Redox-Responsive Magnetic Nanoparticle for Targeted Convection-Enhanced Delivery of O⁶-Benzylguanine to Brain Tumors

Abstract

Resistance to temozolomide (TMZ) based chemotherapy in glioblastoma multiforme (GBM) has been attributed to the upregulation of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Inhibition of MGMT using O6-benzylguanine (BG) has shown promise in these patients, but its clinical use is hindered by poor pharmacokinetics that leads to unacceptable toxicity. To improve BG biodistribution and efficacy, we developed superparamagnetic iron oxide nanoparticles (NP) for targeted convection-enhanced delivery (CED) of BG to GBM. The nanoparticles (NPCP-BG-CTX) consist of a magnetic core coated with a redox-responsive, cross-linked, biocompatible chitosan-PEG copolymer surface coating (NPCP). NPCP was modified through covalent attachment of BG and tumor targeting peptide chlorotoxin (CTX). Controlled, localized BG release was achieved under reductive intracellular conditions and NPCP-BG-CTX demonstrated proper trafficking of BG in human GBM cells in vitro. NPCP-BG-CTX treated cells showed a significant reduction in MGMT activity and the potentiation of TMZ toxicity. In vivo, CED of NPCP-BG-CTX produced an excellent volume of distribution (Vd) within the brain of mice bearing orthotopic human primary GBM xenografts. Significantly, concurrent treatment with NPCP-BG-CTX and TMZ showed a 3-fold increase in median overall survival in comparison to NPCP-CTX/TMZ treated and untreated animals. Furthermore, NPCP-BG-CTX mitigated the myelosuppression observed with free BG in wild-type mice when administered concurrently with TMZ. The combination of favorable physicochemical properties, tumor cell specific BG delivery, controlled BG release, and improved in vivo efficacy demonstrates the great potential of these NPs as a treatment option that could lead to improved clinical outcomes.

Focused Ultrasound‐Augmented Delivery of Biodegradable Multifunctional Nanoplatforms for Imaging‐Guided Brain Tumor Treatment

“…It has been demonstrated that disulfide bonds are sensitive to the reducing environment,19 which have been used to incorporate into the framework of HMONs and to link PA imaging contrast agents (Cu 2− x Se‐PEG‐SH nanoparticles) to HMONs ( Figure 3 a). To investigate the redox‐responsive biodegradable behavior and drug‐releasing pattern of DOX‐HCu, simulated body fluid (SBF) containing different glutathione (GSH) concentration (0, 5, or 10 × 10 −3 m ) was adopted to mimic the reducing TME, followed by observing the structural evolution of HCu by TEM during the biodegradation process.…”

Studies of the Colloidal Properties of Superparamagnetic Iron Oxide Nanoparticles Functionalized with Platinum Complexes in Aqueous and PBS Buffer Media

“…1 Magnetic resonance imaging, 2-4 hyperthermia [5][6][7] and drug delivery [8][9][10][11][12] are some of the practical applications displayed by SPIONs. These nanomaterials are promising due to the biocompatibility of the iron oxide cores, e.g., magnetite (Fe 3 O 4 ) and maghemite (γ-Fe 2 O 3 ).…”

Managing CNS Tumors: The Nanomedicine Approach

“…Furthermore, the versatility of CED has enabled the coadministration of different liposomal formulations to enhance the effect of the anticancer agents [33,34]. Concerning CED, numerous nanomedicines were formulated with a hydrophilic coating of polyethylene glycol and administered as slightly viscous suspensions to achieve optimal distribution volumes that cover the whole brain tumor tissue [35]. In fact, the deprivation of the hydrophilic coating, albeit increased median overall survival in comparison with untreated controls, significantly differed from efficacy findings reported for animals receiving the pegylated nanomedicines [36].…”

“…Nevertheless, it has been postulated the existence of a "threshold extent of pegylation," over which the hindrance conferred by polyethylene glycol to interact with the tumor cells counterbalances the increase in CED distribution volume provided by slight pegylation [37]. On the other hand, the addition of active targeting moieties that preferentially bind to receptors that are overexpressed on brain tumor cells to promote the delivery of nanomedicines to their target cells is controversial: whereas the attachment of OX26 or a cell-penetrating peptide has shown to enhance both tumor and healthy tissue internalization, which led to the appearance of side effects and high morbidity [38], the attachment of chlorotoxin or antibodies that selectively bind to the epidermal growth factor receptor mutant (EGFRvIII) present on human glioblastoma cells achieved significant survival benefits [35,39,40]. The different response could be explained by the choice of the ligand: ligands that preferentially bind to receptors on the cerebral endothelium are pointless in local delivery, whereas ligands that bind to receptors overexpressed on the brain tumor cells are those to be used for active targeting in local delivery.…”

“…O 6 -benzylguanine has been loaded in iron oxide nanoparticles provided with a biocompatible chitosan-polyethylene glycol coating and actively targeted by chlorotoxin. The concurrent CED administration of these magnetic nanoparticles with oral temozolomide in mice implanted with a GBM6 clinically relevant xenograft extended by twofold the survival times in comparison with mice treated without the MGMT inhibitor and greatly mitigated the severe myelosuppression associated with systemic administration of free O 6 -benzylguanine [35].…”