Enhancing Photothermal/Photodynamic Therapy for Glioblastoma by Tumor Hypoxia Alleviation and Heat Shock Protein Inhibition Using IR820-Conjugated Reduced Graphene Oxide Quantum Dots.

We use low-molecular-weight branched polyethylenimine (PEI) to produce cytocompatible reduced graphene oxide quantum dots (rGOQD) as a photothermal agent and covalently bind it with the photosensitizer IR-820. The rGOQD/IR820 shows high photothermal conversion efficiency and produces reactive oxygen species (ROS) after irradiation with near-infrared (NIR) light for photothermal/photodynamic therapy (PTT/PDT). To improve suspension stability, rGOQD/IR820 was PEGylated by anchoring with the DSPE hydrophobic tails in DSPE-PEG-Mal, leaving the maleimide (Mal) end group for covalent binding with manganese dioxide/bovine serum albumin (MnO2/BSA) and targeting ligand cell-penetrating peptide (CPP) to synthesize rGOQD/IR820/MnO2/CPP. As MnO2 can react with intracellular hydrogen peroxide to produce oxygen for alleviating the hypoxia condition in the acidic tumor microenvironment, the efficacy of PDT could be enhanced by generating more cytotoxic ROS with NIR light. Furthermore, quercetin (Q) was loaded to rGOQD through π-π interaction, which can be released in the endosomes and act as an inhibitor of heat shock protein 70 (HSP70). This sensitizes tumor cells to thermal stress and increases the efficacy of mild-temperature PTT with NIR irradiation. By simultaneously incorporating the HSP70 inhibitor (Q) and the in situ hypoxia alleviating agent (MnO2), the rGOQD/IR820/MnO2/Q/CPP can overcome the limitation of PTT/PDT and enhance the efficacy of targeted phototherapy in vitro. From in vivo study with an orthotopic brain tumor model, rGOQD/IR820/MnO2/Q/CPP administered through tail vein injection can cross the blood-brain barrier and accumulate in the intracranial tumor, after which NIR laser light irradiation can shrink the tumor and prolong the survival times of animals by simultaneously enhancing the efficacy of PTT/PDT to treat glioblastoma.

Chitosan-coated magnetic graphene oxide for targeted delivery of doxorubicin as a nanomedicine approach to treat glioblastoma.

In this study, magnetic graphene oxide (mGO) was first prepared and modified with chitosan to prepare chitosan-coated mGO (mGOC). Gastrin-releasing peptide (GRP)-conjugated mGOC (mGOCG) was then prepared from mGOC. The chemo drug doxorubicin (DOX) was adsorbed to mGOCG surface for dual active/magnetic targeted drug delivery. The DOX loading to mGOCG is 1.71 mg/mg, and drug release is pH-sensitive to facilitate drug delivery in endosomes. In vitro studies confirmed enhanced mGOCG endocytosis by U87 glioblastoma cells, with which enhanced cytotoxicity towards cancer cells could be achieved. This could be revealed from the drastically reduced half-maximal inhibitory concentration of mGOCG/DOX compared with DOX and mGOC/DOX. Furthermore, mGOCG/DOX can be localized under the influence of a magnetic field (MF) to exert this cytotoxic effect. An orthotopic brain tumor model by implanting U87 cells in the intracranial area of BALB/c nude mice was used to study the in vivo anti-tumor efficacy by intravenous injection of different samples and followed with bioluminescence imaging. The tumor size in the mGOCG/DOX + MF group demonstrated the best potency to suppress tumor growth and prolong animal survival time compared with mGOCG/DOX, mGOC/DOX, or DOX groups, indicating this new dual-targeting delivery system for DOX can effectively treat glioblastoma.

Safety and efficacy of intracranial vascularized submental lymph node transfer for treating hydrocephalus.

