Biodegradable reduce expenditure bioreactor for augmented sonodynamic therapy via regulating tumor hypoxia and inducing pro-death autophagy.

BACKGROUNDS: Sonodynamic therapy (SDT) as an emerging reactive oxygen species (ROS)-mediated antitumor strategy is challenged by the rapid depletion of oxygen, as well as the hypoxic tumor microenvironment. Instead of the presently available coping strategies that amplify the endogenous O2 level, we have proposed a biodegradable O2 economizer to reduce expenditure for augmenting SDT efficacy in the present study. RESULTS: We successfully fabricated the O2 economizer (HMME@HMONs-3BP-PEG, HHBP) via conjugation of respiration inhibitor 3-bromopyruvate (3BP) with hollow mesoporous organosilica nanoparticles (HMONs), followed by the loading of organic sonosensitizers (hematoporphyrin monomethyl ether; HMME) and further surface modification of poly(ethylene glycol) (PEG). The engineered HHBP features controllable pH/GSH/US-sensitive drug release. The exposed 3BP could effectively inhibit cell respiration for restraining the oxygen consumption, which could alleviate the tumor hypoxia conditions. More interestingly, it could exorbitantly elevate the autophagy level, which in turn induced excessive activation of autophagy for promoting the therapeutic efficacy. As a result, when accompanied with suppressing O2-consumption and triggering pro-death autophagy strategy, the HHBP could achieve the remarkable antitumor activity, which was systematically validated both in vivo and in vitro assays. CONCLUSIONS: This work not only provides a reduce expenditure means for enduring SDT, but also represents an inquisitive strategy for tumor treatments by inducing pro-death autophagy.

Neutrophil-mediated clinical nanodrug for treatment of residual tumor after focused ultrasound ablation.

BACKGROUND: The risk of local recurrence after high-intensity focused ultrasound (HIFU) is relatively high, resulting in poor prognosis of malignant tumors. The combination of HIFU with traditional chemotherapy continues to have an unsatisfactory outcome because of off-site drug uptake. RESULTS: Herein, we propose a strategy of inflammation-tendency neutrophil-mediated clinical nanodrug targeted therapy for residual tumors after HIFU ablation. We selected neutrophils as carriers and PEGylated liposome doxorubicin (PLD) as a model chemotherapeutic nanodrug to form an innovative cell therapy drug (PLD@NEs). The produced PLD@NEs had a loading capacity of approximately 5 µg of PLD per 106 cells and maintained the natural characteristics of neutrophils. The targeting performance and therapeutic potential of PLD@NEs were evaluated using Hepa1-6 cells and a corresponding tumor-bearing mouse model. After HIFU ablation, PLD@NEs were recruited to the tumor site by inflammation (most in 4 h) and released PLD with inflammatory stimuli, leading to targeted and localized postoperative chemotherapy. CONCLUSIONS: This effective integrated method fully leverages the advantages of HIFU, chemotherapy and neutrophils to attract more focus on the practice of improving existing clinical therapies.

Evaluation of superparamagnetic iron oxide-polymer composite microcapsules for magnetic resonance-guided high-intensity focused ultrasound cancer surgery.

