Anti-tumor activity of paclitaxel through dual-targeting carrier of cyclic RGD and transferrin conjugated hyperbranched copolymer nanoparticles

Targeted delivery strategies are becoming increasingly important. Herein, a novel hyperbranched amphiphilic poly[(amine-ester)-co-(d,l-lactide)]/1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine copolymer (HPAE-co-PLA/DPPE) with RGD peptide (cRGDfK) and transferrin (Tf) on the periphery was synthesized and used to prepare paclitaxel-loaded nanoparticles (NPs) for dual-targeting chemotherapy. These NPs show satisfactory size distribution, high encapsulated efficiency and a pH-dependent release profile. The intrinsic fluorescence of the hyperbranched copolymer renders the detection and tracking of NPs in vitro and in vivo conveniently. In vitro cytotoxicity studies proved that the presence of cRGDfK enhanced the cytotoxic efficiency by 10 folds in α_νβ₃ integrin over-expressed human umbilical vein endothelial cells, while Tf improved cytotoxicity by 2 folds in Tf receptor over-expressed human cervical carcinoma cells. The drug-loaded NPs can be efficiently transported into the vascular endothelial cells and the target tumor cells. These results indicate that the cRGDfK and Tf decorated HPAE-co-PLA/DPPE could deliver chemotherapies specifically inside the cell via receptor-mediated endocytosis with greater efficacy. Therefore, such a fluorescent nanocarrier prepared from non-cytotoxic and biodegradable polymers is promising for drug delivery in tumor therapy.     

The transport of non-surfactant based paclitaxel loaded magnetic nanoparticles across the blood brain barrier in a rat model

There is much interest in utilizing the intrinsic properties of magnetic nanoparticles (MNPs) for the theranostic approaches in medicine. With an aim to develop a potential therapeutics for glioma treatment, efficacy of aqueous dispersible paclitaxel loaded MNPs (Pac-MNPs) were studied in glioblastoma cell line (U-87). The identified potential receptor, glycoprotein non-metastatic melanoma protein B (GPNMB) overexpressed by glioblastoma cells, was actively targeted using GPNMB conjugated Pac-MNPs in U-87 cells. As blood brain barrier (BBB) is the primary impediment in the treatment of glioblastoma, therefore, an attempt was taken to evaluate the biodistribution and brain uptake of Pac-MNPs in rats. The bioavailability of Pac-MNPs illustrated a prolonged blood circulation in vivo, which demonstrated the presence of significant amounts of drug in rat brain tissues as compared to native paclitaxel. Further, the transmission electron microscopy (TEM) study revealed significant accumulation of the Pac-MNPs in the brain tissues. Being an effective contrast enhancement agent for magnetic resonance imaging (MRI) at tissue levels, the MNPs devoid of any surfactant demonstrated enhanced contrast effect in liver and brain imaging. Hence, the significant prevalence of drugs in the rat brain tissues, in vitro targeting potentiality as well as the augmented contrast effect elicit the non-invasive assessment and theranostic applications of MNPs for brain tumor therapy.     

Choline transporter-targeting and co-delivery system for glioma therapy

Combination of gene therapy and chemotherapy is a promising approach for glioma therapy. In this study, a co-delivery system of plasmid encoding human tumor necrosis factor-related apoptosis-inducing ligand (pORF-hTRAIL, Trail) and doxorubicin (DOX) has been simply constructed in two steps. Firstly, DOX was intercalated into Trail to form a stable complex. Secondly, DOX-Trail complex was condensed by Dendrigraft poly-l-lysine (DGL) to form a nanoscaled co-delivery system. Choline transporters are both expressed on blood–brain barrier (BBB) and glioma, Herein, a choline derivate with high choline transporter affinity was chosen as BBB and glioma dual targeting ligand. Choline-derivate modified co-delivery system showed higher cellular uptake efficiency and cytotoxicity than unmodified co-delivery system in U87 MG cells. In comparison with single medication or unmodified delivery system, Choline-derivate modified co-delivery system induced more apoptosis both in vitro and in vivo. The therapeutic efficacy on U87 MG bearing xenografts further confirmed the predominance of this dual targeting and co-delivery system.     