Hydrocephalus is routinely treated with ventriculoperitoneal shunt drainage of cerebrospinal fluid (CSF), a procedure plagued by high morbidity and frequent revisions. Vascularized submental lymph node (VSLN) transplants act as lymphatic pumps to drain interstitial fluid (ISF) from lymphedematous extremities. As the field of neuro-lymphatics comes to fruition, we hypothesize the efficacy of VSLN in the drainage of intracranial CSF-ISF. We report novel placement of VSLN in the temporal subdural space in two patients diagnosed with symptomatic communicating hydrocephalus. At a minimum follow-up of 1 month postoperatively, both experienced radiological and clinical improvements.

Lung metastasis-Harnessed in-Situ adherent porous organic nanosponge-mediated antigen capture for A self-cascaded detained dendritic cells and T cell infiltration.

The infiltration of cytotoxic T lymphocytes promises to suppress the most irresistible metastatic tumor for immunotherapy, yet immune privilege and low immunogenic responses in these aggressive clusters often restrict lymphocyte recruitment. Here, an in situ adherent porous organic nanosponge (APON) doubles as organ selection agent and antigen captor to overcome immune privilege is developed. With selective organ targeting, the geometric effect of APON composed of disc catechol-functionalized covalent organic framework (COF) boosts the drug delivery to lung metastases. Along with a self-cascaded immune therapy, the therapeutic agents promote tumor release of damage-associated molecular patterns (DAMPs), and then, in situ deposition of gels to capture these antigens. Furthermore, APON with catechol analogs functions as a reservoir of antigens and delivers autologous DAMPs to detain dendritic cells, resulting in a sustained enhancement of immunity. This disc sponges (APON) at lung metastasis as antigen reservoirs and immune modulators effectively suppress the tumor in 60 days and enhanced the survival rate.

Cetuximab-Conjugated Magnetic Poly(Lactic-co-Glycolic Acid) Nanoparticles for Dual-Targeted Delivery of Irinotecan in Glioma Treatment.

A glioma is the most common malignant primary brain tumor in adults and is categorized according to its growth potential and aggressiveness. Within gliomas, grade 4 glioblastoma remains one of the most lethal malignant solid tumors, with a median survival time less than 18 months. By encapsulating CPT-11 and oleic acid-coated magnetic nanoparticles (OMNPs) in poly(lactic-co-glycolic acid) (PLGA) nanoparticles, we first prepared PLGA@OMNP@CPT-11 nanoparticles in this study. After conjugating cetuximab (CET) with PLGA@OMNP@CPT-11, spherical PLGA@OMNP@CPT-11-CET nanoparticles with 250 nm diameter, 33% drug encapsulation efficiency, and 22% drug loading efficiency were prepared in a single emulsion/evaporation step. The nanoparticles were used for dual-targeted delivery of CPT-11 to U87 primary glioblastoma cells by actively targeting the overexpressed epidermal growth factor receptor on the surface of U87 cells, as well as by magnetic targeting. The physicochemical properties of nanoparticles were characterized in detail. CET-mediated targeting promotes intracellular uptake of nanoparticles by U87 cells, which can release four times more drug at pH 5 than at pH 7.4 to facilitate drug release in endosomes after intracellular uptake. The nanovehicle PLGA@OMNP-CET is cytocompatible and hemocompatible. After loading CPT-11, PLGA@OMNP@CPT-11-CET shows the highest cytotoxicity toward U87 compared with free CPT-11 and PLGA@OMNP@CPT-11 by providing the lowest drug concentration for half-maximal cell death (IC50) and the highest rate of cell apoptosis. In orthotopic brain tumor-bearing nude mice with U87 xenografts, intravenous injection of PLGA@OMNP@ CPT-11-CET followed by guidance with a magnetic field provided the best treatment efficacy with the lowest tumor-associated signal intensity from bioluminescence imaging.

Thermosensitive Cationic Magnetic Liposomes for Thermoresponsive Delivery of CPT-11 and SLP2 shRNA in Glioblastoma Treatment.

