Encapsulation of Temozolomide in a Calixarene Nanocapsule Improves Its Stability and Enhances Its Therapeutic Efficacy against Glioblastoma

Abstract

The alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic for glioblastoma (GBM), a common and aggressive primary brain tumor in adults. However, its poor stability and unfavorable 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 used 1 H-NMR, LC-MS, and UV-Vis spectroscopy to chart the stability of this novel TMZ@Calix complex according to FDA and European Medicines Agency 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 with 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 threefold 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 patients with GBM and warrants further preclinical and clinical evaluation.

Metal ion-responsive nanocarrier derived from phosphonated calix[4]arenes for delivering dauricine specifically to sites of brain injury in a mouse model of intracerebral hemorrhage

“…Among the macromolecules, calixarene is considered to represent the third-generation of host-guest supramolecular chemistry [51]. Calixarene and its derivatives have been reported to have antiviral, antibacterial, antifungal, antitubercular, and anticancer activity [52]. In the present work, from TEM images, we found that the size of PM and ad DPM are same as DLS.…”

Co-Loading of Temozolomide and Curcumin into a Calix[4]arene-Based Nanocontainer for Potential Combined Chemotherapy: Binding Features, Enhanced Drug Solubility and Stability in Aqueous Medium

“…However, prolonged therapy leads to TMZ resistance and poor responsiveness to subsequent treatments. The entrapment of TMZ in the cavity of macrocycles, such as cyclodextrin [14,15], cucurbituril [16], or p-sulfonato-calix [4]arene [17], and in nanostructured systems, including liposome [18], lactoferrin nanoparticle [19], and lipidic nanocarriers [20], has enhanced the chemotherapeutic efficacy of TMZ by increasing its half-life and consequently the amount of drug gaining in the target cells.…”

Accurately Controlled Delivery of Temozolomide by Biocompatible UiO-66-NH2 Through Ultrasound to Enhance the Antitumor Efficacy and Attenuate the Toxicity for Treatment of Malignant Glioma

“…Temozolomide cytotoxicity is mainly manifested in the alkylation of the guanine sixth oxygen atom and seventh nitrogen atom on the DNA molecule. Through mismatch repair of methylated adducts, the cycle of glioma cells is affected, thus the cytotoxic effect is triggered 46 as demonstrated in the results. Moreover, the inhibitory effect in the TMZ@UiO-66-NH 2 + Ultrasound group was more obvious than that in the II group (Figure 7E-G).…”