Abstract
Pentamidine (PTM), which is a diamine that is widely known for its antimicrobial activity, is a very interesting drug whose mechanism of action is not fully understood. In recent years, PTM has been proposed as a novel potential drug candidate for the treatment of mental illnesses, myotonic dystrophy, diabetes, and tumors. Nevertheless, the systemic administration of PTM causes severe side effects, especially nephrotoxicity. In order to efficiently deliver PTM and reduce its side effects, several nanosystems that take advantage of the chemical characteristics of PTM, such as the presence of two positively charged amidine groups at physiological pH, have been proposed as useful delivery tools. Polymeric, lipidic, inorganic, and other types of nanocarriers have been reported in the literature for PTM delivery, and they are all in different development phases. The available approaches for the design of PTM nanoparticulate delivery systems are reported in this review, with a particular emphasis on formulation strategies and in vitro/in vivo applications. Furthermore, a critical view of the future developments of nanomedicine for PTM applications, based on recent repurposing studies, is provided.Graphical abstractCreated with BioRender.com
Highlights
Nanocarrier-based drug delivery has gained ever increasing amounts of attention in recent decades thanks to the characteristics that it can provide: increased drug solubility, modified pharmacokinetics, sustained release, tissue targeting, reduced toxicity, biosafety, and the ability to bypass biological barriers, which result in higher drug efficacy and bioavailability [1–3]
The results showed that encapsulated PTM inhibits S100 calcium-binding protein B (S100B) activity and rescues p53 expression, leading to pro-apoptotic control in colon cancer
PTM is appealing in terms of the design of nano-sized carriers as it is a small molecule whose physico-chemical characteristics can be changed according to the PTM form and the counterion in the salts
Summary
Nanocarrier-based drug delivery has gained ever increasing amounts of attention in recent decades thanks to the characteristics that it can provide: increased drug solubility, modified pharmacokinetics, sustained release, tissue targeting, reduced toxicity, biosafety, and the ability to bypass biological barriers, which result in higher drug efficacy and bioavailability [1–3]. PTM has been reported to exhibit anticancer properties and has shown antiproliferative effects on various human cancer cell types, such as melanoma, prostate, ovarian, colon, breast, lung, and cervical cancers in in vitro and in vivo models In these studies, several different sites of action were proposed for PTM, but the mechanism of its anticancer activity still remains elusive [70–78]. Optimized formulations of PTMloaded methacrylate nanoparticles (mean size: 350 nm) were firstly tested in vitro using a strand of Leishmania major MON 25 and monocytes U 937, with increased drug efficacy being reported, compared to the free drug [111] These interesting results led to Fusai et al describing PTM-loaded polymethacrylate nanoparticles and their efficacy in vivo. The results showed that PTM enhances the radiosensitization effect of PEG-AuNP by exerting a dual action: by inhibiting radiation-induced DNA repair and increasing the cellular uptake of PEG-AuNP after surface adsorption, causing a change in the particle surface charge [153]
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