Thermosensitive cationic magnetic liposomes (TCMLs), prepared from dipalmitoylphosphatidylcholine (DPPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]-2000, and didodecyldimethylammonium bromide (DDAB) were used in this study for the controlled release of drug/gene for cancer treatment. After co-entrapping citric-acid-coated magnetic nanoparticles (MNPs) and the chemotherapeutic drug irinotecan (CPT-11) in the core of TCML (TCML@CPT-11), SLP2 shRNA plasmids were complexed with DDAB in the lipid bilayer to prepare TCML@CPT-11/shRNA with a 135.6 ± 2.1 nm diameter. As DPPC has a melting temperature slightly above the physiological temperature, drug release from the liposomes can be triggered by an increase in solution temperature or by magneto-heating induced with an alternating magnetic field (AMF). The MNPs in the liposomes also endow the TCMLs with magnetically targeted drug delivery with guidance by a magnetic field. The successful preparation of drug-loaded liposomes was confirmed by various physical and chemical methods. Enhanced drug release, from 18% to 59%, at pH 7.4 was observed when raising the temperature from 37 to 43 °C, as well as during induction with an AMF. The in vitro cell culture experiments endorse the biocompatibility of TCMLs, whereas TCML@CPT-11 shows some enhancement of cytotoxicity toward U87 human glioblastoma cells when compared with free CPT-11. The U87 cells can be transfected with the SLP2 shRNA plasmids with very high efficiency (~100%), leading to silencing of the SLP2 gene and reducing the migration ability of U87 from 63% to 24% in a wound-healing assay. Finally, an in vivo study, using subcutaneously implanted U87 xenografts in nude mice, demonstrates that the intravenous injection of TCML@CPT11-shRNA, plus magnetic guidance and AMF treatment, can provide a safe and promising therapeutic modality for glioblastoma treatment.

Effectiveness of the different treatments for medication-related osteonecrosis of the jaws in young players

Medication-related-osteonecrosis of the jaw, MRONJ, is a severe iatrogenic condition. Patients receiving certain types of medications related to the inhibition of osteoclast function may have an increased risk of developing bone necrosis. The overall prevalence of MRONJ is low, and the current treatment methods include antibiotics and surgical intervention. Objective: The main purpose is to compare the effectiveness of different contemporary treatment modalities in relation to MRONJ. Material and methods: A systematic electronic search was performed mainly using Pubmed. After adjustment of the exclusion criteria, a total of 21 articles were selected for this review. Result: The overall success rate for conservative treatment ranged from 0% to 33%, whereas surgical therapy had an overall success rate of 88.57% to 100%. Success rate for adjunctive treatment, including teriparatide, fluorescence guided surgery, low-level laser therapy, and leukocyte- and platelet-rich-fibrine ranged from 5.17% to 99.4%. Conclusion: The chances of achieving complete healing with purely conservative treatments are low. Regardless of MRONJ stage, early surgical treatment can achieve better success rates and prevent disease deterioration. The recent introduction of adjunctive treatments can accelerate bone healing and improve patient morbidity, although more evidence is still needed to confirm which treatment achieves the highest success rates. (AU)

Hyaluronic Acid-Modified Cisplatin-Encapsulated Poly(Lactic-co-Glycolic Acid) Magnetic Nanoparticles for Dual-Targeted NIR-Responsive Chemo-Photothermal Combination Cancer Therapy.

