Local Delivery of Cannabinoid-Loaded Microparticles Inhibits Tumor Growth in a Murine Xenograft Model of Glioblastoma Multiforme

Abstract

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) – the two major ingredients of marijuana – have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1∶1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.

The Combination of Cannabidiol and Δ9-Tetrahydrocannabinol Enhances the Anticancer Effects of Radiation in an Orthotopic Murine Glioma Model

“…This is as an area where there is a notable lack of information, as previous studies investigating the action of cannabinoids in glioma have only been carried out in xenograft models (13,14). Our hypothesis was that cannabinoids could support the cell killing effect of irradiation by engaging and/or priming apoptosis and autophagy mechanisms required for successful cell death.…”

“…This nonantagonistic interaction of CBD and THC, therefore, suggested that combining cannabinoids with other agents that share common pathways may be a viable strategy in a clinical setting; this may also include more conventional chemotherapies (4,11). Indeed, recent studies have highlighted that CBD and THC can combine successfully with other chemotherapy, namely temozolomide, to reduce the progression of glioma cells in a xenograft model (13,14).…”

“…This suggests that receptor activation by some of the cannabinoids may not be a requisite for anticancer activity (3), which highlights the possibility of using cannabinoids in a way that maximizes the anticancer action while simultaneously minimizing psychoactivity (11). In particular, the evidence of the anticancer activity of CBD has grown steadily these past few years (11)(12)(13)(14)(15). These studies have involved its use as a single agent or in combination with other cannabinoids or other treatment modalities, and have included a number of cancer types (5).…”

Efecto neuroprotector de los cannabinoides en las enfermedades neurodegenerativas

“…El mecanismo de acción antitumoral se basa en la capacidad de estos compuestos para: (i) promover la muerte apoptótica de las células cancerosas, (ii) inhibir la angiogénesis del tumor y (iii) reducir la migración de las células cancerosas. Se ha propuesto que la apoptosis inducida por éste se basa en un aumento de la producción de especies reactivas de oxígeno, un mecanismo que parece funcionar también en células de glioma 10 .…”

Cannabinoid receptor activation inhibits cell cycle progression by modulating 14-3-3β

“…Cannabinoids promote tumor regression by modulating signaling pathways involved in processes such as cell cycle progression, cell proliferation, cell death, angiogenesis and metastasis, migration and invasion, and epithelialmesenchymal transition [5,[36][37][38]. It is well known that cannabinoids are capable of inducing cell cycle arrest in all phases [39].…”