Elsevier

Particuology

Volume 64, May 2022, Pages 65-84
Particuology

Review
A critical review of ferritin as a drug nanocarrier: Structure, properties, comparative advantages and challenges

https://doi.org/10.1016/j.partic.2021.04.020Get rights and content

Highlights

  • Structure and properties afford solid foundation for ferritin as a drug nanocarrier.

  • Drug loading approaches are diverse and applicable to different types of drugs.

  • Functionalization of ferritin is by chemical conjugation, gene technology, hybridization.

  • Drug loading performance and administration routes need improvement.

Abstract

Ferritin stores and releases iron ions in mammals. It is globally important as a drug nanocarrier. This is because of its unique hollow-spherical structure, desirable stability and biological properties. Novel drug-loading approaches plus various functionalization approaches have been developed to improve ferritin in response to differing demands in disease treatments. Here, we critically review ferritin drug delivery and evaluate its diverse drug-loading and functionalization approaches, we: (1) Introduce basic structural and property information related to ferritin as a drug nanocarrier; (2) Contrast in detail the different means to load drugs and the selection of drug loading means; (3) Discuss multiple ferritin functionalization approaches, together with related advantages and potential risks; and, (4) Compare ferritin with alternative, commonly-used drug nanocarriers. We conclude that despite that no drugs based on ferritin are commercially available, the market potential for it is significant, and evaluate future research directions. Findings from this work will be of immediate benefit and interest to a wide range of researchers and manufacturers for drug delivery using ferritin.

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.

References (155)

  • G. Fracasso et al.

    Selective delivery of doxorubicin by novel stimuli-sensitive nano-ferritins overcomes tumor refractoriness

    Journal of Controlled Release

    (2016)
  • J. Guo et al.

    Efficient expression of recombinant human heavy chain ferritin (FTH1) with modified peptides

    Protein Expression and Purification

    (2017)
  • J.A. Han et al.

    Ferritin protein cage nanoparticles as versatile antigen delivery nanoplatforms for dendritic cell (DC)-based vaccine development

    Nanomedicine

    (2014)
  • M.J. Haney et al.

    Exosomes as drug delivery vehicles for Parkinson’s disease therapy

    Journal of Controlled Release

    (2015)
  • D. He et al.

    Ferritin family proteins and their use in bionanotechnology

    New Biotechnology

    (2015)
  • J. He et al.

    Ferritin drug carrier (FDC) for tumor targeting therapy

    Journal of Controlled Release

    (2019)
  • P.D. Hempstead et al.

    Comparison of the three-dimensional structures of recombinant human H and horse L ferritins at high resolution

    Journal of Molecular Biology

    (1997)
  • M. Khoshnejad et al.

    Ferritin-based drug delivery systems: Hybrid nanocarriers for vascular immunotargeting

    Journal of Controlled Release

    (2018)
  • S. Kim et al.

    Designing peptide bunches on nanocage for bispecific or superaffinity targeting

    Biomacromolecules

    (2016)
  • M.A. Knovich et al.

    Ferritin for the clinician

    Blood Reviews

    (2009)
  • K. Kono et al.

    Preparation and cytotoxic activity of poly(ethylene glycol)-modified poly(amidoamine) dendrimers bearing adriamycin

    Biomaterials

    (2008)
  • D.M. Lawson et al.

    Identification of the ferroxidase centre in ferritin

    FEBS Letters

    (1989)
  • L.A. Lee et al.

    Adaptations of nanoscale viruses and other protein cages for medical applications

    Nanomedicine

    (2006)
  • N.K. Lee et al.

    Ferritin nanocage with intrinsically disordered proteins and affibody: A platform for tumor targeting with extended pharmacokinetics

    Journal of Controlled Release

    (2017)
  • S.J. Lee et al.

    Magnetic enhancement of iron oxide nanoparticles encapsulated with poly(d,l-latide-co-glycolide)

    Colloids and Surfaces A: Physicochemical and Engineering Aspects

    (2005)
  • E.J. Lee et al.

    Bioengineered protein-based nanocage for drug delivery

    Advanced Drug Delivery Reviews

    (2016)
  • Y. Lei et al.

    Targeted tumor delivery and controlled release of neuronal drugs with ferritin nanoparticles to regulate pancreatic cancer progression

    Journal of Controlled Release

    (2016)
  • J.Y. Li et al.