Combination chemo-photothermal therapy with nanomaterials can reduce the dose of chemotherapeutic drugs required for effective cancer treatment by minimizing toxic side effects while improving survival times. Toward this end, we prepare hyaluronic acid (HA)-modified poly(lactic-co-glycolic acid) (PLGA) magnetic nanoparticles (MNP) for the CD44 receptor-mediated and magnetic field-guided dual-targeted delivery of cisplatin (CDDP). By co-encapsulating the CDDP and oleic acid-coated iron oxide MNP (IOMNP) in PLGA, the PMNPc was first prepared in a single emulsification/solvent evaporation step and successively surface modified with chitosan and HA to prepare the HA/PMNPc. Spherical HA/PMNPc nanoparticles of ~300 nm diameter can be prepared with 18 and 10% (w/w) loading content of CDDP and IOMNP and a pH-sensitive drug release to facilitate the endosomal release of the CDDP after intracellular uptake. This leads to the higher cytotoxicity of the HA/PMNPc toward the U87 glioblastoma cells than free CDDP with reduced IC50, a higher cell apoptosis rate, and the enhanced expression of cell apoptosis marker proteins. Furthermore, the nanoparticles show the hyperthermia effect toward U87 after short-term near-infrared (NIR) light exposure, which can further elevate the cell apoptosis/necrosis rate and upregulate the HSP70 protein expression due to the photothermal effects. The combined cancer therapeutic efficacy was studied in vivo using subcutaneously implanted U87 cells in nude mice. By using dual-targeted chemo-photothermal combination cancer therapy, the intravenously injected HA/PMNPc under magnetic field guidance and followed by NIR laser irradiation was demonstrated to be the most effective treatment modality by inhibiting the tumor growth and prolonging the survival time of the tumor-bearing nude mice.

Wireless charging-mediated angiogenesis and nerve repair by adaptable microporous hydrogels from conductive building blocks.

Traumatic brain injury causes inflammation and glial scarring that impede brain tissue repair, so stimulating angiogenesis and recovery of brain function remain challenging. Here we present an adaptable conductive microporous hydrogel consisting of gold nanoyarn balls-coated injectable building blocks possessing interconnected pores to improve angiogenesis and recovery of brain function in traumatic brain injury. We show that following minimally invasive implantation, the adaptable hydrogel is able to fill defects with complex shapes and regulate the traumatic brain injury environment in a mouse model. We find that placement of this injectable hydrogel at peri-trauma regions enhances mature brain-derived neurotrophic factor by 180% and improves angiogenesis by 250% in vivo within 2 weeks after electromagnetized stimulation, and that these effects facilitate neuron survival and motor function recovery by 50%. We use blood oxygenation level-dependent functional neuroimaging to reveal the successful restoration of functional brain connectivity in the corticostriatal and corticolimbic circuits.

Hyaluronic acid-modified, IR780-conjugated and doxorubicin-loaded reduced graphene oxide for targeted cancer chemo/photothermal/photodynamic therapy.

We used reduced graphene oxide (rGO), which has two times higher photothermal conversion efficiency than graphene oxide (GO), as a photothermal agent for cancer photothermal therapy (PTT). By conjugating a photosensitizer IR780 to rGO, the IR780-rGO could be endowed with reactive oxygen species (ROSs) generation ability for concurrent photodynamic therapy (PDT). The IR780-rGO was coated with hyaluronic acid (HA) by electrostatic interaction to facilitate its intracellular uptake by U87 glioblastoma cells. The IR780-rGO/HA was loaded with doxorubicin (DOX) for chemotherapy (CT), to develop a pH-responsive drug delivery nano-platform for targeted multimodal cancer CT/PTT/PDT. We fully characterized the properties of all nanocomposites during the synthesis steps. The high loading efficiency of DOX on IR780-rGO-HA provides 3 mg/mg drug loading, while IR780-rGO-HA/DOX shows 3 times higher drug release at endosomal pH value (pH 5) than at pH 7.4. The mechanism for PTT/PDT was confirmed from the ability of IR780-rGO-HA to induce time-dependent temperature rise, synthesis of heat shock protein 70 (HSP70) and generation of intracellular ROSs, after exposure to 808 nm near infrared (NIR) laser light. The nano-vehicle IR780-rGO-HA shows high biocompatibility toward 3T3 fibroblast and U87 cancer cell lines, as well as enhanced intracellular uptake by U87 through active targeting. This translates into increased cytotoxicity of IR780-rGO-HA/DOX, by lowering the drug half-maximal inhibitory concentration (IC50) from 0.7 to 0.46 µg/mL. This IC50 is further decreased to 0.1 µg/mL by irradiation with NIR laser for 3 min at 1.5 W/cm2. The elevated cancer cell killing mechanism was supported from flow cytometry analysis, where the highest cell apoptosis/necrosis rate was observed in combination CT/PTT/PDT. Using xenograft tumor model created by subcutaneous implantation of U87 cells in nude mice, IR780-rGO-HA/DOX delivered through intravenous (IV) injection and followed with 808 nm laser treatment for 5 min at 1.5 W/cm2 results in the lowest tumor growth rate, with negligible change of tumor volume from its original value at the end 20-day observation period. The therapeutic efficacy was supported from inhibited cell proliferation rate, increased cell apoptosis rate, and increased production of HSP70 from immunohistochemical staining of tumor tissue slices. The safety of the NIR-assisted multimodal cancer treatment could be confirmed from non-significant change of body weight and hematological parameters of blood sample. Taken together, we conclude that IV delivery of IR780-rGO-HA/DOX plus NIR laser treatment is an effective nanomedicine approach for combination cancer therapy.