BACKGROUND: Superparamagnetic poly (lactic-co-glycolic acid) (PLGA)-coated Fe3O4 microcapsules are receiving increased attention as potential diagnostic and therapeutic modalities in the field of oncology. In this study, PLGA-coated Fe3O4 microcapsules were combined with a magnetic resonance imaging-guided high-intensity focused ultrasound (MR-guided HIFU) platform, with the objective of investigating the effects of these composite microcapsules regarding MR-guided HIFU liver cancer surgery in vivo. METHODS: PLGA-coated Fe3O4 microcapsules consisting of a liquid core and a PLGA-Fe3O4 shell were fabricated using a modified double emulsion evaporation method. Their acute biosafety was confirmed in vitro using MDA cells and in vivo using rabbits. To perform MR-guided HIFU surgery, the microcapsules were intravenously injected into a rabbit liver tumor model before MR-guided HIFU. T2-weighted images and MR signal intensity in normal liver parenchyma and tumor tissue were acquired before and after injection, to assess the MR imaging ability of the microcapsules. After MR-guided HIFU ablation tissue temperature mapping, the coagulative volume and histopathology of the tumor tissue were analyzed to investigate the ablation effects of MR-guided HIFUs. RESULTS: Scanning and transmission electron microscopy showed that the microcapsules displayed a spherical morphology and a shell-core structure (mean diameter, 587 nm). The hysteresis curve displayed the typical superparamagnetic properties of the microcapsules, which are critical to their application in MR-guided HIFU surgery. In MR-guided HIFU surgery, these microcapsules functioned as an MRI contrast agent, induced significant hyperthermal enhancement (P < 0.05) and significantly enhanced the volume of coagulative necrosis (P < 0.05). CONCLUSIONS: The administration of PLGA-coated Fe3O4 microcapsules is a potentially synergistic technique regarding the enhancement of MR-guided HIFU cancer surgery.

Lactic acid responsive sequential production of hydrogen peroxide and consumption of glutathione for enhanced ferroptosis tumor therapy.

Ferroptosis is characterized by the lethal accumulation of lipid reactive oxygen species (ROS), which has great potential for tumor therapy. However, developing new ferroptosis-inducing strategies by combining nanomaterials with small molecule inducers is important. In this study, an enzyme-gated biodegradable natural-product delivery system based on lactate oxidase (LOD)-gated biodegradable iridium (Ir)-doped hollow mesoporous organosilica nanoparticles (HMONs) loaded with honokiol (HNK) (HNK@Ir-HMONs-LOD, HIHL) is designed to enhance ferroptosis in colon tumor therapy. After reaching the tumor microenvironment, the outer LOD dissociates and releases the HNK to induce ferroptosis. Moreover, the released dopant Ir4+ and disulfide-bridged organosilica frameworks deplete intracellular glutathione (GSH), which is followed by GSH-mediated Ir(IV)/Ir(III) conversion. This leads to the repression of glutathione peroxidase 4 (GPX4) activity and decomposition of intratumoral hydrogen peroxide (H2O2) into hydroxyl radicals (•OH) by Ir3+-mediated Fenton-like reactions. Moreover, LOD efficiently depletes lactic acid to facilitate the generation of H2O2 and boost the Fenton reaction, which in turn enhances ROS generation. With the synergistic effects of these cascade reactions and the release of HNK, notable ferroptosis efficacy was observed both in vitro and in vivo. This combination of natural product-induced and lactic acid-responsive sequential production of H2O2 as well as the consumption of glutathione may provide a new paradigm for achieving effective ferroptosis-based cancer therapy.

Ultrasonic neural regulation over two-dimensional graphene analog biomaterials: Enhanced PC12 cell differentiation under diverse ultrasond excitation.

Two-dimensional (2D) biomaterials, with unique planar topology and quantum effect, have been widely recognized as a versatile nanoplatform for bioimaging, drug delivery and tissue engineering. However, during the complex application of nerve repair, in which inflammatory microenvironment control is imperative, the gentle manipulation and trigger of 2D biomaterials with inclusion and diversity is still challenging. Herein, inspired by the emerging clinical progress of ultrasound neuromodulation, we systematically studied ultrasound-excited 2D graphene analogues (graphene, graphene oxide, reduced graphene oxide (rGO) and carbon nitride) to explore their feasibility, accessibility, and adjustability for ultrasound-induced nerve repair in vitro. Quantitative observation of cell differentiation morphology demonstrates that PC12 cells added with rGO show the best compatibility and differentiation performance under the general ultrasound mode (0.5 w/cm2, 2 min/day) compared with graphene, graphene oxide and carbon nitride. Furthermore, the general condition can be improved by using a higher intensity of 0.7 w/cm2, but it cannot go up further. Later, ultrasonic frequency and duty cycle conditions were investigated to demonstrate the unique and remarkable inclusion and diversity of ultrasound over conventional electrical and surgical means. The pulse waveform with power of 1 MHz and duty cycle of 50 % may be even better, while the 3 MHz and 100 % duty cycle may not work. Overall, various graphene analog materials can be regarded as biosafe and accessible in both fundamental research and clinical ultrasound therapy, even for radiologists without material backgrounds. The enormous potential of diverse and personalized 2D biomaterials-based therapies can be expected to provide a new mode of ultrasound neuromodulation.

