Reduction-sensitive nanoparticles (RSNP) consist of nanocarriers that are chemically responsive to reduction. Drug delivery systems using RSNP can be loaded with different drugs that are designed to be released within a concentrated reducing environment, such as the tumor-targeted microenvironment. Reduction-Sensitive Nanoparticles provide an efficient method of targeted drug delivery for the improved controlled release of medication within localized areas of the body.
Redox sensitive nanoparticles vs. reduction sensitive nanoparticles Nanoparticles are small in size with maximized surface area and have an enhanced level of solubility; these elements result in an improved bioavailability. Reduction-sensitive nanoparticles are nanoparticles that are responsive to reduction signalling environments. Redox-sensitive nanoparticles can be responsive to signalling through a reduction activation or an oxidative activation. Therefore, degradation of chemical bonds can be either activated through oxidants or reductants in the localized area. The cleavage/degradation of chemical bonds will enable the drugs loaded within the nanoparticle to be released into the body. Depending on the activation mechanism, redox-sensitive nanoparticles can be associated with reduction-sensitive nanoparticles if the chemical activation method is through reduction.
Nanoparticle drug loading Nanoparticle Drug Loading is dependent on the mass ratio of the drug being loaded and the drug-loaded nanoparticle. Variations necessary to consider are the pore volume size, the surface, shape, and charge of the nanoparticle. The mode of drug loading will depend on the type of drug being administered, which will vary depending on the illness that is treated.
Drug Release
One of the limitations of nanoparticles for drug delivery is the insufficient or slow release of drugs. The rate of release is a critical element to identify how slowed drug release could limit the proper concentration of treatment. If the drug is not administered in concentrations high enough it could result in undertreatment of tumor cells with little to no effect. Concentration thresholds must be met to initiate cell death amongst tumor cells. However, the uncontrolled release of treatment could also permit adverse side effects. RSNPs have improved rates of drug release which improves the medication concentrations that can be administered to a specific area. RSNPs consist of reduction or redox-sensitive bonds. After administration in the body, the RSNP will eventually come into contact with the tumor microenvironment (TME). Nanoparticles can be synthesized to activate when exposed to selective characteristics of the tumor microenvironments. TMEs depict unique characteristics that create a differing microenvironment in comparison to healthy tissue. Thus, nanoparticles can be designed to react to the unique elements of TMEs such as the formation of a reducing environment. The reducing abilities of the TMEs are due to the expression of reducing agents. RSNPs are formulated to express reduction-sensitive bonds that are cleaved when exposed to reducing agents. After the reduction occurs the degradation of the nanoparticles commences and the loaded drugs begin to release.
Physicochemical characterization
RSNPs The physicochemical characteristics of nanoparticles are inclusive of the size, shape, chemical composition, stability, topography, surface charge, and surface area. Deviations of these characteristics can be impacted by the classification of the nanoparticle. For example, the RSNP can be classified as a polymeric, micelle, or lipid-polymeric hybrid. The reduction sensitivity of nanoparticles is reliant on the reduction-responsive chemical structures infused into the nanoparticle. Reduction occurs when the number of electrons increases in a chemical species. Reduction sensitive nanoparticles depict high plasma stability and quick responsiveness/activation. The reducing environment of tumor cells is greatly impacted by the oxidation and reduction states of NADPH/NADP+ and Glutathione.
Tumor microenvironment For the effective application of RSNPs, the physicochemical characteristics of the tumor microenvironment must also be considered. The characteristics depicted by the TME are tumor hypoxia, angiogenesis, metabolism, acidosis, reactive oxygen species (ROS), etc. The elements of the tumor microenvironment can affect the reduction-inducing environment. Tumor cells abnormally regulate redox homeostasis leading to differences in the redox balance and increases in ROS levels. Research trends have shown that increased levels of ROS are correlated with high levels of antioxidant activity, such as intracellular GSH.
Reducing agents
Glutathione (GSH) or γ-glutamyl-cysteinyl-glycine is a critical biological reducing agent for drug delivery applications; it creates an effective reducing environment in the cytosol and nucleus of a cell. Glutathione is an antioxidant that is naturally produced in the liver and takes part in tissue building, tissue repair, immune responses, chemical production, and protein production. GSH is also a significant signaler of cell differentiation, proliferation, apoptosis, and ferroptosis. Furthermore, the glutathione concentration in the tumor microenvironment is reportedly at least four times higher compared to regular tissue. This is due to the high metabolic needs of tumor cells; for example, the rapid proliferation rates of tumor cells. The over-expression of nicotinamide adenine dinucleotide phosphate NADPH can lead to higher ROS levels. NADPH has a lower concentration than GSH in the reducing environment. NADPH is an electron donor that exists among all organisms; additionally, the NADPH is used as a source of reduction to drive anabolic reactions and redox balances. The reduction and oxidation states of NADPH/NADP+ will influence the reduced responsiveness of the environment. Cancer cells express a unique NADPH homeostasis due to the adaptive alterations of signaling pathways and metabolic enzymes.
Subtypes
Reduction sensitive bonds
Disulfide bonds
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