The use of folate-PEG-grafted-hybranched-PEI nonviral vector for the inhibition of glioma growth in the rat

Combined treatment using nonviral agent-mediated enzyme/prodrug therapy and immunotherapy had been proposed as a powerful alternative method of cancer therapy. The present study was aimed to evaluate the cytotoxicity in vitro and the therapeutic efficacy in vivo when the cytosine deaminase/5-fluorocytosine (CD/5-FC) and TNF-related apoptosis-inducing ligand (TRAIL) genes were jointly used against rat C6 glioma cells. The potency of the FA-PEG-PEI used as a nonviral vector was tested in the FR-expressed C6 glioma cells and Wistar rats. The C6 glioma cells and animal model were treated by the combined application of FA-PEG-PEI/pCD/5-FC and FA-PEG-PEI/pTRAIL. The antitumor effect was evaluated by survival assays and tumor volume. This study revealed a significant increase of cytotoxicity in vitro following the combined application of FA-PEG-PEI/pCD/5-FC and FA-PEG-PEI/pTRAIL treatments in C6 glioma cells. Animal studies showed a significant growth inhibition of the C6 glioma xenografts using the combined treatment. These results demonstrated that the combined treatment generated additive cytotoxic effect in C6 glioma cells in both in vitro and in vivo conditions, and indicated that such treatment method using both enzyme/prodrug therapy and TRAIL immunotherapy might be a promising therapeutic strategy in treating glioma.     

Polyethyleneimine-mediated synthesis of folic acid-targeted iron oxide nanoparticles for in vivo tumor MR imaging

We report a facile polyethyleneimine (PEI)-mediated approach to synthesizing folic acid (FA)-targeted magnetic iron oxide nanoparticles (Fe₃O₄ NPs) for in vivo magnetic resonance (MR) imaging of tumors. In this study, stable PEI-coated Fe₃O₄ NPs were prepared by a one-pot hydrothermal route. The aminated Fe₃O₄ NPs with PEI coating enabled covalent conjugation of fluorescein isothiocyanate (FI) and folate-conjugated polyethylene glycol (PEG) with one end of carboxyl groups (FA-PEG-COOH). Followed by final acetylation, FA-targeted PEGylated Fe₃O₄ NPs (Fe₃O₄-PEI-Ac-FI-PEG-FA NPs) were formed. The formed multifunctional Fe₃O₄ NPs were characterized via different techniques. We show that the PEI-mediated approach along with the PEGylation conjugation enables the generation of water-dispersible and stable multifunctional Fe₃O₄ NPs, and the particles are quite cytocompatible and hemocompatible in the given concentration range as confirmed by in vitro cytotoxicity assay, cell morphology observation, and hemolysis assay. In addition, flow cytometry and confocal microscopy data show that the multifunctional Fe₃O₄ NPs are able to target a model cancer cell line (KB cells) overexpressing FA receptors in vitro. Importantly, the FA-targeted Fe₃O₄ NPs are able to be used as an efficient nanoprobe for MR imaging of cancer cells in vitro and a xenografted tumor model in vivo via an active FA targeting pathway. With the facile PEI-mediated formation strategy and PEGylation conjugation chemistry, the Fe₃O₄ NPs may be multifunctionalized with other biological ligands for MR imaging of different biological systems.     