Nanohollow Titanium Oxide Structures on Ti/FTO Glass Formed by Step-Bias Anodic Oxidation for Photoelectrochemical Enhancement.

In this study, a new anodic oxidation with a step-bias increment is proposed to evaluate oxidized titanium (Ti) nanostructures on transparent fluorine-doped tin oxide (FTO) on glass. The optimal Ti thickness was determined to be 130 nm. Compared to the use of a conventional constant bias of 25 V, a bias ranging from 5 V to 20 V with a step size of 5 V for 3 min per period can be used to prepare a titanium oxide (TiOx) layer with nanohollows that shows a large increase in current of 142% under UV illumination provided by a 365 nm LED at a power of 83 mW. Based on AFM and SEM, the TiOx grains formed in the step-bias anodic oxidation were found to lead to nanohollow generation. Results obtained from EDS mapping, HR-TEM and XPS all verified the TiOx composition and supported nanohollow formation. The nanohollows formed in a thin TiOx layer can lead to a high surface roughness and photon absorbance for photocurrent generation. With this step-bias anodic oxidation methodology, TiOx with nanohollows can be obtained easily without any extra cost for realizing a high current under photoelectrochemical measurements that shows potential for electrochemical-based sensing applications.

Targeted delivery of irinotecan and SLP2 shRNA with GRP-conjugated magnetic graphene oxide for glioblastoma treatment.

Magnetic nanoparticles (MNPs) are useful for magnetic targeted drug delivery while ligand-mediated active targeting is another common delivery strategy for cancer therapy. In this work, we intend to prepare magnetic graphene oxide (mGO) by chemical co-precipitation of MNPs on the GO surface, followed by conjugation of the gastrin releasing peptide (GRP) as a targeting ligand, for dual targeted drug/gene delivery in invasive brain glioma treatment. mGO was grafted with chitosan, complexed with shRNA plasmid DNA for stomatin-like protein 2 (SLP2) gene silencing, modified with urocanic acid for plasmid DNA endosomal escape, PEGylated for GRP conjugation, and loaded with the chemotherapeutic drug irinotecan (CPT-11) by π-π interaction for pH-responsive drug release (mGOCUG/CPT-11/shRNA). In addition to the in depth characterization of the physico-chemical and biological properties during each preparation step, we also study the loading/pH-responsive release behavior of CPT-11 and the shRNA plasmid loading/cell transfection efficiency. The targeting and antitumor efficacies of the nanocomposite were studied with U87 human glioblastoma cells in vitro. An in vivo study revealed that intravenous administration followed by magnetic guidance results in the efficient targeted delivery of mGOCUG/CPT-11/shRNA to orthotopic brain tumors in nude mice, and it exhibits excellent antitumor efficacy with a reduced tumor growth rate and prolonged animal survival time. Our work thus highlights a multifunctional mGO-based drug/gene delivery platform for effective combination cancer therapy in glioblastoma treatment.

Rabies Virus Glycoprotein-Mediated Transportation and T Cell Infiltration to Brain Tumor by Magnetoelectric Gold Yarnballs.

