H-ferritin–nanocaged doxorubicin nanoparticles specifically target and kill tumors with a single-dose injection

Abstract

An ideal nanocarrier for efficient drug delivery must be able to target specific cells and carry high doses of therapeutic drugs and should also exhibit optimized physicochemical properties and biocompatibility. However, it is a tremendous challenge to engineer all of the above characteristics into a single carrier particle. Here, we show that natural H-ferritin (HFn) nanocages can carry high doses of doxorubicin (Dox) for tumor-specific targeting and killing without any targeting ligand functionalization or property modulation. Doxloaded HFn (HFn-Dox) specifically bound and subsequently internalized into tumor cells via interaction with overexpressed transferrin receptor 1 and released Dox in the lysosomes. In vivo in the mouse, HFn-Dox exhibited more than 10-fold higher intratumoral drug concentration than free Dox and significantly inhibited tumor growth after a single-dose injection. Importantly, HFn-Dox displayed an excellent safety profile that significantly reduced healthy organ drug exposure and improved the maximum tolerated dose by fourfold compared with free Dox. Moreover, because the HFn nanocarrier has well-defined morphology and does not need any ligand modification or property modulation it can be easily produced with high purity and yield, which are requirements for drugs used in clinical trials. Thus, these unique properties make the HFn nanocage an ideal vehicle for efficient anticancer drug delivery.

An Apoferritin‐based Drug Delivery System for the Tyrosine Kinase Inhibitor Gefitinib

“…Although angiogenesis is enhanced in cancers [ 38 ] suggesting potential competition between endogenous ferritins and H-AFt uptake, a recent study demonstrated successful delivery of doxorubicin encapsulated in H-AFt to tumor sites and in vivo effi cacy. [ 18 ] Thus, we envisage that the observed selective targeting and enhanced effi cacy could be translated in vivo and merits further detailed studies.…”

“…[ 6,9,15,16 ] Recently, selective targeting and cargo delivery with heavy chain apoferritin (H-AFt) was demonstrated both in vitro [ 17 ] and in vivo. [ 18 ] Gefi tinib ("Iressa," ZD1839) is an orally active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. [ 19 ] This receptor family comprises four homologous receptors: EGFR (ErbB1/HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4), which have an extracellular ligand binding domain, a single hydrophobic trans-membrane domain and a cytoplasmic tyrosine kinase domain.…”

Use of Ferritin-Based Metal-Encapsulated Nanocarriers as Anticancer Agents

“…Fts are small enough to penetrate capillary spaces and large enough to avoid renal clearance. Notably, Fts are physiological materials, very soluble in aqueous solutions and in the blood, with low toxicity, susceptible to chemical modifications and being modified by molecular biology techniques [3][4][5][6][7][8][9][10]. Materials such as Fe 3 O 4 , Co 3 O 4 , Mn 3 O 4 , Pt, CoPt, Pd, CdS, CdSe, ZnSe, CaCO 3 , SrCO 3 , Au, Ag and BaCO 3 have been produced and characterized in different ferritin templates [11].…”

Construction of magnetic-carbon-quantum-dots-probe-labeled apoferritin nanocages for bioimaging and targeted therapy

“…The results were considered to be consistent with another use of hydrazone bond to construct pH-sensitive drug delivery system. 35 DOX almost cannot be released from AFn nanocages in normal tissues due to the pH 7.4 of bodily fluid environment. As for partial acid environment of the tumor tissue, a large number of DOX molecules were slowly released from AFn nanocages after Gd-CDs/AFn (DOX)/FA worked on the tumor position, which greatly improved the treatment efficiency of DOX.…”