Controllable synthesis of monodispersed silver nanoparticles as standards for quantitative assessment of their cytotoxicity

Silver nanoparticles (Ag NPs) are appealing due to their excellent antibacterial/antivirus properties. At the meantime, the wide applications of Ag NPs as antibacterial/antivirus agents arise the concern of Ag NPs’ toxicity. However, quantitative understanding of the cytotoxicity of Ag NPs is minimum since that the Ag NPs in current studies have wide size distributions, in which the size effect of Ag NPs on cytotoxicity was unable to be accurately evaluated. In this work, unprecedentedly monodispersed Ag NPs with sizes of 25, 35, 45, 60 and 70 nm were obtained, respectively, by using an optimized polyol method with poly(vinyl pyrrolidone) (PVP) as surfactant. It was found that the reaction temperature, reaction time, concentration of the surfactant and reactants are playing important roles in determining the size and size distribution of Ag NPs. With the monodispersed Ag NPs as standard samples, the size- and dose- dependent cytotoxicity of Ag NPs against Human lung fibroblast (HLF) cells was accurately accomplished in terms of cell viability, apoptosis and necrosis, reactive oxygen species, etc. We expect that the monodispersed Ag NPs will act as the standard samples for quantitatively characterizing the toxicity of Ag NPs in vitro and in vivo.     

Multilayer nanoparticles for sustained delivery of exenatide to treat type 2 diabetes mellitus

A method for the sustained delivery of exenatide was proposed using nanoparticles (NPs) with a core/shell structure. The interactions between lipid bilayers and Pluronics were utilized to form various NPs using a layer-by-layer approach. Transmittance electron microscopy and dynamic light scattering were used to examine the morphology of the NPs. The in vitro release pattern was observed as a function of changes in the structure of the NPs, and the structural integrity of exenatide released was examined by SDS–PAGE analysis. Pharmacokinetics and antidiabetic effects were also observed with the structural change of NPs using in vivo animal models. In vitro–in vivo correlation was discussed in relation to manipulation of the NP structures.     

Vascular toxicity of ultra-small TiO2 nanoparticles and single walled carbon nanotubes in vitro and in vivo

Ultra-small nanoparticles (USNPs) at 1–3 nm are a subset of nanoparticles (NPs) that exhibit intermediate physicochemical properties between molecular dispersions and larger NPs. Despite interest in their utilization in applications such as theranostics, limited data about their toxicity exist. Here the effect of TiO₂-USNPs on endothelial cells in vitro, and zebrafish embryos in vivo, was studied and compared to larger TiO₂-NPs (30 nm) and to single walled carbon nanotubes (SWCNTs). In vitro exposure showed that TiO₂-USNPs were neither cytotoxic, nor had oxidative ability, nevertheless were genotoxic. In vivo experiment in early developing zebrafish embryos in water at high concentrations of TiO₂-USNPs caused mortality possibly by acidifying the water and caused malformations in the form of pericardial edema when injected. Myo1C involved in glomerular development of zebrafish embryos was upregulated in embryos exposed to TiO₂-USNPs. They also exhibited anti-angiogenic effects both in vitro and in vivo plus decreased nitric oxide concentration. The larger TiO₂-NPs were genotoxic but not cytotoxic. SWCNTs were cytotoxic in vitro and had the highest oxidative ability. Neither of these NPs had significant effects in vivo. To our knowledge this is the first study evaluating the effects of TiO₂-USNPs on vascular toxicity in vitro and in vivo and this strategy could unravel USNPs potential applications.     

PEG-PLA nanoparticles modified with APTEDB peptide for enhanced anti-angiogenic and anti-glioma therapy

