Delivery of temozolomide and N3-propargyl analog to brain tumors using an apoferritin nanocage

Bouzinab, Kaouthar; Summers, Helen; Stevens, Malcolm F.G.; Moody, Christopher J.; Thomas, Neil R.; Gershkovich, Pavel; Weston, Nicola; Ashford, Marianne B.; Bradshaw, Tracey D.; Turyanska, Lyudmila

Abstract

Glioblastoma multiforme (GBM) is a grade IV astrocytoma, which is the most aggressive form of brain tumor. The standard of care for this disease includes surgery, radiotherapy and temozolomide (TMZ) chemotherapy. Poor accumulation of TMZ at the tumor site, tumor resistance to drug, and dose-limiting bone marrow toxicity eventually reduce the success of this treatment. Herein, we have encapsulated >500 drug molecules of TMZ into the biocompatible protein nanocage, apoferritin (AFt), using a "nanoreactor" method (AFt-TMZ). AFt is internalized by transferrin receptor 1-mediated endocytosis and is therefore able to facilitate cancer cell uptake and enhance drug efficacy. Following encapsulation, the protein cage retained its morphological integrity and surface charge; hence, its cellular recognition and uptake are not affected by the presence of this cargo. Additional benefits of AFt include maintenance of TMZ stability at pH 5.5 and drug release under acidic pH conditions, encountered in lysosomal compartments. MTT assays revealed that the encapsulated agents displayed significantly increased antitumor activity in U373V (vector control) and, remarkably, the isogenic U373M (MGMT expressing TMZ-resistant) GBM cell lines, with GI50 values 500 molecules of the N3-propargyl imidazotetrazine analog (N3P), developed to combat TMZ resistance, and demonstrated significantly enhanced activity of AFt-N3P against GBM and colorectal carcinoma cell lines. These studies support the use of AFt as a promising nanodelivery system for targeted delivery, lysosomal drug release, and enhanced imidazotetrazine potency for treatment of GBM and wider-spectrum malignancies.

Citation

Bouzinab, K., Summers, H., Stevens, M. F., Moody, C. J., Thomas, N. R., Gershkovich, P., …Turyanska, L. (2020). Delivery of temozolomide and N3-propargyl analog to brain tumors using an apoferritin nanocage. ACS Applied Materials and Interfaces, 12(11), 12609-12617. https://doi.org/10.1021/acsami.0c01514

• Journal Article Type: Article
• Acceptance Date: Feb 19, 2020
• Online Publication Date: Feb 19, 2020
• Publication Date: Mar 18, 2020
• Deposit Date: Mar 2, 2020
• Publicly Available Date: Mar 2, 2020
• Journal: ACS applied materials and Interfaces
• Print ISSN: 1944-8244
• Electronic ISSN: 1944-8252
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 11
• Pages: 12609-12617
• DOI: https://doi.org/10.1021/acsami.0c01514
• Keywords: General Materials Science
• Public URL: https://nottingham-repository.worktribe.com/output/4077357
• Publisher URL: https://pubs.acs.org/doi/10.1021/acsami.0c01514