Hematoporphyrin encapsulated PLGA microbubble for contrast enhanced ultrasound imaging and sonodynamic therapy.

The purpose of this study was to develop a sonosensitizer-loaded multi-functional ultrasound (US) contrast agent for both tumour therapy and imaging. The hematoporphyrin (HP)-encapsulated poly(lactic-co-glycolic acid) microbubbles (HP-PLGA-MBs) were prepared and filled with perfluorocarbon gases. The enhancement of US imaging and its sonodynamically induced anti-tumour effect were evaluated by both in vitro and in vivo experiments. The HP-PLGA-MBs have a narrow size distribution and smooth surface with a mean diameter of 702.6 ± 56.8 nm and HP encapsulation efficiency of 63.50 ± 1.26% and drug-loading efficiency of 2.15 ± 0.13%. The HP-PLGA-MBs could well enhance the ultrasound imaging both in vitro and in vivo. A significant anti-tumour effect was obtained by HP-PLGA-MBs mediated sonodynamic therapy. The tumour growth rate and the tumour proliferation index were the lowest in the HP-PLGA-MBs plus sonication group. And the tumour cell apoptotic index was the biggest in the HP-PLGA-MBs plus sonication group. In conclusion, a sonosensitizer-loaded multi-functional contrast agent was constructed and the feasibility was demonstrated, which might provide a novel strategy for tumour imaging and therapy.

Prussian blue nanozyme-mediated nanoscavenger ameliorates acute pancreatitis via inhibiting TLRs/NF-κB signaling pathway.

Rationale: Acute pancreatitis (AP) is a serious acute condition affecting the abdomen and shows high morbidity and mortality rates. Its global incidence has increased in recent years. Inflammation and oxidative stress are potential therapeutic targets for AP. This study was conducted to investigate the intrinsic anti-oxidative and anti-inflammatory effects of Prussian blue nanozyme (PBzyme) on AP, along with its underlying mechanism. Methods: Prussian blue nanozymes were prepared by polyvinylpyrrolidone modification method. The effect of PBzyme on inhibiting inflammation and scavenging reactive oxygen species was verified at the cellular level. The efficacy and mechanism of PBzyme for prophylactically treating AP were evaluated using the following methods: serum testing in vivo, histological scoring following hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling fluorescence staining, polymerase chain reaction array, Kyoto Encyclopedia of Genes and Genomes analysis and Western blotting analysis. Results: The synthetic PBzyme showed potent anti-oxidative and anti-inflammatory effects in reducing oxidative stress and alleviating inflammation both in vitro and in vivo in the prophylactic treatment of AP. The prophylactic therapeutic efficacy of PBzyme on AP may involve inhibition of the toll-like receptor/nuclear factor-κB signaling pathway and reactive oxygen species scavenging. Conclusion: The single-component, gram-level mass production, stable intrinsic biological activity, biosafety, and good therapeutic efficacy suggest the potential of PBzyme in the preventive treatment of AP. This study provides a foundation for the clinical application of PBzyme.

Co-Immobilization of Ce6 Sono/Photosensitizer and Protonated Graphitic Carbon Nitride on PCL/Gelation Fibrous Scaffolds for Combined Sono-Photodynamic Cancer Therapy.

