**13. Overcoming therapeutic limitations of RES by the application of nanotechnology**

RES has been reported as having notably poor water solubility as well as high sensitivity to heat and pH [115]. Also, since RES is unstable under physiological pH and temperature, *in vivo* assays are challenging to design and *in vitro* assays are likely to have low translatability [92, 120, 121].

Additionally, oral administration of RES has demonstrated unfavourable pharmacokinetics due to its extensive first pass, resulting in the accumulation of potentially recycled conjugates, RES-glucuronides, and RES-sulphates; although these metabolites have also been found to possess biological activity, it may not match that of the parental compound [85].

Previous reports highlighting the physicochemical limitations of RES indicate that meticulous consideration of aqueous solubility, pH, temperature, and light, during the experimental design phase is crucial for the optimisation of clinical translation [122].

Consequently, the search for effective strategies for the improvement of the limited oral bioavailability and stability, is a complex, yet necessary, undertaking for the successful development of RES as a therapeutic.

Regarding RES, improvement of one or more physicochemical and/or pharmacological parameters has been reported when in a nano form, indicating the potential of nanotechnological formulation as a viable strategy for improving its physicochemical stability and pharmacological profile.

Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are commonly employed to improve the therapeutic potential of hydrophobic drugs such as RES. Furthermore, findings that assessed the pharmacological potential of RES-loaded SLNs and NLCs, indicated their higher stability and sustained release compared to RES in its bulk form [123–128].

Further to this, studies seeking out to fortify and/or functionalise foods with RES, reported that nanoencapsulation substantially increased thermostability and photostability whilst retaining or optimising the desired biological activity. For example, an *in vitro* investigation examining the nano-encapsulation of RES in starch, conducted at pH 7.4 at 37° C, was reported to demonstrate an almost ten-fold increase in drug retention following a food extrusion process, as well as higher anti-diabetic, antiobesity, and antioxidant effects, compared to bulk RES [129].

Similarly, the sustained release of RES from ZEIN-encapsulated nanoparticles (NPs) under physiological conditions (pH 7.4, 37°C) was reported [130] and casein-encapsulated RES NPs, designed by Penlava et al., were found to be stable through a continuous pH range mimicking those of the gastrointestinal compartments (i.e., pH 1.2 for 2 h and pH 6.8 for 2–24 h). Interestingly, the latter study

also demonstrated *in vivo* (using rats), a ten-fold increase in oral availability of casein-nano-encapsulated RES compared to the bulk form as determined by blood plasma assays over a 24 h period following a single oral dose of 15 mg/kg of RES (in ddH2O and PEG) or casein-encapsulated RES NPs [131].

These studies and others bring to light the prospect of the customisation of functional foods, to serve as both local and systemic delivery system for the effective prevention, management, and treatment of PD.
