Apigenin-Loaded PLGA-DMSA Nanoparticles: A Novel Strategy to Treat Melanoma Lung Metastasis

Abstract

The flavone apigenin (APG), alone as well as in combination with other chemotherapeutic agents, is known to exhibit potential anticancer effects in various tumors and inhibit growth and metastasis of melanoma. However, the potential of apigenin nanoparticles (APG-NPs) to prevent lung colonization of malignant melanoma has not been well investigated. APG-loaded PLGA-NPs were surface-functionalized with meso-2,3-dimercaptosuccinic acid (DMSA) for the treatment of melanoma lung metastasis. DMSAconjugated APG-loaded NPs (DMSA-APG-NPs) administered by an oral route exhibited sustained APG release and showed considerable enhancement of plasma half-life, C max value, and bioavailability compared to APG-NPs both in plasma and the lungs. DMSAconjugated APG-NPs showed comparably higher cellular internalization in B16F10 and A549 cell lines compared to that of plain NPs. Increased cytotoxicity was observed for DMSA-APG-NPs compared to APG-NPs in A549 cells. This difference between the two formulations was lower in B16F10 cells. Significant depolarization of mitochondrial transmembrane potential and an enhanced level of caspase activity were observed in B16F10 cells treated with DMSA-APG-NPs compared to APG-NPs as well. Western blot analysis of various proteins was performed to understand the mechanism of apoptosis as well as prevention of melanoma cell migration and invasion. DMSA conjugation substantially increased accumulation of DMSA-APG-NPs given by an intravenous route in the lungs compared to APG-NPs at 6 and 8 h. This was also corroborated by scintigraphic imaging studies with radiolabeled formulations administered by an intravenous route. Conjugation also allowed comparatively higher penetration as evident from an in vitro three-dimensional tumor spheroid model study. Finally, the potential therapeutic efficacy of the formulation was established in experimental B16F10 lung metastases, which suggested an improved bioavailability with enhanced antitumor and antimetastasis efficacy of DMSA-conjugated APG-NPs following oral administration.

Development and Optimization of Hybrid Polymeric Nanoparticles of Apigenin: Physicochemical Characterization, Antioxidant Activity and Cytotoxicity Evaluation

“…The cell line viability study reported by different researchers, reported marked activity of AN in different cell lines. Sen et al, formulated AN-PLGA nanoparticles and exhibited 7.8 and 10.8 times less IC 50 than the pure drug against a lung cancer cell line (B16F10 and A549) [ 53 ]. In another study, Zhai et al, formulated and exhibited approximately 5-fold lesser IC 50 value against HepG2 and MCF-7 cell lines than pure AN solution [ 45 ].…”

Chemotherapeutic effects of Apigenin in breast cancer: Preclinical evidence and molecular mechanisms; enhanced bioavailability by nanoparticles

“…Therefore, new formulations or methods should be developed to improve solubility of AP and its bioavailability [86] . Numerous kinds of nanomaterials such as metallic–based nanomaterials, lipid-based and polymeric nanoparticles were developed in order to the highly effective delivery of AP [86] , [87] , [88] . The oral bioavailability of AP nanoparticles was about 5 fold upper compared to the naked AP, and this formulation shows no toxic outcome on the organs of mice [89] .…”

“…The results showed DMSA-conjugated flavone AP causes the COX-2 expression to be down regulated COX-2 expression in B16F10 cells. In fact, decrease in the COX-2 level can be an inhibitor of melanoma cell invasion [88] . Encapsulated AP with nanomaterials such as PLGA showed enhanced effectiveness in treatment of cancer.…”

Drug Delivery Systems and Flavonoids: Current Knowledge in Melanoma Treatment and Future Perspectives

“…Apigenin (Figure 2d) is mainly found in fruits and vegetables and can be isolated from the buds and flowers of Hypericum perforatum [52,64]. Apigenin can induce the apoptotic process in melanoma cells by activation of mitochondrial apoptotic pathway caused by alterations in mitochondrial membrane and increased activity of caspases [12,65]. Furthermore, one study found apigenin caused DNA fragmentation indicating an early apoptotic stage [65].…”

“…Apigenin can induce the apoptotic process in melanoma cells by activation of mitochondrial apoptotic pathway caused by alterations in mitochondrial membrane and increased activity of caspases [12,65]. Furthermore, one study found apigenin caused DNA fragmentation indicating an early apoptotic stage [65]. In another study, it was shown that apigenin decreased the invasion of cells in vitro and inhibited melanoma growth and metastatic potential in vivo [54].…”