Injectable Thermosensitive Hydrogels for a Sustained Release of Iron Nanochelators

Abstract

Deferoxamine (DFO) is an FDA‐approved iron‐chelating agent which shows good therapeutic efficacy, however, its short blood half‐life presents challenges such as the need for repeated injections or continuous infusions. Considering the lifelong need of chelating agents for iron overload patients, a sustained‐release formulation that can reduce the number of chelator administrations is essential. Here, injectable hydrogel formulations prepared by integrating crosslinked hyaluronic acid into Pluronic F127 for an extended release of DFO nanochelators are reported. The subcutaneously injected hydrogel shows a thermosensitive sol–gel transition at physiological body temperature and provides a prolonged release of renal clearable nanochelators over 2 weeks, resulting in a half‐life 47‐fold longer than that of the nanochelator alone. In addition, no chronic toxicity of the nanochelator‐loaded hydrogel is confirmed by biochemical and histological analyses. This injectable hydrogel formulation with DFO nanochelators has the potential to be a promising formulation for the treatment of iron overload disorders.

Drug-Delivery Nanoplatform with Synergistic Regulation of Angiogenesis–Osteogenesis Coupling for Promoting Vascularized Bone Regeneration

“…Among the most promising is the administration of deferoxamine (DFO), a chelator of iron that already has approval by the FDA for the treatment of transfusional iron overload . By chelating iron, DFO can act as a potent prolyl-hydroxylase inhibitor (PHDi) that subsequently inhibits the prolyl-hydroxylation of HIF-1α, thus activating the HIF-1α signaling pathway and ultimately promoting the transactivation of downstream mediators such as VEGF and other secretory factors associated with the formation of new blood vessels. − In addition, DFO also promotes the formation of type H vessels . Although multiple studies have reported that DFO can promote angiogenesis in wound healing applications, its short half-life in plasma ( t 1/2 = 5 min in mice), rapid clearance, and poor biocompatibility limit its biological application. , Thus, it is important and urgent that nanocarrier systems for DFO are identified to address this challenge.…”

“…12 Although multiple studies have reported that DFO can promote angiogenesis in wound healing applications, its short half-life in plasma (t 1/2 = 5 min in mice), rapid clearance, and poor biocompatibility limit its biological application. 15,17 Thus, it is important and urgent that nanocarrier systems for DFO are identified to address this challenge.…”

Ferroptosis: challenges and opportunities for nanomaterials in cancer therapy

“…Deferoxamine, a Food and Drug Administration (FDA)-approved iron-chelating agent, is used to chelate iron ions and alleviate excessive ferroptosis damage in normal cells and tissues. However, its short half-life (∼15 min) severely limits its accumulation in cancer [ 58 ]. Drug resistance is another important factor that has the greatest impact on treatment efficacy and has appeared in SRF-mediated hepatocellular carcinoma therapy, attenuating its ferroptosis-inducing effect [ 59 ].…”

Mechanism-Based Pharmacokinetic Modeling of Absorption and Disposition of a Deferoxamine-Based Nanochelator in Rats

“…This promising nanochelator has demonstrated robust iron chelation in vivo and an improved safety profile compared to native DFO. 10,11 To facilitate clinical translation of this novel therapeutic, the pharmacokinetic profile of DFO-NPs should be fully characterized. Previous pharmacokinetic studies in mice, which evaluated multiple DFO-NP stoichiometries at a subtherapeutic, intravenous (IV) dose, indicated that DFO-NPs are rapidly eliminated from circulation with half-lives of approximately 30 to 60 min.…”

“…In particular, Kang et al have reported on a novel, renal selective DFO-conjugated nanoparticle (DFO-NP; nanochelator) prepared by conjugating DFO to ε-poly-lysine (EPL). This promising nanochelator has demonstrated robust iron chelation in vivo and an improved safety profile compared to native DFO. , …”