Delivery of acetogenin-enriched Annona muricata Linn leaf extract by folic acid-conjugated and triphenylphosphonium-conjugated poly(glycerol adipate) nanoparticles to enhance toxicity against ovarian cancer cells

The study demonstrated the fabrication of new poly(glycerol adipate) (PGA) nanoparticles decorated with folic acid (FOL-PGA) and triphenylphosphonium (TPP-PGA) and the potential on the delivery of acetogenin-enriched Annona muricata Linn leaf extract to ovarian cancer cells. FOL-PGA and TPP-PGA were successfully synthesized and used to fabricate FOL-decorated nanoparticles (FOL-NPs) and FOL-/TPP- decorated nanoparticles (FOL/TPP-NPs) by blending two polymers at a mass ratio of 1:1. All nanoparticles had small size of around 100 nm, narrow size distribution and high negative surface charge about -30 mV. The stable FOL/TPP-NPs showed highest drug loading of 14.9 ± 1.9% at 1:5 ratio of extract to polymer and reached to 35.8 ± 2.1% at higher ratio. Both nanoparticles released the extract in a biphasic sustained release manner over 5 days. The toxicity of the extract to SKOV3 cells was potentiated by FOL-NPs and FOL/TPP-NPs by 2.0 - 2.6 fold through induction of cell apoptosis. FOL/TPP-NPs showed lower IC₅₀ and higher cellular uptake as compared to FOL-NPs. FOL-NPs exhibited folate receptor-mediated endocytosis. FOL/TPP-NPs provided more advantages than FOL-NPs in terms of stability in physiological fluid, uptake efficiency and targeting ability to mitochondria and showed a promising potential PGA platform for targeted delivery of herbal cytotoxic extracts.