Tumor neovasculature and tumor cells dual-targeting chemotherapy can not only destroy the tumor neovasculature, cut off the supply of nutrition and starve the tumor cells, but also directly kill tumor cells, holding great potential in overcoming the drawbacks of anti-angiogenic therapy only and improving the anti-glioma efficacy. In the present study, by taking advantage of the specific expression of fibronectin extra domain B (EDB) on both glioma neovasculature endothelial cells and glioma cells, we constructed EDB-targeted peptide APT_EDB-modified PEG-PLA nanoparticles (APT-NP) for paclitaxel (PTX) loading to enable tumor neovasculature and tumor cells dual-targeting chemotherapy. PTX-loaded APT-NP showed satisfactory encapsulated efficiency, loading capacity and size distribution. In human umbilical vein endothelial cells, APT-NP exhibited significantly elevated cellular accumulation via energy-dependent, caveolae and lipid raft-involved endocytosis, and improved PTX-induced apoptosis therein. Both in vitro tube formation assay and in vivo matrigel angiogenesis analysis confirmed that APT-NP significantly improved the antiangiogenic ability of PTX. In U87MG cells, APT-NP showed elevated cellular internalization and also enhanced the cytotoxicity of the loaded PTX. Following intravenous administration, as shown by both in vivo live animal imaging and tissue distribution analysis, APT-NP achieved a much higher and specific accumulation within the glioma. As a result, APT-NP-PTX exhibited improved anti-glioma efficacy over unmodified nanoparticles and Taxol^® in both subcutaneous and intracranial U87MG xenograft models. These findings collectively indicated that APT_EDB-modified nanoparticles might serve as a promising nanocarrier for tumor cells and neovasculature dual-targeting chemotherapy and hold great potential in improving the efficacy anti-glioma therapy.     

Nanoparticles of 2-deoxy-d-glucose functionalized poly(ethylene glycol)-co-poly(trimethylene carbonate) for dual-targeted drug delivery in glioma treatment

Based on the facilitative glucose transporter (GLUT) over-expression on both blood–brain barrier (BBB) and glioma cells, 2-deoxy-d-glucose modified poly(ethylene glycol)-co-poly(trimethylene carbonate) nanoparticles (dGlu–NP) were developed as a potential dual-targeted drug delivery system for enhancing the BBB penetration via GLUT-mediated transcytosis and improving the drug accumulation in the glioma via GLUT-mediated endocytosis. In vitro physicochemical characterization of the dual-targeted nanoparticulate system presented satisfactory size of 71 nm with uniform distribution, high encapsulation efficiency and adequate loading capacity of paclitaxel (PTX). Compared with non-glucosylated nanoparticles (NP), a significantly higher amount of dGlu–NP was internalized by RG-2 glioma cells through caveolae-mediated and clathrin-mediated endocytosis. Both of the transport ratios across the in vitro BBB model and the cytotoxicity of RG-2 cells after crossing the BBB were significantly greater of dGlu–NP/PTX than that of NP/PTX. In vivo fluorescent image indicated that dGlu–NP had high specificity and efficiency in intracranial tumor accumulation. The anti-glioblastoma efficacy of dGlu–NP/PTX was significantly enhanced in comparison with that of Taxol and NP/PTX. Preliminary safety tests showed no acute toxicity to hematological system, liver, kidney, heart, lung and spleen in mice after intravenous administration at a dose of 100 mg/kg blank dGlu–NP per day for a week. Therefore, these results indicated that dGlu–NP developed in this study could be a potential dual-targeted vehicle for brain glioma therapy.     

Human neural stem cell intracerebral grafts show spontaneous early neuronal differentiation after several weeks

Human neural stem cells (hNSCs) hold great promise for the treatment of neurological diseases. Considerable progress has been made to induce neural differentiation in the cell culture in vitro and upon transplantation in vivo [2] in order to explore restoration of damaged neuronal circuits. However, in vivo conventional strategies are limited to post mortem analysis. Here, we apply our developed first fate mapping platform to monitor neuronal differentiation in vivo by magnetic resonance imaging, bioluminescence imaging, and fluorescence imaging. Ferritin, Luciferase and GFP under neuronal-specific promoters for immature and mature neurons, respectively, were used to generate transgenic hNSCs. Differentiation-linked imaging reporter expression was validated in vitro. The time profile of spontaneous neuronal maturation after transplantation into mouse brain cortex demonstrated early neuronal differentiation within 6 weeks. Fully mature neurons expressing synaptogenesis were observed only after three months or longer. Our trimodal fate mapping strategy represents a unique non-invasive tool to monitor the time course of neuronal differentiation of transplanted stem cells in vivo.     

