Transferrin‐bearing liposomes entrapping plumbagin for targeted cancer therapy

Abstract

The therapeutic potential of plumbagin, a naphthoquinone extracted from the officinal leadwort with anticancer properties, is hampered by its failure to specifically reach tumours at a therapeutic concentration after intravenous administration, without secondary effects on normal tissues. Its use in clinic is further limited by its poor aqueous solubility, its spontaneous sublimation, and its rapid elimination in vivo . We hypothesize that the entrapment of plumbagin within liposomes grafted with transferrin, whose receptors are overexpressed on many cancer cells, could result in a selective delivery to tumours after intravenous administration. The objectives of this study were therefore to prepare and characterize transferrin‐targeted liposomes entrapping plumbagin and to evaluate their therapeutic efficacy in vitro and in vivo . The entrapment of plumbagin in transferrin‐bearing liposomes led to an increase in plumbagin uptake by cancer cells and improved antiproliferative efficacy and apoptosis activity in B16‐F10, A431, and T98G cell lines compared with that observed with the drug solution. In vivo, the intravenous injection of transferrin‐bearing liposomes entrapping plumbagin led to tumour suppression for 10% of B16‐F10 tumours and tumour regression for a further 10% of the tumours. By contrast, all the tumours treated with plumbagin solution or left untreated were progressive. The animals did not show any signs of toxicity. Transferrin‐bearing liposomes entrapping plumbagin are therefore highly promising therapeutic systems that should be further optimized as a therapeutic tool for cancer treatment.

Perspectives on mechanistic implications of ROS inducers for targeting viral infections

“…Although Plumbagin has not been evaluated in humans, results from in vivo experiments reported non-toxic effects along with slight weight loss at 2 mg/kg body weight (intraperitoneal administration for 5 days/week for 3 weeks) ( Cao et al, 2018 ; Sakpakdeejaroen et al, 2019 ; Sandur et al, 2006 ). Further experiments are required to determine the minimal effective dose of Plumbagin required for achieving efficient degradation of viral RNA activity in humans.…”

Liposome Delivery of Natural STAT3 Inhibitors for the Treatment of Cancer

“…Anticancer effects of plumbagin have been documented in several types of cancers, including breast, lung, prostate, cervical, liver, colon, brain, and melanoma [103]. These effects have been attributed to numerous biological and signaling pathways, including suppression of STAT3, NF ‐ κB, MAPK, and AKT/mTOR, and induction of p38, p53, JNK, ROS, and NRF2ARE, among others [39,40,104]. The practicality of this compound as a therapy is limited by its toxicity, poor aqueous solubility (79 μg/mL), and poor bioavailability [104].…”

“…Liposome formulations are composed primarily of DSPE-PEG and cholesterol, showing encapsulation efficiencies ranging from 30% to 65%, and increased water solubility of 300 mg/mL [40]. Plumbagin has been co-encapsulated in several formulations of pegylated liposomes, containing cholesterol [104], celecoxib (COX-2 inhibitor) [39], or transferrin, to target receptors [104], with encapsulation efficiencies all above 60% [39,40,104]. In vitro studies using liposomal plumbagin in several cancer cell lines including human melanoma [39], murine melanoma [104], human epidermoid carcinoma [104], and human glioblastoma [104] showed increased uptake by cancer cells and improved antiproliferative efficacy and apoptosis activity compared to drug alone.…”

“…Plumbagin has been co-encapsulated in several formulations of pegylated liposomes, containing cholesterol [104], celecoxib (COX-2 inhibitor) [39], or transferrin, to target receptors [104], with encapsulation efficiencies all above 60% [39,40,104]. In vitro studies using liposomal plumbagin in several cancer cell lines including human melanoma [39], murine melanoma [104], human epidermoid carcinoma [104], and human glioblastoma [104] showed increased uptake by cancer cells and improved antiproliferative efficacy and apoptosis activity compared to drug alone. Furthermore, plumbagin was shown to inhibit IL-6/STAT3 signaling in large cell lung cancer cells and in esophageal squamous cell carcinoma in vitro [105,106].…”

“…Liposomal plumbagin inhibited tumor growth by up to 75% in B16 models [39,40,104] and by 72% in UACC xenograft mice when treated in combination with celecoxib [39]. Furthermore, treatment with transferrin receptor targeted liposomes encapsulating plumbagin resulted in complete eradication of tumors in 10% of B16-F10 mice [104]. These studies indicate liposome encapsulation improves therapeutic efficacy of plumbagin alone or in combination with other therapies.…”