Enhanced Delivery of 5-Aminolevulinic Acid by Lecithin Invasomes in 3D Melanoma Cancer Model.

Photodynamic therapy (PDT) is a noninvasive therapeutic approach for the treatment of skin cancer and diseases. 5-Aminolevulinic acid is a prodrug clinically approved for PDT. Once internalized by cancer cells, it is rapidly metabolized to the photosensitizer protoporphyrin IX, which under the proper light irradiation, stimulates the deleterious reactive oxygen species (ROS) production and leads to cell death. The high hydrophilicity of 5-aminolevulinic acid limits its capability to cross the epidermis. Lipophilic derivatives of 5-aminolevulinic acid only partly improved skin penetration, thus making its incorporation into nanocarriers necessary. Here we have developed and characterized 5-aminolevulinic acid loaded invasomes made of egg lecithin, either 1,2-dilauroyl-sn-glycero-3-phosphocholine or 1,2-dioleoyl-sn-glycero-3-phosphocholine, and the terpene limonene. The obtained invasomes are highly thermostable and display a spherical morphology with an average size of 150 nm and an encapsulation efficiency of 80%; moreover, the ex vivo epidermis diffusion tests established that nanovesicles containing the terpene led to a much higher skin penetration (up to 80% in 3 h) compared to those without limonene and to the free fluorescent tracer (less than 50%). Finally, in vitro studies with 2D and 3D human cell models of melanoma proved the biocompatibility of invasomes, the enhanced intracellular transport of 5-aminolevulinic acid, its ability to generate ROS upon irradiation, and consequently, its antiproliferative effect. A simplified scaffold-based 3D skin model containing melanoma spheroids was also prepared. Considering the results obtained, we conclude that the lecithin invasomes loaded with 5-aminolevulinic acid have a good therapeutic potential and may represent an efficient tool that can be considered a valid alternative in the topical treatment of melanoma and other skin diseases.

The Tumor Suppressor PTEN as Molecular Switch Node Regulating Cell Metabolism and Autophagy: Implications in Immune System and Tumor Microenvironment.

Recent studies conducted over the past 10 years evidence the intriguing role of the tumor suppressor gene Phosphatase and Tensin Homolog deleted on Chromosome 10 PTEN in the regulation of cellular energy expenditure, together with its capability to modulate proliferation and survival, thus expanding our knowledge of its physiological functions. Transgenic PTEN mice models are resistant to oncogenic transformation, present decreased adiposity and reduced cellular glucose and glutamine uptake, together with increased mitochondrial oxidative phosphorylation. These acquisitions led to a novel understanding regarding the role of PTEN to counteract cancer cell metabolic reprogramming. Particularly, PTEN drives an "anti-Warburg state" in which less glucose is taken up, but it is more efficiently directed to the mitochondrial Krebs cycle. The maintenance of cellular homeostasis together with reduction of metabolic stress are controlled by specific pathways among which autophagy, a catabolic process strictly governed by mTOR and PTEN. Besides, a role of PTEN in metabolic reprogramming and tumor/stroma interactions in cancer models, has recently been established. The genetic inactivation of PTEN in stromal fibroblasts of mouse mammary glands, accelerates breast cancer initiation and progression. This review will discuss our novel understanding in the molecular connection between cell metabolism and autophagy by PTEN, highlighting novel implications regarding tumor/stroma/immune system interplay. The newly discovered action of PTEN opens innovative avenues for investigations relevant to counteract cancer development and progression.