ReviewA critical review of ferritin as a drug nanocarrier: Structure, properties, comparative advantages and challenges
Graphical abstract
Introduction
The advent of drug nanocarriers is a significant step in improved disease therapy and safety (Haney et al., 2015; Parveen, Misra, & Sahoo, 2012; Peer et al., 2007; Xia et al., 2015). Drug nanocarriers are specifically synthesized particles with a nanometer size range. This size results in advantageous properties including, a large surface-to-volume ratio and rapid dispersion. The large-surface-to-volume ratio is advantageous because it permits modification sites and adequate drug storage space. Because of rapid dispersion, drug nanocarriers can be readily used in formulations. In addition, drug nanocarriers improve efficacy and safety in disease therapy via pharmacokinetic profile improvement and targeted delivery. They function to prevent drugs from unwanted degradation and interactions, both in storage and in vivo. They are cleared from circulation relatively slowly, when compared with molecules of other sizes. Some drug nanocarriers have controlled, or sustained drug release at targeted areas. A benefit of drug nanocarriers is an enhanced permeation and retention effect (EPR), namely, passive tumor targeting ability. This has been demonstrated in rodents, although application to human needs study (Danhier, 2016; Maeda, 2017).
Because of these multi-benefits, researchers from multi-disciplines have developed a wide range of drug nanocarriers (Lombardo, Kiselev, & Caccamo, 2019). Commonly used drug nanocarriers include liposome, dendrimer, synthesized polymer-based nanoparticles, metal particles, and metal-organic frameworks. Amongst drug nanocarriers, protein cage is a new category. Its protein nature provides an innate biodegradability and approaches for genetic alteration in contrast with other types of nanocarriers (Lee, Lee, & Kim, 2016; Moon, Lee, Min, & Kang, 2014). Commonly used protein cages include ferritin, virus-like particles and heat-shock protein.
In this review, we focus on ferritin. Ferritin is produced by almost all living organisms, including archaea, bacteria, plants and animals. In mammals, it acts as a buffer against iron-deficiency and iron-overload by storing and releasing iron ions. It has been used as a drug nanocarrier and in medical-related areas for some decades (Belletti et al., 2017; He, Fan, & Yan, 2019; Jutz, van Rijn, Santos Miranda, & Boker, 2015; Khoshnejad, Parhiz, Shuvaev, Dmochowski, & Muzykantov, 2018). Mammalian ferritin structure and properties have been well-investigated. A wide range of drugs targeting different diseases have been loaded onto ferritin, including anti-tumor chemotherapeutics, neutral drugs, antibiotics and genes. Various approaches of drug-loading into ferritin have been studied, and condition optimization has been used to achieve desirable loading performance. As a drug delivery platform, ferritin has a number of advantageous properties. However, poor drug loading performance is a practical limitation. In addition, researchers have worked on functionalization means to incorporate other functional molecules with it to broaden its application. Functionalization will also impact ferritin structure and drug delivery performance.
Despite an increasing global interest, there has not been a substantial review summarizing and evaluating ferritin as a drug nanocarrier in detail, for example, comparing and explaining drug-loading approaches and ferritin functionalization means. In this timely review, we address this need.
The overall aim is to present a critical summary of basic structural and property information, and advantages and drawbacks, together with current approaches for improvement. This review consists of four sections: (1) Introduction of ferritin basic structure and property, with focus on potential for ferritin as a drug nanocarrier; (2) Contrasting different means to load drugs in detail, through investigating mechanisms and comparing these in terms of the crucial evaluation indicator of loading performance. This is because evaluation of indicators and understanding of drug-loading mechanisms guide selection of judicious loading approaches; (3) Discussion of multiple ferritin functionalization approaches, aims, advantages and potential risks; and, (4) Comparison of ferritin with other commonly used drug nanocarriers through aspects related to therapeutic application. Findings will be of immediate interest to a wide range of researchers and benefit to manufacturers of equipment for drug delivery using ferritin.
Section snippets
Ferritin structure and properties: the basis for a new drug nanocarrier
A growing knowledge of ferritin structure and its properties has been accumulated since it was first identified in 1937 (Laufberger, 1937). This growth in understanding has contributed to its potential development for drug delivery because the unique structure and properties are the solid foundation of ferritin to be a drug nanocarrier.
Ferritin drug-loading approaches and mechanisms
When ferritin was initially used as a drug nanocarrier, researchers drew on its natural function, namely, storing Fe ions. This is the reason why various transition metal ions and metal-ion containing molecules were encapsulated into the ferritin cavity (Monti, Ferraro, & Merlino, 2019). This cavity was also explored as a size-constrained synthesis vessel for organic and inorganic nanoparticles (Meldrum, Wade, Nimmo, Heywood, & Mann, 1991). As more detailed information about ferritin structure
Ferritin functionalization
Although ferritin possesses many desirable characteristics as a drug nanocarrier, it needs to be functionalized for a broader application and improvement in treatment outcomes. The two most investigated functions are half-life extension and targeting ability. A 2–3 h half-life in circulation of human H-chain ferritin is unsatisfactory (Wang, Zhang et al., 2018). Passive targeting ability and the limited types of targeted receptors of ferritin cannot always achieve satisfactory safety.
Widely
Ferritin and alternative drug nanocarriers, strength and weakness
Despite significant study of ferritin structure, property, drug-loading and functionalization, no drug based on it has entered the commercial market. In clinical studies, it is used primarily as disease indicator (Knovich, Storey, Coffman, Torti, & Torti, 2009; Orino & Watanabe, 2008). In contrast, a number of other commonly used drug nanocarriers have been approved, which include liposome, polymeric and albumin bound nanoparticles (Anselmo & Mitragotri, 2019). Compared with these, ferritin is
Conclusion and future research with ferritin
The structure and properties of mammalian ferritins have been well understood and made good use of. Diverse drug loading and functionalization approaches have been well-established and a wide range of drugs and functional moieties are able to be applied. However, compared to other nanocarriers, ferritin drug-loading performance and administration need to be improved. Overall, ferritin holds great practical potentials as a drug carrier.
Several aspects need further investigation: (1) New/modified
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was funded by joint PhD Scholarship Scheme of the University of Adelaide and Institute of Process Engineering, Chinese Academy of Sciences, the National Natural Science Foundation of China (Grant No. 21576267), and Beijing Natural Science Foundation (Grant Number 2162041). Great appreciations to Prof Anton Middelberg from the University of Adelaide for his advice.
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2023, Food HydrocolloidsCitation Excerpt :Thus, the decoration of the ferritin with other molecules may have a great effect on the ferritin function. On the other hand, the channels size of ferritin is narrow, with about 0.3–0.5 nm in pore size (Arosio & Levi, 2002; Uchida, Kang, Reichhardt, Harlen, & Douglas, 2010; Yin, Davey, Dai, Liu, & Bi, 2022). These channels link the luminal cavity of ferritin to the external solution, but only permit the entrance and the outflow of the metal ions and organic small molecules (Masuda, Goto, & Yoshihara, 2001; Palombarini, Di Fabio, Boffi, Macone, & Bonamore, 2020).
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2023, International Journal of Biological MacromoleculesCitation Excerpt :Self-assembly is accelerated with an increase of ionic strength and with a decrease of pH (from 7.5 to 5.5). pH-dependent disassembly of the protein shell is widely used in different practical applications (see section “Applications”) [229]. In general, self-assembly is an important feature, which plays a crucial role in protein functionality.