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RSC advances2024; 14(20); 14008-14016; doi: 10.1039/d3ra07430g

Encapsulation of copper phenanthroline within horse spleen apoferritin: characterisation, cytotoxic activity and ability to retain temozolomide.

Abstract: Protein capsules are promising drug delivery vehicles for cancer research therapies. Apoferritin (AFt) is a self-assembling 12 nm diameter hollow nanocage with many desirable features for drug delivery, however, control of drug retention inside the protein cage remains challenging. Here we report the encapsulation of copper(ii)-1,10-phenanthroline (Cu(phen)) within the horse spleen AFt (HSAFt) nanocage, by diffusion of the metal through the pores between the protein subunits. Transmission electron microscopy revealed the formation of organised copper adducts inside HSAFt, without affecting protein integrity. These structures proved stable during storage (>4 months at -20 °C). Exposure to physiologically relevant conditions (37 °C) showed some selectivity in cargo release after 24 h at pH 5.5, relevant to the internalisation of AFt within the endosome (60% release), compared to pH 7.4, relevant to the bloodstream (40% release). Co-encapsulation of temozolomide, a prodrug used to treat glioblastoma multiforme, and Cu(phen) enabled entrapment of an average of 339 TMZ molecules per cage. results from MTT and clonogenic assays identified cytotoxic activity of the Cu(phen), HSAFt-Cu(phen) and HSAFt-Cu(phen)-TMZ adducts against colorectal cancer cells (HCT-116) and glioblastoma cells (U373V, U373M). However, the presence of the metal also contributed to more potent activity toward healthy MRC5 fibroblasts, a result that requires further investigation to assess the clinical viability of this system.
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Publication Date: 2024-04-29 PubMed ID: 38686295PubMed Central: PMC11056943DOI: 10.1039/d3ra07430gGoogle Scholar: Lookup
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Summary

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The research article presents a new method for drug delivery in cancer treatments using protein capsules. Encapsulation of copper phenanthroline within a protein called Apoferritin was explored for potential application in delivering chemotherapy drugs like Temozolomide. Furthermore, the encapsulation showed great stability and exhibited cytotoxic activity against cancer cells.

Encapsulation Process and Stability

  • Apoferritin (AFt), a protein known for self-assembly into a 12 nm diameter hollow nanocage, was identified as a promising substance for drug delivery. The researchers encapsulated copper(ii)-1,10-phenanthroline (Cu(phen)) within AFt from horse spleen.
  • The encapsulation involves the passage of the metal through pores present in-between protein subunits. Using transmission electron microscopy, the researchers confirmed the formation of organized copper adducts inside the nanocage. Impressively, the encapsulation didn’t affect the AFt protein’s integrity.
  • These formations demonstrated excellent stability, remaining in shape even after four months of storage at -20 ℃.

Drug Release Selectivity

  • Exposure to physiological conditions (37 °C) showed interesting selectivity in drug release. At a pH level of 5.5, which simulates conditions within the endosome (the compartment that internalizes substances within cells), approximately 60% of cargo was released after 24 hours.
  • Conversely, under conditions equivalent to the bloodstream (pH 7.4), only 40% of the encapsulated copper was released. This differential release is crucial in delivering drugs to target sites effectively while minimizing possible harm to healthy cells and tissues.

Cytotoxic Activity and Further Investigations

  • A co-encapsulation strategy was adopted to include Temozolomide, a drug used for glioblastoma multiforme treatment, with Cu(phen). On average, 339 Temozolomide molecules were entrapped per protein nanocage.
  • Tests were conducted to measure cytotoxic activity against colorectal cancer cells and glioblastoma cells. The Cu(phen), Apoferritin-Cu(phen), and Apoferritin-Cu(phen)-Temozolomide clusters showed potent cytotoxic activity.
  • However, the presence of the metal contributed to increased activity against healthy MRC5 fibroblasts (a type of cell in connective tissues). This surprising observation highlights the need for further investigation to assess the clinical viability of this system for cancer treatment.

Cite This Article

APA
Cassioli ML, Fay M, Turyanska L, Bradshaw TD, Thomas NR, Pordea A. (2024). Encapsulation of copper phenanthroline within horse spleen apoferritin: characterisation, cytotoxic activity and ability to retain temozolomide. RSC Adv, 14(20), 14008-14016. https://doi.org/10.1039/d3ra07430g

Publication

RSC advances
ISSN: 2046-2069
NlmUniqueID: 101581657
Country: England
Language: English
Volume: 14
Issue: 20
Pages: 14008-14016

Researcher Affiliations

Cassioli, Maria Letizia
  • Faculty of Engineering, University of Nottingham NG7 2RD UK anca.pordea@nottingham.ac.uk.
Fay, Michael
  • Nanoscale and Microscale Research Centre, University of Nottingham NG7 2RD UK.
Turyanska, Lyudmila
  • Faculty of Engineering, University of Nottingham NG7 2RD UK anca.pordea@nottingham.ac.uk.
Bradshaw, Tracey D
  • Biodiscovery Institute, School of Pharmacy, University of Nottingham NG7 2RD UK.
Thomas, Neil R
  • Biodiscovery Institute, School of Chemistry, University of Nottingham NG7 2RD UK.
Pordea, Anca
  • Faculty of Engineering, University of Nottingham NG7 2RD UK anca.pordea@nottingham.ac.uk.

Conflict of Interest Statement

There are no conflicts to declare.

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