Oral delivery of shRNA and siRNA via multifunctional polymeric nanoparticles for synergistic cancer therapy

Galactose modified trimethyl chitosan-cysteine (GTC) conjugates with various galactose grafting densities were developed for oral delivery of Survivin shRNA-expression pDNA (iSur-pDNA) and vascular endothelial growth factor (VEGF) siRNA (siVEGF) in the synergistic and targeted treatment of hepatoma. iSur-pDNA and siVEGF loaded GTC nanoparticles (NPs) were prepared via electrostatic complexation and showed desirable stability in physiological fluids and improved intestinal permeation compared to naked genes. Galactose grafting density of GTC NPs significantly affected their in vitro and in vivo antitumor activities. GTC NPs with moderate galactose grafting density, termed GTC2 NPs, were superior in facilitating cellular uptake, promoting nuclear distribution, and silencing target genes, leading to notable inhibition of cell growth. In tumor-bearing mice, orally delivered GTC2 NPs could effectively accumulate in the tumor tissues and silence the expression of Survivin and VEGF, evoking increased apoptosis, inhibited angiogenesis, and thus the most efficient tumor regression. Moreover, compared with single gene delivery, co-delivery of iSur-pDNA and siVEGF showed synergistic effects on inhibiting in vitro cell proliferation and in vivo tumor growth. This study could serve as an effective approach for synergistic cancer therapy via oral gene delivery, and highlighted the importance of ligand grafting density in the rational design of targeted nanocarriers.     

Dihydroartemisinin and transferrin dual-dressed nano-graphene oxide for a pH-triggered chemotherapy

Dihydroartemisinin (DHA) is a unique anti-malarial drug isolated from the plant Artemisia annua. Recently, it has been studied as an alternative modality for cancer therapy, utilizing its reactive oxygen species (ROS) yielding mechanism from interacting with Ferrous ion (Fe (Ⅱ)). In this work, a novel nanodrug (DHA-GO-Tf) is constructed based on nanoscale Graphene oxide (GO) dual-dressed with DHA and Transferrin (Tf). Tf dually functions as a pilot for the nanoparticle to target tumor cell with over expressed Transferrin receptor (TfR) and a ferric ion carrier. Upon tumor cellular endocytosis, Ferric ion (Fe(Ⅲ)) is released from the Tf, triggered by the low pH in the lysosomes of the tumor cell. The intracellular Fe (Ⅲ) is reduced to Fe (Ⅱ) and interacts with DHA to increase its cytotoxicity. The potential of this alternative anti-tumor modality is demonstrated both in vitro and in vivo. Comparing with DHA alone, the nanodrug DHA-GO-Tf resulted in a significantly enhanced tumor delivery specificity and cytotoxicity, and achieved a complete tumor cure in mice with minimal side-effects.     

Effects of mannose density on in vitro and in vivo cellular uptake and RNAi efficiency of polymeric nanoparticles

To evaluate the effects of mannose density on in vitro and in vivo cellular uptake and RNA interference (RNAi) efficiency of polymeric nanoparticles (NPs) in macrophages, mannose-modified trimethyl chitosan-cysteine (MTC) conjugates with mannose densities of 4%, 13%, and 21% (MTC-4, MTC-13, and MTC-21) were synthesized. Tumor necrosis factor-alpha (TNF-α) siRNA loaded MTC NPs with particle sizes of ∼150 nm exhibited desired structural stability and effectively protected siRNA from enzymatic degradation. Generally, cellular uptake and RNAi efficiency were affected by mannose density. As expected, MTC-21 NPs presented the maximum in vitro uptake and RNAi efficacy in Raw 264.7 cells among all NPs tested. However, MTC-4 NPs exhibited the optimal in vivo uptake by peritoneal exudate cell macrophages (PECs). In the inflammation model of acute hepatic injury, orally delivered MTC-4 and MTC-13 NPs worked better in silencing TNF-α expression and alleviating liver damage than MTC-21 NPs. As for the ulcerative colitis model, MTC-4 NPs outperformed MTC-13 and MTC-21 NPs with respect to TNF-α knockdown and therapeutic efficacy following oral administration. These results highlighted the importance of ligand density in cellular uptake and RNAi efficiency, which could serve as a guideline in the rational design of targeted nanocarriers for anti-inflammation therapy.     