Aiming at developing a moderate and efficient sono-photodynamic therapy for breast cancer, tissue engineering scaffolds may provide an easy and efficient strategy to eliminate serious side effects in conventional surgery or chemotherapy, and thus, they are highly desired. However, the development of ideal sono-photodynamic therapeutic scaffolds is always hindered by the poor stability and incompatibility between the different biomaterial components. Herein, the Food and Drug Administration (FDA)-approved sono/photosensitizer Chlorin e6 (Ce6) was successfully and tightly incorporated into electrospun polycaprolactone/gelatin (PG) scaffolds via positively charged protonated g-C3N4 nanosheets (pCN). The PG fibers were precoated with graphene oxide (GO) to enable the assembly of pCN on the surface through electrostatic interactions. The Ce6@pCN-GO-PG composite scaffolds exhibited good cytocompatibility and excellent sono-photodynamic activity, leading to distinctly boosted reactive oxygen species (ROS) generation and a 95.8% inactivation rate of breast cancer cells through a synergistic sono-photodynamic process triggered by an 808 nm laser and 1 MHz ultrasound (US) excitation, within the clinical therapeutic dose. The as-developed scaffolds with unique ultrasound cavitation therapeutic effects can be used not only for complete eradication of tumor cells after surgery but also as a cell behavior observation platform of sono-photodynamic cancer therapy.

Multifunctional bone cement for synergistic magnetic hyperthermia ablation and chemotherapy of osteosarcoma.

Myelosuppression, gastrointestinal toxicity and hypersensitivities always accompany chemotherapy of osteosarcoma (OS). In addition, the intricate karyotype of OS, the lack of targeted antitumor drugs and the bone microenvironment that provides a protective alcove for tumor cells reduce the therapeutic efficacy of chemotherapy. Here, we developed a multifunctional bone cement loaded with Fe3O4 nanoparticles and the antitumor drug doxorubicin (DOX/Fe3O4@PMMA) for synergistic MH ablation and chemotherapy of OS. The localized intratumorally administered DOX/Fe3O4@PMMA can change from liquid into solid at the tumor site via a polyreaction. The designed multifunctional bone cement was constructed with Fe3O4 nanoparticles, PMMA, and an antitumor drug approved by the U.S. Food and Drug administration (FDA). The injectability, magnetic hyperthermia (MH) performance, controlled drug release profile, and synergistic therapeutic effect of DOX/Fe3O4@PMMA in vitro were investigated in detail. Furthermore, the designed DOX/Fe3O4@PMMA controlled the release of DOX, enhanced the apoptosis of OS tissue, and inhibited the proliferation of tumor cells, demonstrating synergistic MH ablation and chemotherapy of OS in vivo. The biosafety of DOX/Fe3O4@PMMA was also evaluated in detail. This strategy significantly reduced surgical time, avoided operative wounds and prevented patient pain, showing a great clinical translational potential for OS treatment.

An artificially engineered "tumor bio-magnet" for collecting blood-circulating nanoparticles and magnetic hyperthermia.

It is a great challenge to directly endow a tumor with specific functions for theranostic treatment. In this study, we report on a novel approach to transform a tumor into a "bio-magnet", to be magnetized on demand, in order to create an intrinsic tumor magnetic field that would collect magnetic nanoparticles (MNPs) circulating in the blood and achieve simultaneous magnetic hyperthermia. This was achieved by the localized intratumoral injection of liquid Nd2Fe14B/Fe3O4-PLGA, followed by solvent exchange that induces a liquid-to-solid transformation. After the magnetism charging process, the solid Nd2Fe14B/Fe3O4-PLGA implant was endowed with permanent magnetic properties and in situ created the magnetic field within the tumor tissue, making the tumor a "bio-magnet". After the creation of the bio-magnet, intravenously injected MNPs accumulated into the tumor tissue due to the tumor magnetic field. Importantly, both the in vitro and ex vivo results demonstrated the high efficiency of the implanted bio-magnet for magnetic hyperthermia. This new approach achieves magnetic targeting by creating a tumor "bio-magnet", which generates a strong magnetic field within the tumor, paving a new way for the development of an efficient targeting strategy for tumor therapy.

PMMA-Fe3O4 for internal mechanical support and magnetic thermal ablation of bone tumors.

