Reju George Thomas

Magnetic Iron Oxide Nanoparticles for Multimodal Imaging and Therapy of Cancer

Superparamagnetic iron oxide nanoparticles (SPION) have emerged as an MRI contrast agent for tumor imaging due to their efficacy and safety. Their utility has been proven in clinical applications with a series of marketed SPION-based contrast agents. Extensive research has been performed to study various strategies that could improve SPION by tailoring the surface chemistry and by applying additional therapeutic functionality. Research into the dual-modal contrast uses of SPION has developed because these applications can save time and effort by reducing the number of imaging sessions. In addition to multimodal strategies, efforts have been made to develop multifunctional nanoparticles that carry both diagnostic and therapeutic cargos specifically for cancer. This review provides an overview of recent advances in multimodality imaging agents and focuses on iron oxide based nanoparticles and their theranostic applications for cancer. Furthermore, we discuss the physiochemical properties and compare different synthesis methods of SPION for the development of multimodal contrast agents.

Mussel-Inspired Electrospun Nanofibers Functionalized with Size-Controlled Silver Nanoparticles for Wound Dressing Application

Electrospun nanofibers that contain silver nanoparticles (AgNPs) have a strong antibacterial activity that is beneficial to wound healing. However, most of the literature available on the bactericidal effects of this material is based on the use of AgNPs with uncontrolled size, shape, surface properties, and degree of aggregation. In this study, we report the first versatile synthesis of novel catechol moieties presenting electrospun nanofibers functionalized with AgNPs through catechol redox chemistry. The synthetic strategy allows control of the size and amount of AgNPs on the surface of nanofibers with the minimum degree of aggregation. We also evaluated the rate of release of the AgNPs, the biocompatibility of the nanofibers, the antibacterial activity in vitro, and the wound healing capacity in vivo. Our results suggest that these silver-releasing nanofibers have great potential for use in wound healing applications.

Paclitaxel loaded hyaluronic acid nanoparticles for targeted cancer therapy: In vitro and in vivo analysis

The main aim of this work was to evaluate a nanoconjugate system of paclitaxel loaded self-assembling, biodegradable micelles for targeting CD44 overexpression in cancer cells. The shape and size, zeta potential, encapsulation efficiency and cell uptake of these drug-loaded micelles were evaluated. To understand their bio distribution profile, the hyaluronate (HA) micelles were labeled with Flamma™-774 NIR dye and injected into SCC7 tumor induced mice. Cell viability in response to drug loaded and unloaded micelles was studied in SCC7 cancer cells using the MTS assay. An in vivo tumor inhibition study was conducted by intravenous injection of paclitaxel-loaded HA micelle nanoparticles as well as control nanoparticles without paclitaxel. The shape of the nanomicelles was evaluated by loading them with hydrophobic superparamagnetic iron oxide nanoparticle and then visualizing them by TEM. In conclusion, paclitaxel-loaded HA nanoparticulate micelles might be found to be a specific and efficient chemotherapeutic treatment for CD44 overexpressing cancer cells.

Multifunctional Nanocarpets for Cancer Theranostics: Remotely Controlled Graphene Nanoheaters for Thermo-Chemosensitisation and Magnetic Resonance Imaging

A new paradigm in cancer theranostics is enabled by safe multifunctional nanoplatform that can be applied for therapeutic functions together with imaging capabilities. Herein, we develop a multifunctional nanocomposite consisting of Graphene Oxide–Iron Oxide -Doxorubicin (GO-IO-DOX) as a theranostic cancer platform. The smart magnetic nanoplatform acts both as a hyperthermic agent that delivers heat when an alternating magnetic field is applied and a chemotherapeutic agent in a cancer environment by providing a pH-dependent drug release to administer a synergistic anticancer treatment with an enhanced T2 contrast for MRI. The novel GO-IO-DOX nanocomposites were tested in vitro and were observed to exhibit an enhanced tumoricidal effect through both hyperthermia and cancer cell-specific DOX release along with an excellent MRI performance, enabling a versatile theranostic platform for cancer. Moreover the localized antitumor effects of GO-IO-DOX increased substantially as a result of the drug sensitization through repeated application of hyperthermia.

