<p>Enhanced and Prolonged Antitumor Effect of Salinomycin-Loaded Gelatinase-Responsive Nanoparticles via Targeted Drug Delivery and Inhibition of Cervical Cancer Stem Cells</p>

Abstract

Background: Cervical cancer stem cells (CCSCs) represent a subpopulation of tumor cells that possess self-renewal capacity and numerous intrinsic mechanisms of resistance to conventional chemotherapy and radiotherapy. These cells play a crucial role in relapse and metastasis of cervical cancer. Therefore, eradication of CCSCs is the primary objective in cervical cancer therapy. Salinomycin (Sal) is an agent used for the elimination of cancer stem cells (CSCs); however, the occurrence of several side effects hinders its application. Nanoscale drug-delivery systems offer great promise for the diagnosis and treatment of tumors. These systems can be used to reduce the side effects of Sal and improve clinical benefit. Methods: Sal-loaded polyethylene glycol-peptide-polycaprolactone nanoparticles (Sal NPs) were fabricated under mild and non-toxic conditions. The real-time biodistribution of Sal NPs was investigated through non-invasive near-infrared fluorescent imaging. The efficacy of tumor growth inhibition by Sal NPs was evaluated using tumor xenografts in nude mice. Flow cytometry, immunohistochemistry, and Western blotting were used to detect the apoptosis of CSCs after treatment with Sal NPs. Immunohistochemistry and Western blotting were used to examine epithelial-mesenchymal transition (epithelial interstitial transformation) signal-related molecules. Results: Sal NPs exhibited antitumor efficacy against cervical cancers by inducing apoptosis of CCSCs and inhibiting the epithelial-mesenchymal transition pathway. Besides, tumor pieces resected from Sal NP-treated mice showed decreased reseeding ability and growth speed, further demonstrating the significant inhibitory ability of Sal NPs against CSCs. Moreover, owing to targeted delivery based on the gelatinase-responsive strategy, Sal NPs was more effective and tolerable than free Sal. Conclusion: To the best of our knowledge, this is the first study to show that CCSC-targeted Sal NPs provide a potential approach to selectively target and efficiently eradicate CCSCs. This renders them a promising strategy to improve the therapeutic effect against cervical cancer.

Salinomycin-Based Drug Delivery Systems: Overcoming the Hurdles in Cancer Therapy

“…However, Sali is distributed in other organs such as liver, spleen, kidneys to various extents [ 42 , 48 , 49 ]. It has been reported that a dose of 2 mg/kg Sali induces significant changes and inflammatory cell infiltration in lung, heart muscle, liver, and spleen in mice [ 51 ]. Moreover, doses of 8–10 mg/kg Sali in free form have been proven lethal to mice [ 51 , 52 ].…”

“…It has been reported that a dose of 2 mg/kg Sali induces significant changes and inflammatory cell infiltration in lung, heart muscle, liver, and spleen in mice [ 51 ]. Moreover, doses of 8–10 mg/kg Sali in free form have been proven lethal to mice [ 51 , 52 ]. Thus, incorporation of Sali in nanoparticles can reduce its side effects.…”

“…Since most types of nanoparticles are manufactured from GRAS materials approved by regulatory agencies for use in humans, they do not induce any significant toxic effects. Furthermore, owing to the preferential accumulation of the Sali-loaded nanoparticles at tumor sites, collateral toxicity to healthy tissues is minimized, and the treatment is well-tolerated by animals as reflected by the lack of behavioral changes (activity, appetite) or of the body weight [ 50 , 51 , 53 , 54 ].…”

“…Furthermore, the Sali-loaded nanoparticles decreased the expression of CD44 and CD133, and reduced the tumor seeding ability and tumor growth rate in tumor-bearing mice, compared to the free drug, suggesting the cervical CSC targeting ability of Sali. In addition, Sali-loaded nanoparticles reduced the expression of VIM and increased the expression of E-cadherin, suggesting that Sali exhibits inhibitory effects on cervical CSCs by targeting the ZEB1 and ZEB2 pathway, thus inhibiting the EMT process [ 51 ].…”

Synthesis and Characterization of Salinomycin-Loaded High-Density Lipoprotein and Its Effects on Cervical Cancer Cells and Cervical Cancer Stem Cells

“…In recent years, nanoparticles have been widely studied as a drug delivery system because of their unique characteristics. 15 , 41 HDL has unique physicochemical properties, including naturally synthesized physiological components, amphiphilic apolipoproteins, specific protein–protein interactions, hydrophobic agent-incorporating and small size. 18 It has been proved that the phospholipid core of HDL can be combined with hydrophobic drugs to improve the water solubility of drugs and promote the effective release of drugs.…”