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Encapsulation of temozolomide in a calixarene nanocapsule improves its stability and enhances its therapeutic efficacy against glioblastoma

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Title: Encapsulation of temozolomide in a calixarene nanocapsule improves its stability and enhances its therapeutic efficacy against glioblastoma
Authors: Renziehausen, A
Tsiailanis, AD
Perryman, R
Stylos, EK
Chatzigiannis, C
O'Neill, K
Crook, T
Tzakos, AG
Syed, N
Item Type: Journal Article
Abstract: The alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic for glioblastoma (GBM), a common and aggressive primary brain tumour in adults. However, its poor stability and unfavourable pharmacokinetic profile limit its clinical efficacy. There is an unmet need to tailor the therapeutic window of TMZ, either through complex derivatization or by utilizing pharmaceutical excipients. To enhance stability and aqueous solubility, we encapsulated TMZ in a p-sulphonatocalix[4]arene (Calix) nanocapsule and employed 1H-NMR, LC-MS and UV-Vis spectroscopy to chart the stability of this novel TMZ@Calix complex according to FDA and EMA guidelines. LC-MS/MS plasma stability assays were conducted in mice to further explore the stability profile of TMZ@Calix in vivo. The therapeutic efficacy of TMZ@Calix was compared to that of unbound TMZ in GBM cell lines and patient derived primary cells with known O6-methylguanine-DNA methyltransferase (MGMT) expression status and in vivo in an intracranial U87 xenograft mouse model. Encapsulation significantly enhanced the stability of TMZ in all conditions tested. TMZ@Calix was more potent than native TMZ at inhibiting the growth of established GBM cell lines and patient derived primary lines expressing MGMT and highly resistant to TMZ. In vivo, native TMZ was rapidly degraded in mouse plasma, whereas the stability of TMZ@Calix was enhanced 3-fold with increased therapeutic efficacy in an orthotopic model. In the absence of new effective therapies, this novel formulation is of clinical importance serving as an inexpensive and highly efficient treatment that could be made readily available to GBM patients and warrants further pre-clinical and clinical evaluation.
Issue Date: 1-Sep-2019
Date of Acceptance: 11-Jun-2019
URI: http://hdl.handle.net/10044/1/71600
DOI: 10.1158/1535-7163.mct-18-1250
ISSN: 1535-7163
Publisher: American Association for Cancer Research (AACR)
Journal / Book Title: Molecular Cancer Therapeutics
Volume: 18
Issue: 9
Copyright Statement: Copyright ©2019, American Association for Cancer Research.
Sponsor/Funder: Barrow Foundation UK
Brain Tumour Research Campaign
Brain Tumour Research
Funder's Grant Number: N/A
N/A
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
ADJUVANT TEMOZOLOMIDE
NANOPARTICLES
DELIVERY
DNA
RADIOTHERAPY
FLUORESCENT
CONCOMITANT
DOXORUBICIN
NANOFIBERS
RELEASE
1112 Oncology and Carcinogenesis
1115 Pharmacology and Pharmaceutical Sciences
Oncology & Carcinogenesis
Publication Status: Published
Online Publication Date: 2019-06-18
Appears in Collections:Department of Brain Sciences