Exosomal formulation of anthocyanidins against multiple cancer types

Abstract

Over the last two decades, berries and berry bioactives, particularly anthocyanins and their aglycones anthocyanidins (Anthos) have demonstrated excellent anti-oxidant, anti-proliferative, apoptotic and anti-inflammatory properties. However, their physicochemical and pharmacokinetic limitations such as, low permeability, and poor oral bioavailability are considered as unfavorable properties for development as drugs. Therefore there is a need to develop systems for efficient systemic delivery and robust bioavailability. In this study we prepared nano-formulation of bilberry-derived Anthos using exosomes harvested from raw bovine milk. Exosomal formulation of Anthos enhanced antiproliferative and anti-inflammatory effects compared with the free Anthos against various cancer cells in vitro. Our data also showed significantly enhanced therapeutic response of exosomal-Anthos formulation compared with the free Anthos against lung cancer tumor xenograft in nude mice. The Anthos showed no signs of gross or systemic toxicity in wild-type mice. Thus, exosomes provide an effective alternative for oral delivery of Anthos that is efficacious, cost-effective, and safe, and this regimen can be developed as a non-toxic, widely applicable therapeutic agent.

Milk MicroRNAs in Health and Disease

“…Milk EVs have been extensively studied for their biological functions upon consumption (Agrawal et al., ; Aqil et al., ; Aqil, Munagala, Jeyabalan, Agrawal, & Gupta, ; Arntz et al., ; Badawy, El‐Magd, & AlSadrah, ; Leiferman et al., ; Matsuda & Patel, ; Munagala, Aqil, Jeyabalan, & Gupta, ; Munagala et al., ; Oliveira et al., , 2017) and numerous studies have reported that milk EVs are bioaccessible (survive digestion; Benmoussa et al., ; Kahn et al., ; Liao et al., ; Rani et al., ; Shandilya, Rani, Onteru, & Singh, ; Vashisht, Rani, Onteru, & Singh, ) and bioavailable (Le Doare et al., ; Wang et al., ; Zempleni, ; Zempleni et al., ).…”

“…Twenty‐one studies involving milk EVs from humans, rat, camels, and most often cow milks reported milk EVs bioactivity in vitro on cells (Admyre et al., ; Aqil et al., , ; Badawy et al., ; Golan‐Gerstl et al., ; Hock et al., ; Martin et al., ; Matsuda & Patel, ; Mobley et al., ; Munagala et al., ; Naslund et al., ; Qin et al., ; Vashisht et al., ; Yu et al., ) and in vivo in animal models (Agrawal et al., ; Aqil et al., , ; Badawy et al., ; Leiferman et al., ; Munagala et al., ; Munagala et al., ; Somiya et al., ).…”

Prevention and treatment of familial adenomatous polyposis and colorectal cancer by bilberry-derived anthocyanidins.

“…Additional mechanistic studies are planned to clearly elucidate the specifics of the pathway(s). We also plan to examine the effects of These results correspond with our previous findings for other drugs delivered using exosomes [104]. Therefore, the results support our initial hypothesis that exosomal delivery will improve Anthos potency presumably due to increased bioavailability and stability of Anthos.…”

“…These results suggest that colostrum exosomes possess no in vitro toxicity to the normal cells and that they possess an intrinsic activity against colon cancer cells specifically. This "internal payload" effect is an exciting feature that our lab has also identified for other cancers such as breast and lung cancers [104].…”

Exosomes as Theranostics for Lung Cancer

“…However, due to their poor bioavailability and retention, these compounds cannot be used efficiently. In a recent study, Munagala et al attempted to encapsulate these compounds in exosomal lumen and showed enhanced therapeutic effect in cancer cells and in lung cancer xenografts in nude mice, suggesting the benefit of using exosomes as drug delivery vehicles (Munagala et al, 2017). …”