Cannabidiol loaded extracellular vesicles sensitize triple-negative breast cancer to doxorubicin in both in-vitro and in vivo models

• Published in: International journal of pharmaceutics Vol. 607; p. 120943
• Main Authors: Patel, Nilkumar, Kommineni, Nagavendra, Surapaneni, Sunil Kumar, Kalvala, Anil, Yaun, Xuegang, Gebeyehu, Aragaw, Arthur, Peggy, Duke, Leanne C., York, Sara B., Bagde, Arvind, Meckes, David G., Singh, Mandip
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 25.09.2021
• Subjects: Breast Neoplasms - drug therapy; Cannabidiol; Cell Line, Tumor; Doxorubicin; Doxorubicin and triple negative breast cancer; Extracellular Vesicles; Female; Humans; Sensitization; Triple Negative Breast Neoplasms - drug therapy; EE; DDS; EVs; CBD; hUCMSCs; Extracellular vesicles; Cannabidiol; Doxorubicin and triple negative breast cancer; Sensitization; NTA; TNBC; DOX
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2021.120943

[Display omitted] •CBD EVs were successfully formulated for the first time with good entrapment efficiency and particle size.•Sustained release of CBD was observed from CBD EVs.•Fluorescent labelled EVs showed rapid intracellular and intratumoral uptake as determined by confocal microscopy.•CBD EVs (5 mg/kg) and DOX combination significantly reduced the tumor burden in MDA-MB-231 xenograft model of athymic nude mice.•CBD EVs sensitized the MDA-MB-231 tumors to DOX by decreasing inflammation, migration, metastasis and facilitating apoptosis. Extracellular Vesicles (EVs) were isolated from human umbilical cord mesenchymal stem cells (hUCMSCs) and were further encapsulated with cannabidiol (CBD) through sonication method (CBD EVs). CBD EVs displayed an average particle size of 114.1 ± 1.02 nm, zeta potential of −30.26 ± 0.12 mV, entrapment efficiency of 92.3 ± 2.21% and stability for several months at 4 °C. CBD release from the EVs was observed as 50.74 ± 2.44% and 53.99 ± 1.4% at pH 6.8 and pH 7.4, respectively after 48 h. Our in-vitro studies demonstrated that CBD either alone or in EVs form significantly sensitized MDA-MB-231 cells to doxorubicin (DOX) (*P < 0.05). Flow cytometry and migration studies revealed that CBD EVs either alone or in combination with DOX induced G1 phase cell cycle arrest and decreased migration of MDA-MB-231 cells, respectively. CBD EVs and DOX combination significantly reduced tumor burden (***P < 0.001) in MDA-MB-231 xenograft tumor model. Western blotting and immunocytochemical analysis demonstrated that CBD EVs and DOX combination decreased the expression of proteins involved in inflammation, metastasis and increased the expression of proteins involved in apoptosis. CBD EVs and DOX combination will have profound clinical significance in not only decreasing the side effects but also increasing the therapeutic efficacy of DOX in TNBC.