Background: Minimally invasive modalities are of great interest in the field of treating bone tumors. However, providing reliable mechanical support and fast killing of tumor cells to achieve rapid recovery of physical function is still challenging in clinical works. Methods: A material with two functions, mechanical support and magnetic thermal ablation, was developed from Fe3O4 nanoparticles (NPs) distributed in a polymethylmethacrylate (PMMA) bone cement. The mechanical properties and efficiency of magnetic field-induced thermal ablation were systematically and successfully evaluated in vitro and ex vivo. CT images and pathological examination were successfully applied to evaluate therapeutic efficacy with a rabbit bone tumor model. Biosafety evaluation was performed with a rabbit in vivo, and a cytotoxicity test was performed in vitro. Results: An NP content of 6% Fe3O4 (PMMA-6% Fe3O4, mFe: 0.01 g) gave the most suitable performance for in vivo study. At the 56-day follow-up after treatment, bone tumors were ablated without obvious side effects. The pathological examination and new bone formation in CT images clearly illustrate that the bone tumors were completely eliminated. Correspondingly, after treatment, the tendency of bone tumors toward metastasis significantly decreased. Moreover, with well-designed mechanical properties, PMMA-6%Fe3O4 implantation endowed tumor-bearing rabbit legs with excellent bio-mimic bone structure and internal support. Biosafety evaluation did not induce an increase or decrease in the immune response, and major functional parameters were all at normal levels. Conclusion: We have presented a novel, highly efficient and minimally invasive approach for complete bone tumor regression and bone defect repair by magnetic thermal ablation based on PMMA containing Fe3O4 NPs; this approach shows excellent heating ability for rabbit VX2 tibial plateau tumor ablation upon exposure to an alternating magnetic field (AMF) and provides mechanical support for bone repair. The new and powerful dual-function implant is a promising minimally invasive agent for the treatment of bone tumors and has good clinical translation potential.

Phase-shift, targeted nanoparticles for ultrasound molecular imaging by low intensity focused ultrasound irradiation.

PURPOSE: Ultrasound (US) molecular imaging provides a non-invasive way to visualize tumor tissues at molecular and cell levels and could improve diagnosis. One problem of using US molecular imaging is microbubbles challenges, including instability, short circulation time, and poor loading capacity and penetrability. It is urgent to design new acoustic contrast agents and new imaging methods to facilitate tumor-targeted imaging. In this study, phase-shift poly lactic-co-glycolic acid (PLGA) nanoparticles modified with folate as an efficient US molecular probe were designed and the long-term targeted imaging was achieved by low-intensity focused US (LIFU) irradiation. METHODS: A new 5-step method and purification procedure was carried out to obtain uniform folic acid polyethylene glycol PLGA (PLGA-PEG-FA), the structure of which was confirmed by 1H nuclear magnetic resonance spectroscopy and thin-layer chromatography. Perflenapent (PFP) was wrapped in PLGA-PEG-FA by a double emulsion solvent evaporation method to obtain PFP/PLGA-PEG-FA nanoparticles. The targeted ability of the resulting nanoparticles was tested in vivo and in vitro. LIFU irradiation can irritate nanoparticle phase-shift to enhance tumor imaging both in vivo and in vitro. RESULTS: PLGA-PEG-FA was a light yellow powder with a final purity of at least 98%, the structure of which was confirmed by 1H nuclear magnetic resonance spectroscopy and thin-layer chromatography. Highly dispersed PFP/PLGA-PEG-FA nanoparticles with spherical morphology have an average diameter of 280.9±33.5 nm, PFP load efficiency of 59.4%±7.1%, and shells, thickness of 28±8.63 nm. The nanoparticles can specifically bind to cells expressing high folate receptor both in vivo and in vitro. Ultrasonic imaging was significantly enhanced in vitro and in vivo by LIFU irradiation. The retention time was significantly prolonged in vivo. CONCLUSION: Phase-shift PFP/PLGA-PEG-FA nanoparticles induced by LIFU can significantly enhance ultrasonic imaging, specifically targeting tumors expressing folate receptor. As a potential targeting acoustic molecular probe, PFP/PLGA-PEG-FA nanoparticles can be used to achieve targeted localization imaging.

