Receptor-targeted nanoparticles modulate cannabinoid anticancer activity through delayed cell internalization

Abstract

AbstractΔ9-tetrahydrocannabinol (Δ9-THC) is known for its antitumor activity and palliative effects. However, its unfavorable physicochemical and biopharmaceutical properties, including low bioavailability, psychotropic side effects and resistance mechanisms associated to dosing make mandatory the development of successful drug delivery systems. In this work, transferring (Tf) surface-modified Δ9-THC-loaded poly(lactide-co-glycolic) nanoparticles (Tf-THC-PLGA NPs) were proposed and evaluated as novel THC-based anticancer therapy. Furthermore, in order to assess the interaction of both the nanocarrier and the loaded drug with cancer cells, a double-fluorescent strategy was applied, including the chemical conjugation of a dye to the nanoparticle polymer along with the encapsulation of either a lipophilic or a hydrophilic dye. Tf-THC PLGA NPs exerted a cell viability decreased down to 17% vs. 88% of plain nanoparticles, while their internalization was significantly slower than plain nanoparticles. Uptake studies in the presence of inhibitors indicated that the nanoparticles were internalized through cholesterol-associated and clathrin-mediated mechanisms. Overall, Tf-modification of PLGA NPs showed to be a highly promising approach for Δ9-THC-based antitumor therapies, potentially maximizing the amount of drug released in a sustained manner at the surface of cells bearing cannabinoid receptors.

Exploring the Potential of Cannabinoid Nanodelivery Systems for CNS Disorders

“…CBD in combination with nanomiceles was studied in triple-negative breast cancer [ 110 ], and with lipid nanoparticles in ovarian cancer [ 111 ]. The transferring (Tf) surface-modified 9-THC-loaded poly(lactide-co-glycolic) nanoparticles (Tf-THC-PLGA NPs) were evaluated as a highly promising approach for colorectal cancer [ 112 ].…”

“…Nanoparticle internalization occurred through cholesterol-associated and clathrin-mediated mechanisms. Overall, Tf-modification of PLGA NPs is a highly promising approach for THC-based antitumor therapies, potentially maximizing the amount of drug released in a sustained manner on the surface of cells bearing cannabinoid receptors [ 112 ]. Another study by Aparicio Blanco et al (2019) introduced a pilot brain tumor targeting strategy with CBD [ 116 ].…”

NOAEL cancer therapy: a tumor targetable docetaxel–inorganic polymer nanohybrid prevents drug-induced neutropenia

“…In addition, the cellular internalization of PTX-Cy5.5 was investigated after pre-treatment with endocytosis inhibitors. 21,22 for 1 h, such as CPZ 23 and K + depletion 24 (clathrin-mediated endocytosis inhibitors), genistein (a caveolae-mediated endocytosis inhibitor), 25 and amiloride (a micropinocytosis inhibitor), 26 respectively. As seen in Fig.…”

Mechanisms of chemotherapeutic resistance and the application of targeted nanoparticles for enhanced chemotherapy in colorectal cancer

“…It is up-regulated in various tumor cells and is available as targeted therapy. Durán-Lobato et al [ 153 ] used diamine bonds to attach Tf to the surface of PLGA NPs and loaded Δ9-tetrahydrocannabinol, effectively improving the bioavailability, reducing side effects, and targeting Tf-high expressing tumor cells for action. Compared to proteins, Tf-binding peptides with short sequences are readily modifiable and are more suitable for targeted nanomedicine development.…”