Modulation of blood-brain tumor barrier for delivery of magnetic hyperthermia to brain cancer.

Glioblastoma (GBM) is the most invasive brain tumor and remains lack of effective treatment. The existence of blood-brain tumor barrier (BBTB) constitutes the greatest barrier to non-invasive delivery of therapeutic agents to tumors in the brain. Here, we propose a novel approach to specifically modulate BBTB and deliver magnetic hyperthermia in a systemic delivery mode for the treatment of GBM. BBTB modulation is achieved by targeted delivering fingolimod to brain tumor region via dual redox responsive PCL-SeSe-PEG (poly (ε-caprolactone)-diselenium-poly (ethylene glycol)) polymeric nanocarrier. As an antagonist of sphingosine 1-phosphate receptor-1 (S1P1), fingolimod potently inhibits the barrier function of BBB by blocking the binding of sphingosine 1-phosphate (S1P) to S1P1 in endothelial cells. We found that the modulated BBTB showed slight expression level of tight junction proteins, allowing efficient accumulation of zinc- and cobalt- doped iron oxide nanoclusters (ZnCoFe NCs) with enhanced magnetothermal conversion efficiency into tumor tissues through the paracellular pathway. As a result, the co-delivery of heat shock protein 70 inhibitor VER-155008 with ZnCoFe NCs could realize synergistic magnetic hyperthermia effects upon exposure to an alternating current magnetic field (ACMF) in both GL261 and U87 brain tumor models. This modulation approach brings new ideas for the treatment of central nervous system diseases that require delivery of therapeutic agents across the blood-brain barrier (BBB).

Vessel-Targeting Nanoclovers Enable Noninvasive Delivery of Magnetic Hyperthermia-Chemotherapy Combination for Brain Cancer Treatment.

Despite being promising, the clinical application of magnetic hyperthermia for brain cancer treatment is limited by the requirement of highly invasive intracranial injections. To overcome this limitation, here we report the development of gallic acid-coated magnetic nanoclovers (GA-MNCs), which allow not only for noninvasive delivery of magnetic hyperthermia but also for targeted delivery of systemic chemotherapy to brain tumors. GA-MNCs are composed of clover-shaped MNCs in the core, which can induce magnetic heat in high efficiency, and polymerized GA on the shell, which enables tumor vessel-targeting. We demonstrate that intravenous administration of GA-MNCs following alternating magnetic field exposure effectively inhibited brain cancer development and preferentially disrupted tumor vasculature, making it possible to efficiently deliver systemic chemotherapy for further improved efficacy. Due to the noninvasive nature and high efficiency in killing tumor cells and enhancing systemic drug delivery, GA-MNCs have the potential to be translated for improved treatment of brain cancer.

Enhanced Tumor Synergistic Therapy by Injectable Magnetic Hydrogel Mediated Generation of Hyperthermia and Highly Toxic Reactive Oxygen Species.

Nanoparticle-mediated tumor magnetic induction hyperthermia has received tremendous attention. However, it has been a challenge to improve the efficacy at 42 °C therapeutic temperatures without resistance to induced thermal stress. Therefore, we designed a magnetic hydrogel nanozyme (MHZ) utilizing inclusion complexation between PEGylated nanoparticles and α-cyclodextrin, which can enhance tumor oxidative stress levels by generating reactive oxygen species through nanozyme-catalyzed reactions based on tumor magnetic hyperthermia. MHZ can be injected and diffused into the tumor tissue due to shear thinning as well as magnetocaloric phase transition properties, and magnetic heat generated by the Fe3O4 first gives 42 °C of hyperthermia to the tumor. Fe3O4 nanozyme exerts peroxidase-like properties in the acidic environment of tumor to generate hydroxyl radicals (•OH) by the Fenton reaction. The hyperthermia promotes the enzymatic activity of Fe3O4 nanozyme to produce more •OH. Simultaneously, •OH further damages the protective heat shock protein 70, which is highly expressed in hyperthermia to enhance the therapeutic effect of hyperthermia. This single magnetic nanoparticle exerts dual functions of hyperthermia and catalytic therapy to synergistically treat tumors, overcoming the resistance of tumor cells to induced thermal stress without causing severe side effects to normal tissues at 42 °C hyperthermia.