High-intensity focused ultrasound-triggered nanoscale bubble-generating liposomes for efficient and safe tumor ablation under photoacoustic imaging monitoring.

High-intensity focused ultrasound (HIFU) is widely applied to tumors in clinical practice due to its minimally invasive approach. However, several issues lower therapeutic efficiency in some cases. Many synergists such as microbubbles and perfluorocarbon nanoparticles have recently been used to improve HIFU treatment efficiency, but none were determined to be effective and safe in vivo. In this study, nanoscale bubble-generating liposomes (liposomes containing ammonium bicarbonate [Lip-ABC]) were prepared by film hydration followed by sequential extrusion. Their stable nanoscale particle diameter was confirmed, and their bubble-generating capacity after HIFU triggering was demonstrated with ultrasound imaging. Lip-ABC had good stability in vivo and accumulated in the tumor interstitial space based on the enhanced permeability and retention effect evaluated by photoacoustic imaging. When used to synergize HIFU ablation to bovine liver in vitro and implanted breast tumors of BALB/c nude mice, Lip-ABC outperformed the control. Importantly, all mice survived HIFU treatment, suggesting that Lip-ABC is a safe HIFU synergist.

Injectable PLGA/Fe3O4 implants carrying cisplatin for synergistic magnetic hyperthermal ablation of rabbit VX2 tumor.

Magnetic hyperthermia ablation has attracted wide attention in tumor therapy for its minimal invasion. Although the chemo-hyperthermal synergism has been proven to be effective in subcutaneously xenografted tumors of nude mice in our previous experiment, the occurrence of residual tumors due to incomplete ablation is more common in relatively larger and deeper-seated tumors in anti-tumor therapy. Thus, a larger tumor and larger animal model are needed for further study of the therapeutic efficacy. In this study, we tested the efficiency of this newly developed technique using a rabbit tumor model. Furthermore, we chose cisplatin (DDP), which has been confirmed with high efficiency in enhancing hyperthermia therapy as the chemotherapeutic drug for the synergistic magnetic hyperthermal ablation therapy of tumors. In vitro studies demonstrated that developed DDP-loaded magnetic implants (DDP/PLGA-Fe3O4) have great heating efficacy and the drug release can be significantly boosted by an external alternating magnetic field (AMF). In vivo studies showed that the phase-transitional DDP/PLGA-Fe3O4 materials that are ultrasound (US) and computerized tomography (CT) visible can be well confined in the tumor tissues after injection. When exposed to AMF, efficient hyperthermia was induced, which led to the cancer cells' coagulative necrosis and accelerating release of the drug to kill residual tumors. Furthermore, an activated anti-tumor immune system can promote apoptosis of tumor cells. In conclusion, the DDP/PLGA-Fe3O4 implants can be used efficiently for the combined chemotherapy and magnetic-hyperthermia ablation of rabbit tumors.

A Laser-Activated Biocompatible Theranostic Nanoagent for Targeted Multimodal Imaging and Photothermal Therapy.

