Ultrasound-Responsive Nrf2-Targeting siRNA-Loaded Nanobubbles for Enhancing the Treatment of Melanoma

Abstract

The siRNA-mediated inhibition of nuclear factor E2-related factor 2 (Nrf2) can be an attractive approach to overcome chemoresistance in various malignant tumors, including melanoma. This work aims at designing a new type of chitosan-shelled nanobubble for the delivery of siRNA against Nrf2 in combination with an ultrasound. A new preparation method based on a water–oil–water (W/O/W) double-emulsion was purposely developed for siRNA encapsulation in aqueous droplets within a nanobubble core. Stable, very small NB formulations were obtained, with sizes of about 100 nm and a positive surface charge. siRNA was efficiently loaded in NBs, reaching an encapsulation efficiency of about 90%. siNrf2-NBs downregulated the target gene in M14 cells, sensitizing the resistant melanoma cells to the cisplatin treatment. The combination with US favored NB cell uptake and transfection efficiency. Based on the results, nanobubbles have shown to be a promising US responsive tool for siRNA delivery, able to overcome chemoresistance in melanoma cancer cells.

Interventional Ultrasound in Dermatology: A Pictorial Overview Focusing on Cutaneous Melanoma Patients

“…PET‐CT also yielded a 4% false‐positive rate. Interestingly, Argenziano et al 26 designed a new type of chitosan‐shelled nanobubbles for the delivery of siRNA‐mediated inhibition of nuclear factor E2‐related factor 2 in combination with an ultrasound. This novel approach can be attractive to overcome chemoresistance in melanoma cells.…”

Targeted chitosan nanobubbles as a strategy to down-regulate microRNA-17 into B-cell lymphoma models

“…Intriguingly, chitosan has been proposed for the manufacturing of polymer-shelled nanobubbles, showing a great binding capacity with siRNA and miRNA, due to the cationic properties of the shell [43,44]. Interestingly, the transfection capacity of polymer-shelled nanobubbles could be further enhanced by using ultrasound (US) combined treatments, making the NB formulation a promising targeted tool for B-cell malignancies [45]. Moreover, these nanosystems might allow the co-delivery of antagomiR17 with other drugs, considering the different domains of the NB structure [46,47].…”

The Proteoglycan Glypican-1 as a Possible Candidate for Innovative Targeted Therapeutic Strategies for Pancreatic Ductal Adenocarcinoma

“…Since chitosan is positively charged, it can interact with the negative charge of cell membranes through electrostatic interactions, resulting in increased cellular uptake, an important feature for drug delivery systems [ 136 ]. Thanks to its promising properties, chitosan has already been used as a matrix polymer for NBs (CS NBs) to achieve two different goals: NBs for the delivery of nucleic acids, such as DNA, antisense oligonucleotides (AON), or siRNA, or NBs for cancer treatment [ 128 , 129 , 137 , 138 , 139 , 140 , 141 ]. In the first case, CS NBs were used as transfection agents in conjunction with US or external shock waves (ESW), which resulted in the enhanced transfer of DNA and siRNA into cells, whereas they showed impairment in AON delivery [ 138 , 139 , 140 ].…”

“…Thanks to its promising properties, chitosan has already been used as a matrix polymer for NBs (CS NBs) to achieve two different goals: NBs for the delivery of nucleic acids, such as DNA, antisense oligonucleotides (AON), or siRNA, or NBs for cancer treatment [ 128 , 129 , 137 , 138 , 139 , 140 , 141 ]. In the first case, CS NBs were used as transfection agents in conjunction with US or external shock waves (ESW), which resulted in the enhanced transfer of DNA and siRNA into cells, whereas they showed impairment in AON delivery [ 138 , 139 , 140 ]. In the second case, folate-coated CS NBs were used as smart bombs targeting folate-receptor-positive cells [ 141 ].…”