Magnetic targeting combined with active targeting of dual-ligand iron oxide nanoprobes to promote the penetration depth in tumors for effective magnetic resonance imaging and hyperthermia.

The combination of multi-targeting magnetic nanoprobes and multi-targeting strategies has potential to facilitate magnetic resonance imaging (MRI) and magnetic induction hyperthermia of the tumor. Although the thermo-agents based on magnetic iron oxide nanoparticles (MION) have been successfully used in the form of intratumoral injection in clinical cure of glioblastoma, the tumor-targeted thermotherapy by intravenous administration remains challenging. Herein, we constructed a c(RGDyK)- and d-glucosamine-grafted bispecific molecular nanoprobe (Fe3O4@RGD@GLU) with a magnetic iron oxide core of size 22.17 nm and a biocompatible shell of DSPE-PEG2000, which can specially target the tumor vessel and cancer cells. The selection of c(RGDyK) could make the nanoprobe enter the neovascularization endotheliocyte through αvß3-mediated endocytosis, which drastically reduced the dependence on the enhanced permeability and retention (EPR) effect in tumor. This dual-ligand nanoprobe exhibited strong magnetic properties and favorable biocompatibility. In vitro studies confirmed the anti-phagocytosis ability against macrophages and the specific targeting capability of Fe3O4@RGD@GLU. Then, the imaging effect and anti-tumor efficacy were compared using different targeting strategies with untargeted nanoprobes, dual-targeted nanoprobes, and magnetic targeting combined with dual-targeted nanoprobes. Moreover, the combination strategy of magnetic targeting and active targeting promoted the penetration depth of nanoprobes in addition to the increased accumulation in tumor tissue. Thus, the dual-targeted magnetic nanoprobe together with the combined targeting strategy could be a promising method in tumor imaging and hyperthermia through in vivo delivery of theranostic agents. STATEMENT OF SIGNIFICANCE: Magnetic induction hyperthermia based on iron oxide nanoparticles has been used in clinic for adjuvant treatment of recurrent glioblastoma. Nonetheless, this application is limited to intratumoral injection, and tumor-targeted hyperthermia by intravenous injection remains challenging. In this study, we developed a multi-targeted strategy by combining magnetic targeting with active targeting of dual-ligand magnetic nanoprobes. This combination mode acquired optimum contrast imaging effect through MRI and tumor-suppressive effect through hyperthermia under an alternating current magnetic field. The design of the nanoprobe was suitable for targeting most tumor lesions, which enabled it to be an effective theranostic agent with extensive uses. This study showed significant enhancement of the penetration depth and accumulation of nanoprobes in the tumor tissue for efficient imaging and hyperthermia.

Injectable thermosensitive magnetic nanoemulsion hydrogel for multimodal-imaging-guided accurate thermoablative cancer therapy.

Ferrofluid-based magnetic hyperthermia of cancers has gained significant attention in recent years due to its excellent efficacy, few deleterious side effects and unlimited tissue penetration capacity. However, the high tumor osmotic pressure causes injection leakage and thus position imprecision because of the fluidity of the ferrofluid and the absence of multimodal imaging guidance, which create tremendous challenges for clinical application. Here, a body temperature-induced gelation strategy is constructed for accurate localized magnetic tumor regression based on the unique behaviors of a magnetic nanoemulsion hydrogel (MNH) within tumors. The rapid intra-tumor gelation can securely restrict the MNH in tumor tissue without diffusion and leakage. The magnetically induced nanoparticle assembly-enhanced heating in the hydrogel and the heat accumulation caused by crosslinking among the nanoemulsion droplets further increased the heating efficiency. Meanwhile, US/MR/NIR multimodal imaging can guide the whole therapeutic process, achieving excellent magnetic hyperthermia therapeutic efficiency. This work highlights the great promise for improving the magnetic hyperthermia efficiency and the precision of the injection site for localized tumor therapy.