Development of a New Nanocarrier for Dietary Garcinol: Characterization and In Vitro Efficacy Evaluation Using Breast Cancer Stem Cells Grown in Hypoxia

Abstract

Garcinol (GA), a polyisoprenylated benzophenone derivative, is one of the major phytochemicals found in a number of fruits of Garcinia. This study aimed to develop a new nanodelivery system comprising GA, hyaluronic acid (HA), and poly(lactic-co-glycolic acid) (PLGA) to actively target breast cancer stem cells (bCSCs) grown under hypoxic conditions. HA has been reported to show higher affinity for the cluster-determinant 44 receptor (CD44), while PLGA is an FDA-approved biodegradable polymer used in clinical applications. Nanoparticles (NPs) were prepared by emulsion solvent diffusion technique using DMAB as the emulsifier. Following preparation, particle size, surface charge, and polydispersity index of NPs were characterized. Antiproliferative effects of NPs were assessed by the WST-1 cell proliferation assay. Apoptotic effects of NPs were evaluated by the caspase-3/7 assay. Effects of prepared NPs on the expression of genes related to hypoxia-inducing factors (HIF-1α and HIF-2α) and notch ligands (DLL1 and Jagged1) were evaluated using real-time PCR. HA-coated garcinol-loaded NPs (HA-GA-NPs) showed greater antiproliferative effects in bCSCs grown under hypoxia. Moreover, HA-GA-NPs showed an improved cellular uptake via receptor-mediated endocytosis compared to non-HA-coated GA-NPs. Exposure to GA-HA-NPs resulted in a significant downregulation in hypoxia-inducing factors and notch pathway-related genes. Activation of caspase-3/7 confirmed the HA-GA-NPs can induce apoptosis in bCSCs. Overall findings of the study confirm that HA-GA-NPs can be considered as an effective nanodelivery system to target bCSCs grown under the hypoxic microenvironment.

Natural Products-Based Nanoformulations: A New Approach Targeting CSCs to Cancer Therapy

“…By downregulating hypoxia-inducible factors (HIF-1α and HIF-2α) and the Notch pathway to induce apoptosis and inhibit CSCs proliferation, garcinol nanoformulations were able to inhibit CD44+ breast CSCs growing in a hypoxic microenvironment. 152 …”

“…By downregulating hypoxia-inducible factors (HIF-1α and HIF-2α) and the Notch pathway to induce apoptosis and inhibit CSCs proliferation, garcinol nanoformulations were able to inhibit CD44+ breast CSCs growing in a hypoxic microenvironment. 152 Silibinin is a flavonoid compound isolated from the fruit and seeds of milk thistle (Silybum marianum L. Gaertn), and it has been widely used in clinical practice as a hepatoprotective drug. 153 In recent years, the anticancer and tumor preventive effects exhibited by silibinin have shown great potential for development and improved bioavailability with nanomaterials.…”

Recent Advances in Garcinia cambogia Nutraceuticals in Relation to Its Hydroxy Citric Acid Level. A Comprehensive Review of Its Bioactive Production, Formulation, and Analysis with Future Perspectives

“…It also showed enhanced cellular uptake via receptor-mediated endocytosis, and apoptosis potential confirmed by caspase-3/7 activation. 82 Moreover, pH-sensitive biodegradable nanoparticles has been formulated using garcinol, poly(lactic- co -glycolic acid), and Eudragit S100 (GAR-PLGA-ES100 NPs) as illustrated in Figure 3 . It specifically targeted the colonic pH where it releases the drug to exert its anti-inflammatory effect of potential for application in ulcerative colitis.…”

“…HA-GA-NPs exhibited higher antiproliferative activity using WST-1 cell proliferation assay (IC 50 5.54, 4.03, and 0.81 μg/mL at 24, 48, 72 h, respectively) compared to that of pure garcinol (IC 50 21.16, 17.06, 10.22 μg/mL, respectively). It also showed enhanced cellular uptake via receptor-mediated endocytosis, and apoptosis potential confirmed by caspase-3/7 activation . Moreover, pH-sensitive biodegradable nanoparticles has been formulated using garcinol, poly­(lactic- co -glycolic acid), and Eudragit S100 (GAR-PLGA-ES100 NPs) as illustrated in Figure .…”