The brain targeting mechanism of Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone) nanoparticles

In order to evaluate the potential and mechanism of Angiopep-conjugated poly(ethylene glycol)-co-poly(?-caprolactone)nanoparticles (ANG-PEG-NP) as brain targeting drug delivery system, Rhodamine B isothiocyanate (RBITC) was used as a fluorescent probe molecule to label ANG-PEG-NP through covalent bonding. The brain transcytosis across the blood-brain barrier (BBB) and brain delivery in mice of RBITC labeled ANG-PEG-NP were investigated in this paper. Results showed that ANG-PEG-NP enhanced significantly the uptake by BCECs compared with that of PEG-NP through caveolae- and clathrin-mediated endocytosis, involving a time-dependent, concentration-dependent and energy-dependent mode. The transport of ANG-PEG-NP across the in vitro BBB model was significantly increased than that of PEG-NP. After injection a dose of 100 mg/kg RBITC labeled ANG-PEG-NP or PEG-NP in mouse caudal vein, the brain coronal section showed a higher accumulation of ANG-PEG-NP in the cortical layer, lateral ventricle, third ventricles and hippocampus than that of PEG-NP. By using an excess of free LRP ligand (Angiopep-2 and/or Aprotinin) as a specific receptor inhibitor, it was evidenced that the uptake by BCECs in vitro, transport across in vitro BBB model and penetration into brain tissue in vivo of RBITC labeled ANG-PEG-NP could be inhibited significantly, which demonstrated the brain targeting mechanism of Angiopep-conjugated poly(ethylene glycol)-co-poly(?-caprolactone)nanoparticles might be a LRP receptor mediated transcytosis process. Understanding these issues is important for the future development of ANG-PEG-NP as a brain targeting drug delivery system for neurodegenerative disorders including glioma and Alzheimer’s disease.     

The impact of a chlorotoxin-modified liposome system on receptor MMP-2 and the receptor-associated protein ClC-3

Currently, it is unknown whether a receptor-associated protein will be affected when a ligand modified delivery system interacts with its receptor. Besides, chlorotoxin (ClTx)-modified liposomes can target to glioma cells, but the target molecule is not clear: MMP-2, ClC-3 or both? Here a comparative study of ClTx-conjugated liposomes was conducted on two types of tumor cells: U87, a human glioma cell line with high expression of both MMP-2 and ClC-3, and A549, a human lung cancer cell line with expression of only MMP-2. ClTx-modified liposomes behaved similarly in these two cancer cells in terms of in vitro cell uptake, endocytosis pathway, intracellular trafficking and in vivo targeting efficacy, though the two tested cell lines were very different in ClC-3 expression. These results revealed that the targeted delivery of ClTx modified liposomes to U87 tumor was MMP-2-mediated and not correlated with the chloride channel ClC-3. On the other hand, ClTx modified on the liposomes did activate the receptor-associated protein ClC-3 via the binding with MMP-2, leading to the inhibition on cell migration and chloride currents. This is significant because cell migration is a key step in tumor metastasis. Interestingly, higher in vitro cellular uptake and lower in vivo tumor accumulation of liposomal systems was found in U87 compared to the A549 model, possibly due to the biological differences between in vitro and in vivo models. In general, ClTx-modified delivery systems may potentially target to tumors other than glioma that express a high level of MMP-2, and its effect on ClC-3 may help prevent tumor metastasis.     

