Microwave Responsive Nanoplatform via P-Selectin Mediated Drug Delivery for Treatment of Hepatocellular Carcinoma with Distant Metastasis.

Hepatocellular carcinoma (HCC) with metastatic disease is associated with a low survival in clinical practice. Many curative options including liver resection, transplantation, and thermal ablation are effective in local but limited for patients with distant metastasis. In this study, the efficacy, specificity, and safety of P-selectin targeted delivery and microwave (MW) responsive drug release is investigated for development of HCC therapy. By encapsulating doxorubicin (DOX) and MW sensitizer (1-butyl-3-methylimidazolium-l-lactate, BML) into fucoidan conjugated liposomal nanoparticles (TBP@DOX), specific accumulation and prominent release of DOX in orthotopic HCC and lung metastasis are achieved with adjuvant MW exposure. This results in orthotopic HCC growth inhibition that is not only 1.95-fold higher than found for nontargeted BP@DOX and 1.6-fold higher than nonstimuli responsive TP@DOX but is also equivalent to treatment with free DOX at a 10-fold higher dose. Furthermore, the optimum anticancer efficacy against distant lung metastasis and effective prevention of widespread dissemination with a prolonged survival is described. In addition, no adverse metabolic events are identified using the TBP@DOX nanodelivery system despite these events being commonly observed with traditional DOX chemotherapy. Therefore, administering TBP@DOX with MW exposure could potentially enhance the therapeutic efficacy of thermal-chemotherapy of HCC, especially those in the advanced stages.

Imaging-guided synergetic therapy of orthotopic transplantation tumor by superselectively arterial administration of microwave-induced microcapsules.

It is an ambitious target to improve overall Hepatocellular Carcinoma therapeutic effects. Recently, MW ablation has emerged as a powerful thermal ablation technique, affording favorable survival with excellent local tumor control. To achieve better therapeutic effects of MW ablation, MW sensitizers are prepared for enhanced MW ablation to preferentially heat tumor territory. However, it is still not practicable for treatment of the orthotopic transplantation tumor. Herein, biocompatible and degradable methoxy poly(ethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA) microcapsules with hierarchical structure have been designed for microwave-induced tumor therapy. Chemical drug doxorubicin hydrochloride (DOX·HCl), microwave (MW) sensitizers and CT imaging contrast MoS2 nanosheets and MR imaging contrast Fe3O4 nanoparticles are co-incorporated into the microcapsules. In vitro/vivo MR/CT dual-modal imaging results prove the potential application for guiding synergetic therapy and predicting post-therapy tumor progression in the orthotopic transplantation tumor model. After blocking the tumor-feeding arteries, these microcapsules not only exclude the cooling effect by cutting off the blood flow but also enhance MW heating conversion at tumor site. The focused MW heating makes microcapsules mollescent or ruptured and releases DOX·HCl from the microcapsules, achieving the controlled release of drugs for chemical therapy. Compared with MW ablation, 29.4% increase of necrosis diameter of normal liver in rabbit is obtained under MW ablation combined with transcatheter arterial blocking, and the average size of necrosis and inhibition rate of VX-2 liver orthotopic transplantation tumor in rabbit has increased by 129.33% and 73.46%. Moreover, it is proved that the superselectively arterial administration of the as-prepared microcapsules has no recognizable toxicity on the animals. Therefore, this research provides a novel strategy for the construction of MW-induced microcapsules for orthotopic transplantation tumor ablation with the properties of MW sensitizing, superselective arterial blocking, control release and enhanced accumulation of DOX·HCl, and MR/CT dual-modal imaging, which exhibits great potential applications in the field of HCC therapy.

Therapeutic efficacy of novel microwave-sensitized mPEG-PLGA@ZrO2@(DOX + ILS) drug-loaded microspheres in rabbit VX2 liver tumours.

The use of nanomaterials as drug delivery systems shows good effects in treating tumors. However, the effective dose of drugs targeted to tumor tissues is very low because of the effect of the reticuloendothelial system (RES) in removing such foreign substances. In order to eliminate the RES effect, we developed mPEG-PLGA@ZrO2@(DOX + ILS) (mPEG-PLGA@ZrO2@[DOX + ILS]) drug-loaded microspheres. These microwave (MW)-sensitized microspheres directly embolized the blood-supply vessels of tumors to induce tumor ischemia and hypoxia, as well as to aggregate drugs within tumor tissues in a long-lasting manner. Additionally, combination with MW ablation can triple the effects for the inhibition of tumor growth. The MW sensitive ionic liquid (ILS) in microspheres can rapidly produce a high temperature in a MW field on the basis of MW sensitization, thus accelerating the degradation of microspheres to release DOX-loaded ZrO2 into the lesions to kill tumors. Microspheres can also prolong the pharmacological time and effect of drugs through the enhanced permeability and retention (EPR) effect of nanocarriers, as well as the sustained release of nanomaterials. Studies performed in vivo revealed that mPEG-PLGA@ZrO2@(DOX + ILS) showed good biosafety. We undertook sensitized microsphere embolism therapy using novel mPEG-PLGA@ZrO2@(DOX + ILS) microspheres in a rabbit VX2 liver tumor model. Three, 6 and 9 d after treatment, computed tomography indicated no significant change in tumor size, and diffusion weighted imaging showed a marked decrease of residual tumor tissues. With the multiple functions of inducing embolisms, sensitization, and the sustained release of chemotherapeutics, novel mPEG-PLGA@ZrO2@(DOX + ILS) microspheres can achieve good therapeutic efficacy, in combination with MW ablation and chemotherapy, while embolizing the blood vessels of arterial tumors.

