Extending Half Life of H-Ferritin Nanoparticle by Fusing Albumin Binding Domain for Doxorubicin Encapsulation

Abstract

Nanoparticles based on the heavy chain of the human ferritin (HFn) are arousing growing interest in the field of drug delivery due to their exceptional characteristics. However, the unsatisfied plasma half life of HFn substantially limits its application as a delivery platform for antitumor agents. Herein we fused an albumin binding domain (ABD) variant that basically derives from the streptococcal protein G and possesses a long-acting characteristic in serum albumin to the N-terminus of the HFn for the aim of half-life extension. This ABD-HFn construct was highly expressed and fully self-assembled into symmetrical and spherical structure in E. coli bacteria. The purified ABD-HFn showed a similar particle size with wild-type HFn and also exhibited an extremely high binding affinity with human serum albumin. To evaluate the therapeutic potential of this ABD-HFn construct in terms of half-life extension, we encapsulated a model antitumor agent doxorubicin (DOX) into the ABD-HFn. Significantly outstanding loading efficacy of above 60 molecules doxorubicin for each ABD-HFn cage was achieved. The doxorubicin-loaded ABD-HFn nanoparticle was characterized and further compared with the recombinant HFn counterpart. The ABD-HFn/DOX nanoparticle showed dramatically improved stability and comparable cell uptake rate when compared with HFn/DOX counterpart. Pharmacokinetics study in Sprague-Dawley rats showed that ABD-HFn/DOX nanoparticle possessed significantly prolonged plasma half life of ∼17.2 h, exhibiting nearly 19 times longer than that of free doxorubicin and 12 times for HFn/DOX. These optimal results indicated that fusion with ABD will be a promising strategy to extend the half life for protein-based nanoparticles.

Remote Light‐Responsive Nanocarriers for Controlled Drug Delivery: Advances and Perspectives

“…Cheng and co-workers recently constructed a nanosystem based on coumarin-anchored low generation dendrimers, which could self-assembly into nanostructures in aqueous solution via hydrophobic interactions. [82] 5-Fluorouracil (5-Fu) as an anticancer drug and plasmid DNA for encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were efficiently loaded into the nanostructures. After cross-linking the coumarin substitutes upon irradiation with 365 nm UV light, the obtained nanomaterials possessed low toxicity, improved DNA binding, and gene transfection efficacy as well as high cellular uptake.…”

Developing Protein-Based Nanoparticles as Versatile Delivery Systems for Cancer Therapy and Imaging

“…In a similar study, ferritin was genetically modified to display a serum albumin-binding domain (from the streptococcal protein G) on its external surface (ABD–Hfn), enabling the facile non-covalent attachment of serum albumin coatings upon entering the blood plasma [26]. ABD–Hfn was loaded with DOX as a drug model and fluorescent reporter in pharmacokinetic studies performed in mice.…”

The Interaction of Temozolomide with Blood Components Suggests the Potential Use of Human Serum Albumin as a Biomimetic Carrier for the Drug

“…Another interesting property of HSA is its exceptional long half-life in serum (≈18-19 days). Therefore, from a drug delivery perspective, this protein is an ideal carrier because of its combination of longevity and stability [32][33][34][35][36]. In addition, it has been reported that albumin-binding receptors (e.g., SPARC and gp60) are overexpressed on tumor cells and tumor vessel endothelium to increase the uptake of nutrients necessary for growth [37,38].…”

“…In addition, it has been reported that albumin-binding receptors (e.g., SPARC and gp60) are overexpressed on tumor cells and tumor vessel endothelium to increase the uptake of nutrients necessary for growth [37,38]. In consequence, HSA can act as a molecular carrier to selectively transport and accumulate anticancer drugs in target tumor tissues and cells [32][33][34][35]39].…”