# Endowed Polyphenols in Advanced Delivery Systems for Vaginal Infections
## 7 Polyphenols in Advanced Systems  
As mentioned previously, pathogens such as bacteria, fungi, parasites, and viruses cause infectious diseases, and the number of patients identified with resistant microbial infections is increasing [151]. Unfortunately, bacteria that are resistant to standard antibiotics have emerged rapidly over the past few decades, resulting in 700,000 global annual deaths, of which over 200,000 are infants [152]. In this regard, alternative bio-derived products have been employed as a potential strategy to fight infectious diseases. Specifically, polyphenolic compounds have been explored as antibacterial agents, and previous reports indicate efficacy for treating several of these microbial infections (reviewed in [153]). However, due to their physicochemical features and typically limited water solubility, polyphenolic delivery has been challenging. In this context, several innovative drug delivery methods can provide some advantages, such as improved bioavailability and controlled release of polyphenolic compounds [154]. Drug delivery systems can be defined as techniques where materials are employed to deliver therapeutic agents to specified targets in a regulated or controlled manner [155]. [PERSON] et al. (2020) [111] developed an advanced delivery system consisting of resveratrol-loaded liposomes incorporated in a chitosan hydrogel, for the treatment of _Chlamydia trachomatis_ infection. In this study, both free resveratrolol and resveratrol liposomes inhibited _C. trachomatis_ proliferation. Nonetheless, the effect was higher when incorporated into the mentioned delivery system, with inhibition of 78% and 94% for 1.5 and 3 g/mL resveratrolol, respectively, compared to 43% and 72%, for free resveratrol at the same concentrations. Furthermore, resveratrol liposomes in hydrogel demonstrated a potent anti-inflammatory effect in vitro, inhibiting nitric oxide (NO) generation in LPS-treated macrophages (RAW 264.7 cells), in a concentration-dependent manner. In 2019, [PERSON] and colleagues [4] performed similar work, developing a delivery system comprising resveratrol- or epicatechin-loaded liposomes formulated in a chitosan-based hydrogel for vaginal application. In this work, liposomes presented an approximate size of 200 nm and entrapment efficiencies of 81 and 77% for resveratrol and epicatechin, respectively, and medium molecular weight chitosan at 2.5% \(w/w\) concentration has been shown to exhibit optimum textural features and mucoadhesiveness in ex vivo conditions. This system was non-toxic, and epicatechin-loaded liposomes exhibited superior radical scavenging activity at lower concentrations than vitamins C and E. This epicatechin superiority was also demonstrated with the higher inhibitory effect on the NO production by RAW 264.7 cells (higher anti-inflammatory activity), compared to the resveratrol-loaded formulation. [PERSON] et al. (2020) [100] produced novel liposomes for the simultaneous administration of two polyphenols, quercetin and gallic acid, that, when released into the vaginal cavity, functioned to eliminate infection, while reducing VVC symptoms. Quercetin was chosen for its anti-itching and anti-inflammatory effects, whereas gallic acid was chosen for its anti-_Candida_ activity. Quercetin-, gallic acid- and (quercetin + gallic acid)-loaded liposomes with a 200 nm size were developed. Quercetin entrapment efficiency was 85% in both quercetin liposomes, whereas gallic acid was less efficiently entrapped, with 30 and 25% in (quercetin + gallic acid) and gallic acid liposomes, respectively. Liposomes, particularly (quercetin + gallic acid) ones, promoted the prolonged release of both polyphenols, and their joint administration improved the antioxidant activity. Also, liposomes were non-cytotoxic and had greater anti-inflammatory effects than free polyphenols. Finally, gallic acid and (quercetin + gallic acid) liposomes significantly inhibited _C. albicans_ growth. In another study, [PERSON] et al.