Porous PLGA microspheres with recruited ions and doxorubicin for triple-combination therapy of larger hepatocellular carcinoma.

Easy recurrence of large hepatocellular carcinoma (HCC) after microwave (MW) ablation or transarterial chemoembolization (TACE) is still very challenging. In this study, porous polylactide-co-glycolide (PLGA) microspheres as a MW-susceptible TACE agent (P-PLGA@DN microspheres) for triple-combination therapy of large HCC were developed via the double emulsion technique using recruited ions (Na+ and Cl-) and doxorubicin hydrochloride (DOX·HCl) to enhance the efficiency of MW absorption and DOX chemotherapy after tumor embolization. The as-prepared microspheres with superior MW-heat conversion can enlarge the ablation area by >53% in a simulated physiological environment. The in vivo efficiencies of chemotherapy and thermal therapy for ICR mice bearing H22 tumor cells under the assistance of P-PLGA@DN microspheres reach to 100%. In the experiments of synergistic therapy combining TACE with MW ablation on VX2 tumor-bearing New Zealand white rabbits, PLGA@DN microspheres can increase ablation area by more than 50%, enhancing the necrosis of tumor cells and effectively inhibiting tumor growth. These results demonstrate that the potential application of P-PLGA@DN microspheres in synergistic therapy of large HCC can be envisioned.

Multisynergistic Platform for Tumor Therapy by Mild Microwave Irradiation-Activated Chemotherapy and Enhanced Ablation.

Microwave (MW) therapy, as a promising type of thermal therapy, has been attracting more and more attention from scientists. The combination of thermal and chemotherapy is of great significance in the latest studies of synergistic tumor therapy. However, the research on the MW therapy mechanism, especially the nonthermal effect applied in the combined cancer therapy, is not thorough enough. Pleasantly, we have discovered that nonthermal MW irradiation can promote the cellular uptake of nanoparticles and anticancer drugs via experiments in vitro and in vivo. Therefore, multifunctional nanoplatforms have been designed for enhanced tumor inhibition by loading ionic liquids (ILs), doxorubicin hydrochloride (DOX), and phase change materials (PCMs) into ZrO2 hollow nanoparticles. PCMs act as MW switches. The as-made IL-DOX-PCM@ZrO2 nanoplatforms were injected into H22-tumor-bearing mice via the tail vein. Mild microwave irradiation (0.9 W, 450 MHz) was then applied. The thermal effect of MW could cause the temperature of the tumor site to rise (58 °C). On the other hand, it will trigger the MW switch to open and release DOX when the temperature is high enough. At the same time as drug release, a MW nonthermal effect could improve the cellular uptake of nanomaterials and anticancer drugs. The multisynergistic effect can promote the survival rate of the IL-DOX-PCM@ZrO2+MW group to 100%. The results of the tumor therapy experiment in vivo demonstrated that as-made multifunctional IL-DOX-PCM@ZrO2 nanoplatforms could enhance the therapeutic outcome of combined thermal and chemotherapy under mild MW irradiation.

In Vivo Magnetic Resonance Imaging and Microwave Thermotherapy of Cancer Using Novel Chitosan Microcapsules.

Herein, we develop a novel integrated strategy for the preparation of theranostic chitosan microcapsules by encapsulating ion liquids (ILs) and Fe3O4 nanoparticles. The as-prepared chitosan/Fe3O4@IL microcapsules exhibit not only significant heating efficacy in vitro under microwave (MW) irradiation but also obvious enhancement of T2-weighted magnetic resonance (MR) imaging, besides the excellent biocompatibility in physiological environments. The chitosan/Fe3O4@IL microcapsules show ideal temperature rise and therapeutic efficiency when applied to microwave thermal therapy in vivo. Complete tumor elimination is realizing after MW irradiation at an ultralow power density (1.8 W/cm(2)), while neither the MW group nor the chitosan microcapsule group has significant influence on the tumor development. The applicability of the chitosan/Fe3O4@IL microcapsules as an efficient contrast agent for MR imaging is proved in vivo. Moreover, the result of in vivo systematic toxicity shows that chitosan/Fe3O4@IL microcapsules have no acute fatal toxicity. Our study presents an interesting type of multifunctional platform developed by chitosan microcapsule promising for imaging-guided MW thermotherapy.