Multifunctional nanoparticles have been reported for cancer detection and treatment currently. However, the accurate diagnosis and efficient treatment for tumors are still not satisfied. Here we report on the development of targeted phase change multimodal polymeric nanoparticles for the imaging and treatment of HER2-positive breast cancer. METHODS: We evaluated the multimodal imaging capabilities of the prepared nanoparticles in vitro using agar-based phantoms. The targeting performance and cytotoxicity of the nanoparticles were examined in cell culture using SKBR3 (over-expressing HER2) and MDA-MB-231 (HER2 negative) cells. We then tested the magnetic resonance (MR)/ photoacoustic (PA)/ ultrasound (US)/ near-infrared fluorescence (NIRF) multimodal imaging properties and photothermal effect of the nanoparticles in vivo using a SKBR3 breast xenograft model in nude mice. Tissue histopathology and immunofluorescence were also conducted. RESULTS: Both in vitro and in vivo systematical studies validated that the hybrid nanoparticles can be used as a superb MR/US/PA/NIRF contrast agent to simultaneously diagnose and guide tumor photothermal therapy (PTT). When irradiated by a near infrared laser, the liquid PFP vaporizes to a gas, rapidly expelling the contents and damaging surrounding tissues. The resulting micro-sized bubbles provide treatment validation through ultrasound imaging. Localization of DIR and SPIO in the tumor region facilitate photothermal therapy for targeted tumor destruction. The mice treated with HER2 targeted nanoparticles had a nearly complete response to treatment, while the controls showed continued tumor growth. CONCLUSION: This novel theranostic agent may provide better diagnostic imaging and therapeutic potential than current methods for treating HER2-positive breast cancer.

Injectable and thermally contractible hydroxypropyl methyl cellulose/Fe3O4 for magnetic hyperthermia ablation of tumors.

The development of efficient strategies for the magnetic hyperthermia ablation of tumors remains challenging. To overcome the significant safety limitations, we developed a thermally contractible, injectable and biodegradable material for the minimally invasive and highly efficient magnetic hyperthermia ablation of tumors. This material was composed of hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA) and Fe3O4. The thermal contractibility of HPMC/Fe3O4 was designed to avoid damaging the surrounding normal tissue upon heating, which was confirmed by visual inspection, ultrasound imaging and computed tomography (CT). The efficient injectability of HPMC/Fe3O4 was proven using a very small needle. The biosafety of HPMC/Fe3O4 was evaluated by MTT and biochemical assays as well as flow cytometry (FCM). All the aforementioned data demonstrated the safety of HPMC/Fe3O4. The results of in vitro and ex vivo experiments showed that the temperature and necrotic volume of excised bovine liver were positively correlated with the HPMC/Fe3O4 weight, iron content and heating duration. The in vivo experimental results showed that the tumors could be completely ablated using 0.06 ml of HPMC/60%Fe3O4 after 180 s of induction heating. We believe that this novel, safe and biodegradable material will promote the rapid bench-to-bed translation of magnetic hyperthermia technology, and it is also expected to bring a new concept for the biomaterial research field.

Nanoparticle-enhanced synergistic HIFU ablation and transarterial chemoembolization for efficient cancer therapy.

High-intensity focused ultrasound (HIFU) is being generally explored as a non-invasive therapeutic modality to treat solid tumors. However, the clinical use of HIFU for large and deep tumor-ablation applications such as hepatocellular carcinoma (HCC) is currently entangled with long treatment duration and high operating energy. This critical issue can be potentially resolved by the introduction of HIFU synergistic agents (SAs). Traditional SAs such as microbubbles and microparticles face the problem of large size, short cycle time, damage to mononuclear phagocytic system and unsatisfactory targeting efficiency. In this work, we have developed a facile and versatile nanoparticle-based HIFU synergistic cancer surgery enhanced by transarterial chemoembolization for high-efficiency HCC treatment based on elaborately designed Fe3O4-PFH/PLGA nanocapsules. Multifunctional Fe3O4-PFH/PLGA nanocapsules were administrated into tumor tissues via transarterial injection combined with Lipiodol to achieve high tumor accumulation because transarterial chemoembolization by Lipiodol could block the blood vessels. The high synergistic HIFU ablation effect was successfully achieved against HCC tumors based on the phase-transformation performance of the perfluorohexane (PFH) inner core in the composite nanocapsules, as systematically demonstrated in VX2 liver tumor xenograft in rabbits. Multifunctional Fe3O4-PFH/PLGA nanocapsules were also demonstrated as efficient contrast agents for ultrasound, magnetic resonance and photoacoustic tri-modality imagings, potentially applicable for imaging-guided HIFU synergistic surgery. Therefore, the elaborate integration of traditional transarterial chemoembolization with recently developed nanoparticle-enhanced HIFU cancer surgery could efficiently enhance the HCC cancer treatment outcome, initiating a new and efficient therapeutic protocol/modality for clinic cancer treatment.