T lymphocyte infiltration with immunotherapy potentially suppresses most devastating brain tumors. However, local immune privilege and tumor heterogeneity usually limit the penetration of immune cells and therapeutic agents into brain tumors, leading to tumor recurrence after treatment. Here, a rabies virus glycoprotein (RVG)-camouflaged gold yarnball (RVG@GY) that can boost the targeting efficiency at a brain tumor via dual hierarchy- and RVG-mediated spinal cord transportation, facilitating the decrease of tumor heterogeneity for T cell infiltration, is developed. Upon magnetoelectric irradiation, the electron current generated on the GYs activates the electrolytic penetration of palbociclib-loaded dendrimer (Den[Pb]) deep into tumors. In addition, the high-density GYs at brain tumors also induces the disruption of cell-cell interactions and T cell infiltration. The integration of the electrolytic effects and T cell infiltration promoted by drug-loaded RVG@GYs deep in the brain tumor elicits sufficient T cell numbers and effectively prolongs the survival rate of mice with orthotopic brain tumors.

Concomitant spinal dural arteriovenous fistula and nodular fasciitis in an adolescent: case report.

BACKGROUND: Spinal dural arteriovenous fistula (SDAVF) usually occurs during the 4th to 6th decades of life, and adolescent SDAVF is rarely reported. SDAVF arising around a tumor is also rare, and reported tumors are mostly schwannoma and lipoma. CASE PRESENTATION: We reported a 16-year-old male presented with progressive weakness and numbness of lower limbs for 3 months. A SDAVF was found, which was fed by right radicular arteries from segmental artery at L2 level and drained retrogradely into perimedullary veins. A concomitant spinal extradural nodular fasciitis at right L1/L2 intervertebral foramen was also noted. The SDAVF was completely obliterated by endovascular treatment and the tumor was debulked. The patient recovered well after the procedures. CONCLUSIONS: Our case report suggests SDAVF can occur in adolescent. The concomitant presence with a nodular fasciitis indicates that although it usually arises in subcutaneous tissue but can rarely form on the dura of spine.

Maintenance of multi-domain neurocognitive functions in patients with newly-diagnosed primary CNS lymphoma after primary cranial radiotherapy combined with methotrexate-based chemotherapy: A preliminary case-series study.

Conventional treatment for treating primary central nervous system lymphoma (PCNSL) has consisted of either whole-brain radiotherapy (WBRT) or methotrexate (MTX)-based combined modality therapy. However, delayed cognitive sequelae have emerged as a significant debilitating complication in PCNSL patients. A prospective observational case-series study with prospective assessments of neurocognitive functions (NCFs), neuroimaging, and activities of daily living in newly-diagnosed PCNSL patients was undertaken. A battery of neuropsychological measures, used to evaluate NCFs, is composed of ten standardized NCF tests, representing four domains sensitive to disease and treatment effects (executive function, attention, verbal memory, psychomotor speed), and activities of daily living. A total of 15 patients with newly-diagnosed PCNSL were consecutively enrolled in this study. Comparing the NCF scores between the baseline (before WBRT) and post-treatment (after combined chemoradiation therapy) intervals (Mean = 122.33 days, SD = 34.49, range = 77-196), neurobehavioral outcomes consistently remained improving or stable in almost each domain of NCF. Specifically, the scores on Paced Auditory Serial Addition Test-Revised (PASAT-R) were significantly improved between the baseline and post-chemoradiation assessment. Under the multidisciplinary treatment guidelines for treating patients with newly-diagnosed PCNSL, multi-domain NCF become stabilized and even improved after the course of conformal WBRT combined with or without MTX-based chemotherapy.

Visible-Light-Assisted Photoelectrochemical Biosensing of Uric Acid Using Metal-Free Graphene Oxide Nanoribbons.

