Therapeutic potential of quercetin in diabetic foot ulcer: Mechanistic insight, challenges, nanotechnology driven strategies and future prospects

Diabetic foot ulcer (DFU) is a complicated condition with symptoms of neuropathic pain, immunological and biochemical impairments promotes delayed wound healing processes and foot amputations. Currently available therapeutic options for the management of DFU are excruciating and expensive; hence affect the global socioeconomic burden. An optimal therapy for DFU should exhibit easy acceptability, reliability and cost-efficient feature. Interestingly, quercetin displays excellent antidiabetic, anti-inflammatory, antioxidant, antimicrobial and wound healing properties which makes it a promising molecule for the management of diabetic wounds. It enhances the process of angiogenesis by activating multiple factors such as Msr-1, Arg-1, VEGF-α, HO-1, PECAM-1 as well as known for its action on PI3K/Akt/eNOS pathway to promote the cell proliferation, collagen deposition and angiogenesis. Despite numerous therapeutic benefits of quercetin, its use in DFU is limited owing to pharmaceutical challenges such as low aqueous solubility (0.48 ± 0.1 μg/mL), poor permeability (log P 1.82 ± 0.3), instability in gastro-intestinal tract, average terminal half-life (3.5 h), poor oral bioavailability (4%) and extensive first past metabolism. Further, lacking of clinical data and insufficient understanding of mechanism of action have listed the quercetin only as a complementary and alternative medicine or a nutraceutical. Therefore, in present review, we have discussed complete etiology of diabetic foot, available therapies and their shortcomings. In addition, an attempt has also been undertaken to enlist the possible target sites for quercetin to boost the wound healing process along with application of artificial intelligence (AI)-based techniques for the development of stable, cost-effective and patient-friendly topical drug delivery systems for better management of DFU in future.