Exosomes for the Enhanced Tissue Bioavailability and Efficacy of Curcumin

Abstract

Exosomes are extracellular microvesicles with a particle size of 30-100 nm and carry a cargo of proteins, lipids, RNA, and DNA. Their properties of shuttling in-and-out of the cells suggest that these particles can be exploited as a nano drug carrier. In this manuscript, we show that curcumin can be delivered effectively using milk-derived exosomes. Curcumin when mixed with exosomes in the presence of 10% ethanol:acetonitrile (1:1) provided a drug load of 18-24%, and the formulation stored at - 80°C was stable for 6 months as determined by particle size analysis, drug load, and antiproliferative activity. The uptake of exosomes by cancer cells involved caveolae/clathrin-mediated endocytosis. Oral administration of exosomal curcumin (ExoCUR) in Sprague-Dawley rats demonstrated 3-5 times higher levels in various organs versus free agent. ExoCUR showed enhanced antiproliferative activity against multiple cancer cell lines including, breast, lung, and cervical cancer compared with the free curcumin. ExoCUR showed significantly higher anti-inflammatory activity measured as NF-κB activation in human lung and breast cancer cells. To determine in vivo antitumor activity, nude mice bearing the cervical CaSki tumor xenograft were treated with ExoCUR by oral gavage, curcumin diet, exosomes alone, and PBS as controls. While curcumin via dietary route failed to elicit any effect, exosomes had a modest (25-30%) tumor growth inhibition. However, ExoCUR showed significant inhibition (61%; p < 0.01) of the cervical tumor xenograft. No gross or systemic toxicity was observed in the rats administered with the exosomes or ExoCUR. These results suggest that exosomes can be developed as potential nano carriers for delivering curcumin which otherwise has encountered significant tissue bioavailability issues in the past.

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., ).…”

“…According to more than 30 studies, from different teams around the world, milk EVs resisted in vitro digestion (Benmoussa et al., ; Kahn et al., ; Liao et al., ; Rani et al., ; Shandilya et al., ; Vashisht et al., ) were internalized by recipient cells upon co‐incubation (Admyre et al., , 2008; Aqil et al., , ; Badawy et al., ; Golan‐Gerstl et al., ; Hock et al., ; Kahn et al., ; Liao et al., ; Maburutse, Park, Oh, & Kim, ; Martin et al., ; Matsuda & Patel, ; Mobley et al., ; Munagala et al., ; Naslund et al., ; Qin et al., ; Vashisht, Rani, Onteru, & Singh, ; Yu et al., ), transduced through the intestinal wall in vitro (Rani et al., ; Shandilya et al., ; Wolf et al., ), and were detected in animal models after ingestion (Manca et al., ; Munagala et al., ) or intravenous injection (Somiya, Yoshioka, & Ochiya, ).…”

“…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., ).…”

Therapeutic use of curcumin‐encapsulated and curcumin‐primed exosomes

“…With oral or intraperitoneal administration of 100 mg/kg body weight curcumin, a plasma concentration of 1,250 ng/ml in 30 min is achieved (5–10 times that of administration of curcumin alone) that persists for 12 hr (Sun et al, ). Several other studies confirm that the incorporation of curcumin into exosomes increases the solubility, the stability, and the bioavailability of curcumin (Aqil, Munagala, Jeyabalan, Agrawal, & Gupta, ; Kalani, Kamat, Kalani, & Tyagi, ; Mandal, ; Sun et al, ; Vashisht, Rani, Onteru, & Singh, ). Exosomes have been shown to be safe and non‐cytotoxic; their high target specificity and high drug carrying capacity makes their use an effective and applicable method to increase the bioavailability and solubility of therapeutic agents and can be superior to synthetic nanoparticles as a delivery device (Sun et al, , ).…”

Exosomes as Theranostics for Lung Cancer

“…The complex was made by mixing curcumin with exosomes in the presence of 10% ethanol:acetonitrile (1:1) to form a complex called ExoCUR. Upon oral administration, the curcumin complex produced significantly higher antiinflammatory response, as measured through NF-κB activation in human lung and breast cancer cells (Aqil, Munagala, Jeyabalan, Agrawal, & Gupta, 2017). …”