    Scara5 is a ferritin receptor mediating non-transferrin iron delivery

    Developmental Cell

    (2009)
  • L. Li et al.

    Comparison of two endogenous delivery agents in cancer therapy: Exosomes and ferritin

    Pharmacological Research

    (2016)
  • M. Li et al.

    Apoferritin nanocages with Au nanoshell coating as drug carrier for multistimuli-responsive drug release

    Materials Science & Engineering C

    (2019)
  • M. Mir et al.

    Recent applications of PLGA based nanostructures in drug delivery

    Colloids and Surfaces B: Biointerfaces

    (2017)
  • N.M. Molino et al.

    Caged protein nanoparticles for drug delivery

    Current Opinion in Biotechnology

    (2014)
  • D.M. Monti et al.

    Ferritin-based anticancer metallodrug delivery: Crystallographic, analytical and cytotoxicity studies

    Nanomedicine

    (2019)
  • B. Ahn et al.

    Four-fold channel-nicked human ferritin nanocages for active drug loading and pH-responsive drug release

    Angewandte Chemie International Edition

    (2018)
  • A.C. Anselmo et al.

    Nanoparticles in the clinic: An update

    Bioengineering & Translational Medicine

    (2019)
  • D. Belletti et al.

    Protein cage nanostructure as drug delivery system: Magnifying glass on apoferritin

    Expert Opinion on Drug Delivery

    (2017)
  • C. Bharti et al.

    Mesoporous silica nanoparticles in target drug delivery system: A review

    International Journal of Pharmaceutical Investigation

    (2015)
  • I. Blazkova et al.

    Apoferritin modified magnetic particles as doxorubicin carriers for anticancer drug delivery

    International Journal of Molecular Sciences

    (2013)
  • A. Bonizzi et al.

    Everolimus nanoformulation in biological nanoparticles increases drug responsiveness in resistant and low-responsive breast cancer cell lines

    Pharmaceutics

    (2019)
  • M. Boumaiza et al.

    Production and characterization of functional recombinant hybrid heteropolymers of camel hepcidin and human ferritin H and L chains

    Protein Engineering Design and Selection

    (2017)
  • W. Cai et al.

    Metal-organic framework-based nanomedicine platforms for drug delivery and molecular imaging

    Small

    (2015)
  • A.M. Caminade et al.

    Dendrimers and hyperbranched polymers

    Chemical Society Reviews

    (2015)
  • Z. Chen et al.

    Apoferritin nanocage for brain targeted doxorubicin delivery

    Molecular Pharmaceutics

    (2017)
  • X. Cheng et al.

    TfR1 binding with H-ferritin nanocarrier achieves prognostic diagnosis and enhances the therapeutic efficacy in clinical gastric cancer

    Cell Death & Disease

    (2020)
  • D. Cioloboc et al.

    Targeted cancer cell delivery of arsenate as a reductively activated prodrug

    Journal of Biological Inorganic Chemistry

    (2020)
  • L. Conti et al.

    L-Ferritin targets breast cancer stem cells and delivers therapeutic and imaging agents

    Oncotarget

    (2016)
  • T.A. Cornell et al.

    The crystal structure of a maxi/mini-ferritin chimera reveals guiding principles for the assembly of protein cages

    Biochemistry

    (2017)
  • R.R. Crichton et al.

    Subunit interactions in horse spleen apoferritin. Dissociation by extremes of pH

    Biochemical Journal

    (1973)
  • H. Daraee et al.

    Application of gold nanoparticles in biomedical and drug delivery

    Artificial Cells, Nanomedicine, and Biotechnology

    (2016)
  • V. de Turris et al.

    Humanized archaeal ferritin as a tool for cell targeted delivery

    Nanoscale

    (2017)
  • Cited by (16)

    • A novel view of ferritin in cancer

      2023, Biochimica et Biophysica Acta - Reviews on Cancer
    • Formation of ferritin-agaro oligosaccharide-epigallocatechin gallate nanoparticle induced by CHAPS and partitioned by the ferritin shell with enhanced delivery efficiency

      2023, Food Hydrocolloids
      Citation 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).

    • Ferritin self-assembly, structure, function, and biotechnological applications

      2023, International Journal of Biological Macromolecules
      Citation 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.

    View all citing articles on Scopus
    View full text