grafted on Met-LPs, which has no effect on physicochemical properties of LPs. The grafting increased the cellular internalization by TROP 2 overexpressing MDA-MB-468 cells 4-fold in 2D, and 9-fold in 3D in vitro models. In addition, the efficacy of Met in ImmunoLPs compared to LPs was increased two times in the ability to reduce ATP levels and spheroid growth.Finally, Dox was incorporated in Immuno-LPs. The combination treatment consisting of Met-ImmunoLPs and Dox-ImmunoLPs showed a rapid reduction of MDA-MB-468 cell viability in 2D and 3D in vitro models, and induction of cell death, when compared to Met/Dox LPs.

Financial support: Labex MabImprove grant (ANR-10-LABX-53-01)

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