Multifunctional PEG-GO/CuS nanocomposites for near-infrared chemo-photothermal therapy

The synergistic therapy, the combination of photothermal therapy and chemotherapy, has become a potential treatment in the battles with cancer. Here, we developed a synergistic therapy tool that based on CuS nanoparticles-decorated graphene oxide functionalized with polyethylene glycol (PEG-GO/CuS) for cervical cancer treatment. The as-synthesized PEG-GO/CuS nanocomposites with excellent biocompatibility was revealed to have high storage capacity for anticancer drug of doxorubicin (Dox) and high photothermal conversion efficiency, and were effectively employed for the ablation of tumor. In addition, the therapeutic efficacy of Dox-loaded PEG-GO/CuS (PEG-GO/CuS/Dox) nanocomposites was evaluated in vitro and in vivo for cervical cancer therapy. In vitro cell cytotoxicity tests of PEG-GO/CuS/Dox demonstrate about 1.3 and 2.7-fold toxicity than PEG-GO/CuS and free Dox under 5 min irradiation with NIR laser at 1.0 W/cm², owing to both PEG-GO/CuS-mediated photothermal ablation and cytotoxicity of light-triggered Dox release. In mouse models, mouse cervical tumor growth was found to be significantly inhibited by the chemo-photothermal effect of PEG-GO/CuS/Dox nanocomposites, resulting in effective tumor reduction. Overall, compared with chemotherapy or photothermal therapy alone, the combined treatment demonstrates better therapeutic efficacy of cancer in vitro and in vivo. These findings highlight the promise of the highly versatile multifunctional nanoparticles in biomedical application.     

Iron/iron oxide core/shell nanoparticles for magnetic targeting MRI and near-infrared photothermal therapy

The development of photothermal agents (PTAs) with good stability, low toxicity, highly targeting ability and photothermal conversion efficiency is an essential pre-requisite to near-infrared photothermal therapy (PTT) in vivo. Herein, we report the readily available PEGylated Fe@Fe₃O₄ NPs, which possess triple functional properties in one entity – targeting, PTT, and imaging. Compared to Au nanorods, they exhibit comparable photothermal conversion efficiency (∼20%), and much higher photothermal stability. They also show a high magnetization value and transverse relaxivity (∼156 mm⁻¹ s⁻¹), which should be applied for magnetic targeting MRI. With the Nd-Fe-B magnet (0.5 T) beside the tumour for 12 h on the xenograft HeLa tumour model, PEGylated Fe@Fe₃O₄ NPs exhibit an obvious accumulation. In tumour, the intensity of MRI signal is ∼ three folds and the increased temperature is ∼ two times than those without magnetic targeting, indicating the good magnetic targeting ability. Notably, the intrinsic high photothermal conversion efficiency and selective magnetic targeting effect of the NPs in tumour play synergistically in highly efficient ablation of cancer cells in vitro and in vivo.     

Porous chitosan-hyaluronic acid scaffolds as a mimic of glioblastoma microenvironment ECM

Cancer therapeutics are developed through extensive screening; however, many therapeutics evaluated with 2D in vitro cultures during pre-clinical trials suffer from lower efficacy in patients. Replicating the in vivo tumor microenvironment in vitro with three-dimensional (3D) porous scaffolds offers the possibility of generating more predictive pre-clinical models to enhance cancer treatment efficacy. We developed a chitosan and hyaluronic acid (HA) polyelectrolyte complex 3D porous scaffold and evaluated its physical properties. Chitosan-HA (C-HA) scaffolds had a highly porous network. C-HA scaffolds were compared to 2D surfaces for in vitro culture of U-118 MG human glioblastoma (GBM) cells. C-HA scaffold cultures promoted tumor spheroid formation and increased stem-like properties of GBM cells as evidenced by the upregulation of CD44, Nestin, Musashi-1, GFAP, and HIF-1α as compared with 2D cultures. Additionally, the invasiveness of GBM cells cultured in C-HA scaffolds was significantly enhanced compared to those grown in 2D cultures. C-HA scaffold cultures were also more resistant to chemotherapy drugs, which corresponded to the increased expression of ABCG2 drug efflux transporter. These findings suggest that C-HA scaffolds offer promise as an in vitro GBM platform for study and screening of novel cancer therapeutics.