Polyester-Based Dendrimer Nanoparticles Combined with Etoposide Have an Improved Cytotoxic and Pro-Oxidant Effect on Human Neuroblastoma Cells

Abstract

Etoposide (ETO) is a cytotoxic drug that exerts its effect by increasing reactive oxygen species (ROS) production. Although ETO is widely used, fast metabolism, poor solubility, systemic toxicity, and multi-drug resistance induction all limit its administration dosage and its therapeutic efficiency. In order to address these issues, a biodegradable dendrimer was prepared for entrapping and protecting ETO and for enhancing its solubility and effectiveness. The achieved dendrimer complex with ETO (CPX 5) showed the typical properties of a well-functioning delivery system, i.e., nanospherical morphology (70 nm), optimal Z-potential (−45 mV), good drug loading (37%), very satisfying entrapment efficiency (53%), and a remarkably improved solubility in biocompatible solvents. In regards to its cytotoxic activity, CPX 5 was tested on neuroblastoma (NB) cells with very promising results. In fact, the dendrimer scaffold and ETO are able to exert per se a cytotoxic and pro-oxidant activity on human NB cells. When CPX 5 is combined with ETO, it shows a synergistic action, slowly releasing the drug over time and significantly improving and protracting bioactivity. On the basis of these findings, the prepared ETO reservoir represents a novel biodegradable and promising device for the delivery of ETO into NB cells.

From Nanobiotechnology, Positively Charged Biomimetic Dendrimers as Novel Antibacterial Agents: A Review

“…Thus, similarly to other ADs, in CADs, the multivalence in terms of positive charges plays a key role in their antimicrobial activity, and high-generation cationic Ds proved to be biocides with high activity, capability of bring localized in specific organs reduced systemic toxicity and increased duration of action [ 50 ]. Research on these agents, in fact, focuses both on their intrinsic antimicrobial activity and on the possibility they offer as drug release systems, since they are suitable for encapsulating or covalently connecting biologically active agents [ 10 , 11 , 12 ]. This latter strategy improves the solubility of poorly soluble antibiotics, protects them from fast metabolism, increases their residence time in the circle, targets the drugs transported to specific sites of action and achieves synergistic cooperation between the cationic dendrimer carrier and the antibiotic, thus allowing a reduced dosage [ 2 , 15 , 48 ].…”

“…Recently, cationic antimicrobial macromolecules, inspired by natural CAMPs, have gained increasing attention from the scientific community because, compared to small molecules of drug, they possess several advantages such as higher long-term activity, limited residual toxicity, chemical stability, non-volatility and the inability to permeate through the skin due to their macromolecular structure and high molecular weight (MW) [ 2 , 8 ]. Among polymers, dendrimers (Ds), a specific class of nanoscaled, hyperbranched, tree-like macromolecules, with a symmetric well-defined structure and a three-dimensional architecture [ 9 , 10 , 11 , 12 ], have recently shown to function as antibacterial agents and as antimicrobial surface coatings as well [ 3 ]. The first synthesis of dendrimer materials, whose structure was conceptualized in the early 1970s, dates back to the mid-eighties [ 3 ].…”

“…Commercially available PAMAM and PPI dendrimers (PAMAM Ds and PPI Ds) are the most investigated, but despite their considerable broad-spectrum activity observed in vitro, if not opportunely modified to tone down several issues, such as low biodegradability, susceptibility to opsonization, toxicity to mammalian cells, including hemolytic toxicity, cytotoxicity, and hematological toxicity, as well as fast clearance [ 9 , 10 , 11 , 12 ], in their native form they are not suitable for clinical applications. To address these issues, as in other biomedical applications, uncharged dendrimer matrices, decorated with protonable residues [ 1 , 18 ], are worthy of consideration as a less toxic alternative [ 19 ].…”

Oxidative Stress, Antioxidant Capabilities, and Bioavailability: Ellagic Acid or Urolithins?

“…These groups may sometimes induce significant DNA damage in the presence of Cu (II) or may create ROS through the reduction of Cu (II) → Cu. The pro-oxidant activity, peculiar of small polyphenols, can trigger apoptosis in cancer cells [142]. In contrast, large molecular-weight phenols, such as ETs, have little or no pro-oxidant properties [143].…”

Telodendrimers: Promising Architectural Polymers for Drug Delivery

“…This elegant and versatile set of macromolecules ( Figure 2 ) are intriguing alternatives to heavily utilized PAMAM dendrimers, with ease of tunable surface functionalization with a variety of functional groups, leading to neutral and charged nanostructures with low toxicities. These biocompatible scaffolds are promising candidates for applications in biology, as demonstrated by their potential in a series of therapeutic evaluations [ 99 , 100 , 101 , 102 , 103 , 104 , 105 ]. Such a structural outline, i.e., a dendron with an alkyl chain at the focal point, was previously reported by Newkome et al [ 30 ], and investigated for its ability to form micelle structures.…”