In this study, we demonstrate the visible-light-assisted photoelectrochemical (PEC) biosensing of uric acid (UA) by using graphene oxide nanoribbons (GONRs) as PEC electrode materials. Specifically, GONRs with controlled properties were synthesized by the microwave-assisted exfoliation of multi-walled carbon nanotubes. For the detection of UA, GONRs were adopted to modify either a screen-printed carbon electrode (SPCE) or a glassy carbon electrode (GCE). Cyclic voltammetry analyses indicated that all Faradaic currents of UA oxidation on GONRs with different unzipping/exfoliating levels on SPCE increased by more than 20.0% under AM 1.5 irradiation. Among these, the GONRs synthesized under a microwave power of 200 W, namely GONR(200 W), exhibited the highest increase in Faradaic current. Notably, the GONR(200 W)/GCE electrodes revealed a remarkable elevation (~40.0%) of the Faradaic current when irradiated by light-emitting diode (LED) light sources under an intensity of illumination of 80 mW/cm2. Therefore, it is believed that our GONRs hold great potential for developing a novel platform for PEC biosensing.

Magnetic and GRPR-targeted reduced graphene oxide/doxorubicin nanocomposite for dual-targeted chemo-photothermal cancer therapy.

Herein, we design a rGO-based magnetic nanocomposite by decorating rGO with citrate-coated magnetic nanoparticles (CMNP). The magnetic rGO (mrGO) was modified by phospholipid-polyethylene glycol to prepare PEGylated mrGO, for conjugating with gastrin-releasing peptide receptor (GRPR)-binding peptide (mrGOG). The anticancer drug doxorubicin (DOX) was bound to mrGO (mrGOG) by π-π stacking for drug delivery triggered by the low pH value in the endosome. The mrGOG showed enhanced photothermal effect under NIR irradiation, endorsing its role for dual targeted DOX delivery. With efficient DOX release in the endosomal environment and heat generation from light absorption in the NIR range, mrGOG/DOX could be used for combination chemo-photothermal therapy after intracellular uptake by cancer cells. We characterized the physico-chemical as well as biological properties of the synthesized nanocomposites. The mrGOG is stable in biological buffer solution, showing high biocompatibility and minimum hemolytic properties. Using U87 glioblastoma cells, we confirmed the magnetic drug targeting effect in vitro for selective cancer cell killing. The peptide ligand-mediated targeted delivery increases the efficiency of intracellular uptake of both nanocomposite and DOX up to ~3 times due to the over-expressed GRPR on U87 surface, leading to higher cytotoxicity. The increased cytotoxicity using mrGOG over mrGO was shown from a decreased IC50 value (0.70 to 0.48 µg/mL) and an increased cell apoptosis rate (19.8% to 47.1%). The IC50 and apoptosis rate changed further to 0.19 µg/mL and 76.8% in combination with NIR laser irradiation, with the photothermal effect supported from upregulation of heat shock protein HSP70 expression. Using U87 tumor xenograft model created in nude mice, we demonstrated that magnetic guidance after intravenous delivery of mrGOG/DOX could significantly reduce tumor size and prolong animal survival over free DOX and non-magnetic guided groups. Augmented with NIR laser treatment for 5 min, the anti-cancer efficacy significantly improves with elevated cell apoptosis and reduced cell proliferation. Together with safety profiles from hematological as well as major organ histological analysis of treated animals, the mrGOG nanocomposite is an effective nanomaterial for combination chemo-photothermal cancer therapy.

An Endoscopic Transcanal Transpromontorial Approach for Vestibular Schwannomas using a Computer-Based Three-Dimensional Imaging System.

