Temozolomide–Doxorubicin Conjugate as a Double Intercalating Agent and Delivery by Apoferritin for Glioblastoma Chemotherapy

Abstract

We designed a conjugated compound by coupling temozolomide (TMZ) with doxorubicin (DOX) via an acylhydrazone linkage as a potential prodrug used for glioblastoma multiforme (GBM) treatment. Viscosity and spectroscopic studies revealed that the drug conjugate could act as a nonclassical double intercalating agent. Although free TMZ is an inefficient DNA binder in comparison to DOX, the TMZ moiety interacted with DNA as an induced intercalator, arising from the synergistic effect of DOX moiety that mediated conformational changes of the DNA helix. Two binding modes were proposed to interpret the double intercalating effect of the drug conjugate on intra-and inter-DNA interactions that could cause DNA cross-linking and fibril aggregates. We also developed a delivery nanoplatform with a loading efficiency of 83% using copper-bound apoferritin as a nanocarrier. In sharp contrast to the short half-life of free TMZ, the nanocomposite was stable under physiological conditions without detectable drug decomposition after a 2 week storage, and drug release was activatable in the presence of glutathione at millimolar levels. The antitumor effect of the drug conjugate and nanocomposite against GBM cells was reported to demonstrate the potential therapeutic applications of double intercalating materials.

Doxorubicin-Induced Cognitive Impairment: The Mechanistic Insights

“…It was generally believed that doxorubicin has a limited capacity to penetrate the blood-brain barrier and thus the brain is protected from its damage. However, several studies have shown that doxorubicin has potential antitumor effects on brain cancer ( 14 ). Clinical as well as animal studies have shown that doxorubicin was detected in the brain after peripheral administration of the drug ( 15 , 16 ).…”

Research progress of anti-glioma chemotherapeutic drugs (Review)

“…DOX is an anthracycline antibiotic chemotherapy agent and is one of the most extensively used antitumor drugs ( 94 ). Its main mechanism of action is by quickly entering the nuclei of tumor cells and inhibiting the proliferation of tumor cells by binding to DNA and blocking DNA replication ( 95 , 96 ). DOX has been found to inhibit the proliferation of glioma cells.…”

Nanoparticulation of Prodrug into Medicines for Cancer Therapy

“…[81] It is also found that the drug-drug conjugate may change the mechanism of action, exemplified by temozolomide (TMZ)-Dox prodrug double intercalating with DNA although TMZ itself is a weak DNA binder and functioned as an induced intercalator. [82] Figure 5. A) Synthesis of PTX 2 and Self-assembly of PTX 2 in aqueous solution.…”