A smart, phase transitional and injectable DOX/PLGA-Fe implant for magnetic-hyperthermia-induced synergistic tumor eradication.

Magnetic hyperthermia ablation is a new and minimally invasive modality for localized tumor removal. However, an inadequate ablation dosage can leave a residual tumor or cause a variety of complications. In addition, commonly used magnetic nanoparticles can easily escape from the tumor tissue, which present potential safety problems. In this study, a smart phase transitional and injectable implant based on biocompatible poly lactic-co-glycolic acid (PLGA) implant incorporating magnetic material (Fe powder) and anti-cancer drug (doxorubicin (DOX)) was developed. The magnetic-induced hyperthermia and release efficiency of DOX were evaluated in vitro. Drug release can be controlled under external alternating current magnetic field (AMF). The results of the in vivo tumor therapeutic efficacy showed that when exposed to external AMF, this smart injectable DOX/PLGA-Fe implant could converse magnetic energy into heat and accelerate the release of DOX, which leads to increasing the temperature to achieve tumor coagulative necrosis and accelerating the release of DOX to enhance residual tumor apoptosis. Furthermore, there was no leakage of magnetic material, as demonstrated using real-time ultrasound (US) and computerized tomography (CT) imaging, realizing the guidance and monitoring of tumor therapy. In conclusion, this smart phase transitional and injectable implant DOX/PLGA-Fe has the ability to improve the efficiency of this newly developed minimally invasive magnetic ablation of tumor treatment technique, and will provide a new avenue of developing minimally invasive synergistic tumor therapy.

Phase-Shifted PFH@PLGA/Fe3O4 Nanocapsules for MRI/US Imaging and Photothermal Therapy with near-Infrared Irradiation.

Photothermal therapy (PTT) utilizes photothermal conversion reagents to generate heat energy from absorbed light to effectively treat various malignant diseases. This approach has attracted broad and increasing interest in cancer treatment. Near-infrared (NIR)-induced PTT is particularly attractive because of its minimal absorbance by normal tissue and relatively deep tissue penetration. To improve the efficacy of PTT, we have developed nanocapsules encapsulating superparamagnetic iron oxide (Fe3O4) as synergistic agents for NIR-induced PTT. In this study, phase-shift and NIR photoabsorbing poly(lactic-co-glycolic acid) (PLGA) nanocapsules (perfluorohexane (PFH)@PLGA/Fe3O4) were fabricated for MRI/US dual-modal imaging-guided PTT. The multifunctional nanocapsules can be used not only to increase the local tumor temperature by absorbing the NIR energy but also as bimodal contrast agents for both MRI and US imaging. Such nanocapsules can be converted into microbubbles under NIR irradiation, which produces excellent contrast for US imaging and enhanced cancer ablation. We refer to the nanocapsule phase transition process induced by the infrared lamp as NIR radiation droplet vaporization (NIRDV).

Magnetic Hyperthermia Ablation of Tumors Using Injectable Fe3O4/Calcium Phosphate Cement.

In this work, we have developed an injectable and biodegradable material using CPC containing Fe3O4 nanoparticles for minimally invasive and efficiently magnetic hyperthermia ablation of tumors. When exposed to an alternating magnetic field, the MCPC could quickly generate heat. The temperature of PBS and the excised bovine liver increased with the MCPC weight, iron content, and time. The ablated liver tissue volume for 0.36 g of 10% MCPC was 0.2 ± 0.03, 1.01 ± 0.07, and 1.96 ± 0.19 cm(3), respectively, at the time point of 60, 180, and 300 s. In our in vivo experiment, the MCPC could be directly injected into the center of the tumors under the guidance of ultrasound imaging. The formed MCPC was well-restricted within the tumor tissues without leakage, and the tumors were completely ablated by 0.36 g of 10% injectable MCPC after 180 s of induction heating.