Local Delivery of Cannabinoid-Loaded Microparticles Inhibits Tumor Growth in a Murine Xenograft Model of Glioblastoma Multiforme
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 (11 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.
Δ9-Tetrahydrocannabinol (THC), the main active component of the hemp plant Cannabis sativa , exerts a wide variety of biological effects by mimicking endogenous substances – the endocannabinoids – that bind to and activate specific cannabinoid receptors . So far, two G protein–coupled cannabinoid-specific receptors have been cloned and characterized from mammalian tissues: CB1, abundantly expressed in the brain and at many peripheral sites, and CB2, expressed in the immune system and also present in some neuron subpopulations and glioma cells , . One of the most active areas of research in the cannabinoid field is the study of the potential application of cannabinoids in the treatment of different pathologies , . Among these therapeutic applications, cannabinoids are being investigated as anti-tumoral agents , . Thus, cannabinoid administration curbs the growth of several types of tumor xenografts in rats and mice ,  including gliomas –. Based on this preclinical evidence, a pilot clinical trial has been recently run to investigate the anti-tumor action of THC on recurrent gliomas . The mechanism of THC anti-tumoral action relies on the ability of this compound to: (i) promote the apoptotic death of cancer cells (ii) to inhibit tumour angiogenesis and (iii) to reduce the migration of cancer cells .
Aside from THC, C. sativa produces approximately 70 other cannabinoids although, unlike THC, many of them exhibit little affinity for CB receptors , . Of interest, at least one of these components, namely cannabinol (CBD), has been shown to reduce the growth of different types of tumor xenografts including gliomas –. Although the mechanism of CBD anti-tumoral action has not been completely clarified yet, it has been proposed that CBD-induced apoptosis relies on an increased production of reactive oxygen species (ROS) , a mechanism that seems to operate also in glioma cells , . To note, co-administration of THC and CBD – an option that is being therapeutically explored also for other applcations , ; has been shown to promote cancer cell death and reduce the growth of glioma xenografts , .
One of the factors limiting the efficacy of anticancer treatments is the difficulty to reach effective concentration of antineoplasic agents at the tumour site. For example, the poor water solubility of certain anticancer agents such as paclitaxel or camptothecin hinders their application and complicates direct parenteral administration. In the case of cannabinoids, several pharmaceutical preparations have been developed and approved for cannabinoid administration including oral capsules of THC (Marinol®, Unimed Pharmaceuticals Inc.) and of its synthetic analogue nabilone (Cesamet®, Meda Pharmaceuticasl) and an oro-mucosal spray of standardized cannabis extract (Sativex®, GW Pharmaceuticals). These formulations have been approved for several clinical applications , . Specifically, cannabinoids are well-known to exert palliative effects in cancer patients , . The best-established use is the inhibition of chemotherapy-induced nausea and vomiting ,  (Marinol® and Cesamet®). Cannabinoids also inhibit pain, and Sativex® has been already approved in Canada and is currently subject of large-scale Phase III clinical trials for managing cancer-associated pain. However, from the perspective of the utilization of cannabinoid-based medicines as antineoplastic agents, one of the issues that needs to be clarified is whether systemic administration of cannabinoids allows reaching effective concentrations of these highly lipid soluble agents  at the tumor site without enhancing undesired side affects , .
Local administration of polymeric implants for interstitial sustained release of anti-neoplasic agents allows enhancing the concentration of anticancer active substances in the proximity of the tumour– and could be an alternative strategy to systemic delivery at least for certain types of cancer. The aim of the present study was therefore to evaluate the antitumor efficacy of biodegradable polymeric microparticles allowing the controlled release of the phytocannabinoids THC and CBD. Our findings show that administration of cannabinoid-loaded microparticles reduces the growth of glioma xenografts supporting that this method of administration could be exploited for the design of cannabinoid-based anticancer treatments.
Learn more here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3551920/