A 2D monocular endoscope has been used in transcanal transpromontory vestibular schwannoma surgery instead of craniotomy. However, the absence of depth perception is the limitation of this approach. With the loss of depth perception, the surgeon will be not able to perform delicate and particularly complicated surgery. A binocular endoscope has been developed to provide stereoscopic vision with better depth perception for complicated anatomic structures and has been applied in some endoscopic surgeries. However, the diameter of the endoscope is a limitation in the performance of transcanal otologic surgeries. A small diameter endoscope facilitates easier surgery in a restricted space. A computer-based 3D imaging system can obtain 3D images in real-time using a small monocular endoscope. In this study, to evaluate the feasibility of a computer-based 3D imaging system for endoscopic lateral skull base surgery, we applied this 3D imaging system in a transcanal transpromontorial approach in two patients with vestibular schwannomas. The surgical procedure was completed without complication in these two cases. There was no mortality, perioperative complications, nor notable postoperative complications. Using this computer-based 3D imaging system, a better depth perception and stereoscopic vision was observed compared to a conventional 2D endoscope. The improvement in depth perception offers superior management of the complicated surgical anatomy.

Liposomal IR-780 as a Highly Stable Nanotheranostic Agent for Improved Photothermal/Photodynamic Therapy of Brain Tumors by Convection-Enhanced Delivery.

As a hydrophobic photosensitizer, IR-780 suffers from poor water solubility and low photostability under near infrared (NIR) light, which severely limits its use during successive NIR laser-assisted photothermal/photodynamic therapy (PTT/PDT). To solve this problem, we fabricate cationic IR-780-loaded liposomes (ILs) by entrapping IR-780 within the lipid bilayer of liposomes. We demonstrate enhanced photostability of IR-780 in ILs with well-preserved photothermal response after three repeated NIR laser exposures, in contrast to the rapid decomposition of free IR-780. The cationic nature of ILs promotes fast endocytosis of liposomal IR-780 by U87MG human glioblastoma cells within 30 min. For PTT/PDT in vitro, ILs treatment plus NIR laser irradiation leads to overexpression of heat shock protein 70 and generation of intracellular reactive oxygen species by U87MG cells, resulting in enhanced cytotoxicity and higher cell apoptosis rate. Using intracranial glioma xenograft in nude mice and administration of ILs by convection enhanced delivery (CED) to overcome blood-brain barrier, liposomal IR-780 could be specifically delivered to the brain tumor, as demonstrated from fluorescence imaging. By providing a highly stable liposomal IR-780, ILs significantly improved anti-cancer efficacy in glioma treatment, as revealed from various diagnostic imaging tools and histological examination. Overall, CED of ILs plus successive laser-assisted PTT/PDT may be an alternative approach for treating brain tumor, which can retard glioma growth and prolong animal survival times from orthotopic brain tumor models.

MCP-1-Functionalized, Core-Shell Gold Nanorod@Iron-Based Metal-Organic Framework (MCP-1/GNR@MIL-100(Fe)) for Photothermal Therapy.

The low vessel density and oxygen concentration in hypoxia are the main causes of reduced efficiency of anticancer therapeutics and can stimulate the tumor's relapse. Research showed that macrophages could cross the blood-vessel barriers and reach the hypoxic regions of tumors. Using macrophages in a drug delivery system has been a promising method for tumor targeting in recent years. In this work, we successfully modified monocyte chemoattractant protein-1 (MCP-1) and iron-based metal-organic framework (MIL-100(Fe)) on the photothermal agent, gold nanorods (GNRs) (i.e., MCP-1/GNR@MIL-100(Fe)), to increase cellular uptake and biocompatibility. The results of TEM, UV-vis, and FTIR all confirmed that we'd synthesized MCP-1/GNR@MIL-100(Fe) successfully, and the MCP-1/GNR@MIL-100(Fe) also showed good biocompatibility. A transwell migration assay illustrated that our material attracted macrophages, and the material uptake amount was increased by 1.5 times after MCP-1 functionalization. It also indicated that the macrophages have a tumor-targeting ability. In the in vivo experiment, we subcutaneously implanted U251 MG cells in nude mice as a xenograft model to demonstrate the photothermal activity of MCP-1/GNR@MIL-100(Fe). With successive NIR treatment, the tumor growth could be controlled, and the tumor volume still remained below 100 mm3 after laser treatment. MCP-1/GNR@MIL-100(Fe) combined with the laser treatment showed an excellent antitumor efficacy from the histology of tumor tissues, survival rates, and bioluminescence imaging.