Antitumor Effect of Hyperoside Loaded in Charge Reversed and Mitochondria-Targeted Liposomes

Abstract

Introduction Hyperoside (HYP), a flavonol glycoside compound, has been shown to significantly inhibit the proliferation of malignant tumors. Mitochondria serve as both “energy factories” and “suicide weapon stores” of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy. Objective We report a novel dual-functional liposome system possessing both extracellular charge reversal and mitochondrial targeting properties to enhance drug accumulation in mitochondria and trigger apoptosis of cancer cells. Methods L-lysine was used as a linker to connect 2,3-dimethylmaleic anhydride (DMA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to yield a new compound, DSPE-Lys-DMA (DLD). Then, DLD was mixed with other commercially available lipids to form charge reversed and mitochondria-targeted liposomes (DLD-Lip). The size, morphology, zeta potential, serum stability, and protein adsorption of the HYP loaded DLD-Lip (HYP/DLD-Lip) were measured. The release profile, cellular uptake, in vitro and in vivo toxicity, and anticancer activity of HYP/DLD-Lip were investigated. Results The results showed that the mean diameter of the liposomes was less than 200 nm. The zeta potential of the liposomes was negative at pH 7.4. However, the zeta potential was positive at weak acidic pH values with the cleavage of the DMA amide. The charge reversion of HYP/DLD-Lip facilitated the cellular internalization and mitochondrial accumulation for enhanced antitumor effect. The strongest tumor growth inhibition (TGI 88.79%) without systemic toxicity was observed in DLD/HYP-Lips-treated CBRH-7919 tumor xenograft BALB/C mice. Conclusion The charge reversed and mitochondria-targeted liposomes represented a promising anticancer drug delivery system for enhanced anticancer therapeutic efficacy.

Multifunctional Mitochondria-Targeting Nanosystems for Enhanced Anticancer Efficacy

“… Feng et al (2021) constructed a smart, dual-functional liposome delivery system having characteristics of both pH-responsive charge reversal and mitochondria targeting to facilitate agent accumulation in mitochondria and inhibit the growth of tumor cells. Briefly, L-lysine acted as a linker to link 2,3-dimethylmaleic anhydride (DMA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to synthesize a pH-responsive lipid derivative (named DLD).…”

Calcium Orthophosphate in Liposomes for Co-Delivery of Doxorubicin Hydrochloride/Paclitaxel in Breast Cancer

“…Liposomes composed of natural phospholipids and cholesterol have been widely investigated as anti-cancer drug carriers for the delivery of hydrophobic drugs. Liposomes exhibit excellent biocompatibility and biodegradation, and drugs delivered by liposomes can accumulate at tumor sites due to their EPR effect. − Despite their excellent properties, applications of liposomes with a size smaller than 100 nm are often limited due to the poor stability caused by spontaneous fusion between liposomes, resulting in load loss and unsatisfactory mixing. A number of studies have been conducted by incorporating polyethylene glycol (PEG) into lipid vesicles to prevent engulfment by the mononuclear capture system and reticuloendothelial system, by which a longer circulation time can be achieved in the body.…”

Protein Engineering of PhUGT, a Donor Promiscuous Glycosyltransferase, for the Improved Enzymatic Synthesis of Antioxidant Quercetin 3-O-N-Acetylgalactosamine

“…Hyperoside (quercetin 3- O -β- d -galactoside, 2 ) is a frequently documented quercetin 3- O -glycoside (Q3G) for its numerous pharmacological functions (Figure S1), like antioxidative action, − antitumor activity, − anti-inflammatory effect, − and antiviral property. − In addition, hyperoside is also a dietary flavonoid widely distributed in vegetables, fruits, and plant-based beverages. − Hyperoside is thus regarded as one of the important sources of innovative drugs and dietary flavonoids.…”