Mitochondria targeted liposomes of metformin for improved anticancer activity: Preparation and evaluation

Abstract

In recent times, mitochondria have emerged as an effective target for treatment of cancer because of their prominent role in maintaining cellular homeostasis. Metformin hydrochloride (MET), an antidiabetic drug has been reported to be effective against several types of cancers, primarily by acting on mitochondria. So, enabling mitochondria targeted delivery of MET could be an effective strategy for successful chemotherapy. Objective of the study was to develop mitochondria targeted liposomes (Mito-liposomes) of MET for improved therapy of cancer and thereby enable its repurposing for treatment of cancer.In the first step, mitochondria targeting lipid was synthesized by conjugating DPPE (Dipalmitoyl phosphatidyl ethanolamine) with triphenylphosphonium (TPP), a widely reported mitochondria targeting ligand; the synthesized targeting lipid (DPPE-TPP) was confirmed by IR and NMR. Simple liposomes were prepared by thin film hydration technique, wherein Tween 80 was used to maximize MET entrapment; concentrations of Tween 80 and MET were optimized to achieve particle size in the range of 60–100 nm and maximum MET entrapment. To prepare MET Mito-liposomes, the same optimized method was used by replacing 20 μmoles of Lipoid S-100 with DPPE-TPP for mitochondria targeting ability. The MET Mito-liposomes were characterized for various physicochemical properties. Particle size of MET Mito-liposomes were found to be 85.28 ± 0.86 nm with zeta potential of 29.8 ± 1.47 mV. The liposomes and Mito-liposomes provided sustained release of MET for 12 h, compared to 2 h in case of free drug. Evaluation of anticancer activity on HeLa cells was assessed by MTT assay; IC50 values indicated around 15 fold increase in potency of MET Mito-liposomes as compared to free MET. This increased potency may be attributed to mitochondria specific delivery, wherein the Mito-liposomes mediate their activity via mitochondria. In conclusion, targeted delivery of MET to the Mitochondria through Mito-liposomes can provide a novel and versatile approach to achieve improved anticancer activity.