Improving Dermal Delivery of Rose Bengal by Deformable Lipid Nanovesicles for Topical Treatment of Melanoma

Abstract

Cutaneous melanoma is one of the most aggressive and metastatic forms of skin cancer. However, current therapeutic options present several limitations, and the annual death rate due to melanoma increases every year. Dermal delivery of nanomedicines can effectively eradicate primary melanoma lesions, avoid the metastatic process, and improve survival. Rose Bengal (RB) is a sono-photosensitizer drug with intrinsic cytotoxicity toward melanoma without external stimuli but the biopharmaceutical profile limits its clinical use. Here, we propose deformable lipid nanovesicles, also known as transfersomes (TF), for the targeted dermal delivery of RB to melanoma lesions to eradicate them in the absence of external stimuli. Considering RB’s poor ability to cross the stratum corneum and its photosensitizer nature, transfersomal carriers were selected simultaneously to enhance RB penetration to the deepest skin layers and protect RB from undesired photodegradation. RB-loaded TF dispersion (RB-TF), prepared by a modified reverse-phase evaporation method, were nanosized with a ζ-potential value below −30 mV. The spectrophotometric and fluorimetric analysis revealed that RB efficiently interacted with the lipid phase. The morphological investigations (transmission electron microscopy and small-angle X-ray scattering) proved that RB intercalated within the phospholipid bilayer of TF originating unilamellar and deformable vesicles, in contrast to the rigid multilamellar unloaded ones. Such outcomes agree with the results of the in vitro permeation study, where the lack of a burst RB permeation peak for RB-TF, observed instead for the free drug, suggests that a significant amount of RB interacted with lipid nanovesicles. Also, RB-TF proved to protect RB from undesired photodegradation over 24 h of direct light exposure. The ex vivo epidermis permeation study proved that RB-TF significantly increased RB’s amount permeating the epidermis compared to the free drug (78.31 vs 38.31%). Finally, the antiproliferative assays on melanoma cells suggested that RB-TF effectively reduced cell growth compared to free RB at the concentrations tested (25 and 50 μM). RB-TF could potentially increase selectivity toward cancer cells. Considering the outcomes of the characterization and cytotoxicity studies performed on RB-TF, we conclude that RB-TF represents a valid potential alternative tool to fight against primary melanoma lesions via dermal delivery in the absence of light.

Triazine–Carbosilane Dendrimersomes Enhance Cellular Uptake and Phototoxic Activity of Rose Bengal in Basal Cell Skin Carcinoma Cells

“… 63–66 In the case of RB, increased cellular uptake seems to be critical for phototoxic activity: regardless of the level of singlet oxygen generation, RB-loaded dendrimersomes generate significantly higher levels of intracellular ROS, which translates into a stronger phototoxic effect. The IC 50 values for RB-loaded dendrimersomes in vitro are remarkably low (~1 µM RB for both formulations), considerably lower than those for most formulations mentioned above (for instance 28 , 30 , 32 , 36 ). Importantly, the dark toxicity of RB-loaded dendrimersomes is negligible in the concentration range used.…”

“…A promising way to increase bioavailability of RB is to deliver it in nanoformulations. 8 To date, various types of RB-loaded nanocarriers have been designed for skin cancer PDT in vitro and in vivo, including lipid-based formulations 28–30 polymeric nanoparticles, 31–33 upconversion nanoparticles, 34 , 35 inorganic nanoparticles 36 and so on.…”

Novel Utilization of Therapeutic Coatings Based on Infiltrated Encapsulated Rose Bengal Microspheres in Porous Titanium for Implant Applications

“…UV analysis was employed for the RB quantification. Evaluation of RB content in PBS buffer (pH 7.4), used for both the determination of the drug content (Section 2.4) and in vitro drug release studies (Section 2.5), was carried out with a UV spectrophotometer (Shimadzu UV-1800, Kyoto, Japan) (λ = 549 nm) [12]. RB concentrations were calculated by interpolation of the calibration curve prepared in PBS buffer (pH 7.4).…”

“…In order to bypass antibiotic resistance phenomena, some new chemicals have been designed against multidrug resistant (MDR) strains and appear as suitable alternatives in late-stage clinical studies [11]. For this purpose, although rose bengal (RB) has been legally approved just as a dye for the diagnosis of ocular disorders, it has recently been explored for its unique activity against cancer [12] and infections [13]. Recently, a work published in collaboration with Provectus Biopharmaceuticals reported that RB was very effective, and as an antimicrobial drug in skin and soft tissue infections (SSTIs), associated with Gram-positive bacteria and MDR strains [14].…”

Enhanced Delivery of Rose Bengal by Amino Acids Starvation and Exosomes Inhibition in Human Astrocytoma Cells to Potentiate Anticancer Photodynamic Therapy Effects

“…Nevertheless, RB demonstrated a broad spectrum of induced cytotoxicity against tumor and microbial cells [ 19 ]. In oncology, the main relevant applications of RB (namely PV-10, a 10% RB solution) were reported in the treatments of local and metastatic melanoma, both in the absence of external stimuli such as ultrasound and PDT stimuli [ 20 ]. In melanoma cells, RB was reported to induce death pathways as necrosis and caspase-dependent and-independent apoptosis [ 21 , 22 , 23 , 24 ].…”