Four‐fold Channel‐Nicked Human Ferritin Nanocages for Active Drug Loading and pH‐Responsive Drug Release

Abstract

Human ferritins are emerging platforms for non-toxic protein-based drug delivery, owing to their intrinsic or acquirable targeting abilities to cancer cells and hollow cage structures for drug loading. However, reliable strategies for high-level drug encapsulation within ferritin cavities and prompt cellular drug release are still lacking. Ferritin nanocages were developed with partially opened hydrophobic channels, which provide stable routes for spontaneous and highly accumulated loading of Fe -conjugated drugs as well as pH-responsive rapid drug release at endoplasmic pH. Multiple cancer-related compounds, such as doxorubicin, curcumin, and quercetin, were actively and heavily loaded onto the prepared nicked ferritin. Drugs on these minimally modified ferritins were effectively delivered inside cancer cells with high toxicity.

Tumor microenvironment responsive drug delivery systems

“…Thus, adenocarcinoma and soft tissue sarcoma might be more responsive to pH-triggered drug delivery systems. This can also explain the reason why most reported DDSs with pH responsiveness utilized adenocarcinoma cells such as MCF-7 cells [50 , 51] , HeLa cells [52 , 53] , and BxPC-3 cells [54] as models to investigate the curative effect. The existing pH differences have received wide application in “size shrinkage” for enhanced tumor penetration, “surface charge conversion” for improved cellular internalization and “stability change” for on-demand drug release at cellular or subcellular level.…”

“…Meanwhile, endogenous biomolecules were also demonstrated as new carriers with pH responsiveness, including proteins [50 , 72 , 73] and DNA [74] . Ferritin is one of the popular acidic responsive proteins whose self-assemble promotes the formation of a hollow cage structure where metal ions especially Fe (II) can be bound.…”

Recent advances in drug delivery systems for enhancing drug penetration into tumors

“…In terms of this 5 step cascade, researchers have achieved considerable success in long cycling (C) (Klibanov et al., 1990 ; Hu et al., 2011 ), tumor enrichment (A) (Wu et al., 2014 ; Song et al., 2015 ), enhancement of intracellular endocytosis (I) (Mizuhara et al., 2015 ; Deng et al., 2016 ), and intracellular release (R) (Yu et al., 2015 ; Ahn et al., 2018 ), etc ., but the penetration of nanomaterials into tumor tissues (P) remains the bottleneck in nanomaterial delivery (Kim et al., 2017 ), preventing intracellular entry (I) and release (R) into tumor cells far from blood vessels, especially in hypoxic regions, resulting in unsatisfactory efficacy, an important reason for the failure of many recently developed nano-drugs in clinical trials. For example, DOXIL (Barenholz, 2012 ), a nano-drug consisting of doxorubicin hydrochloride in liposomes, was able to circulate steadily in the blood for several days, with a significantly higher concentration of DOXIL at the tumor site than that of a control group injected with the small molecule adriamycin.…”

Ferritin Nanocages for Protein Delivery to Tumor Cells

“…Pt-based compounds are widely used in clinics for the treatment of several types of cancer, but they show significant side effects. Delivery systems like ferritin improve their overall biocompatibility, half-time life in the bloodstream, and target selectivity [63,64].…”

“…Alternative approaches, which involve the use of denaturing agents such as 8 M urea, do not substantially improve the incorporation efficiency, even leading to an excessive waste of the drug [64,70]. More recently, a new technique based on high hydrostatic pressure (HHP) has been developed to reversibly change protein conformation [71].…”