Hyaluronic acid conjugated superparamagnetic iron oxide nanoparticle for cancer diagnosis and hyperthermia therapy

Recently, superparamagnetic iron oxide nanoparticles (SPIONs) have been prepared for magnetic resonance (MR) imaging and hyperthermia therapy. Here, we have developed hyaluronic acid (HA) coated SPIONs primarily for use in a hyperthermia application with an MR diagnostic feature with hydrodynamic size measurement of 176nm for HA-PEG10-SPIONs and 149nm for HA-SPIONs. HA-coated SPIONs (HA-SPIONs) were prepared to target CD44-expressed cancer where the carrier was conjugated to PEG for analyzing longer circulation in blood as well as for biocompatibility (HA-PEG10 SPIONs). Characterization was conducted with TEM (shape), DLS (size), ELS (surface charge), TGA (content of polymer) and MRI (T2-relaxation time). The heating ability of both the HA-SPIONs and HA-PEG10-SPIONs was studied by AMF and SAR calculation. Cellular level tests were conducted using SCC7 and NIH3T3 cell lines to confirm cell viability and cell specific uptake. HA-SPIONs and HA-PEG10-SPIONs were injected to xenograft mice bearing the SCC7 cell line for MRI cancer diagnosis. We found that HA-SPION-injected mice tumors showed nearly 40% MR T2 contrast compared to the 20% MR T2 contrast of the HA-PEG10-SPION group over a 3h time period. Finally, in vitro hyperthermia studies were conducted in the SCC7 cell line that showed less than 40% cell viability for both HA-SPIONs and HA-PEG10-SPIONs in AMF treated cells. In conclusion, HA-SPIONs were targeted specifically to the CD44, and the hyperthermia effect of HA-SPIONs and HA-PEG10-SPIONs was found to be significant for future studies.

Biomedical Applications of Magnetically Functionalized Organic/Inorganic Hybrid Nanofibers

Nanofibers are one-dimensional nanomaterial in fiber form with diameter less than 1 µm and an aspect ratio (length/diameter) larger than 100:1. Among the different types of nanoparticle-loaded nanofiber systems, nanofibers loaded with magnetic nanoparticles have gained much attention from biomedical scientists due to a synergistic effect obtained from the unique properties of both the nanofibers and magnetic nanoparticles. These magnetic nanoparticle-encapsulated or -embedded nanofiber systems can be used not only for imaging purposes but also for therapy. In this review, we focused on recent advances in nanofibers loaded with magnetic nanoparticles, their biomedical applications, and future trends in the application of these nanofibers.

Radio frequency triggered curcumin delivery from thermo and pH responsive nanoparticles containing gold nanoparticles and its in vivo localization studies in an orthotopic breast tumor model

Non-invasive radiofrequency (RF) electric fields as an energy source for thermal activation of nanoparticles and thereby delivering drugs within cancer cells could be a valuable addition to nano-mediated RF based cancer therapies. Utilizing the high penetration of RF waves would be useful for the controlled release of encapsulated drug molecules from smart thermo and pH responsive nanoparticles. Herein, we demonstrate that breast cancer cells could selectively internalize hemocompatible, 170 ± 20 nm sized curcumin encapsulated chitosan-graft-poly(N-vinyl caprolactam) nanoparticles containing gold nanoparticles (Au-CRC-TRC-NPs). Au-CRC-TRC-NPs were predominantly accumulated within the cytoplasm. After “optimum RF exposure” at 40 watts for 5 minutes, Au-CRC-TRC-NPs absorbed and dissipated energy as heat in the range of 42 °C, which is the lower critical solution temperature (LCST) of chitosan-graft-poly(N-vinyl caprolactam), causing controlled curcumin release and inducing apoptosis to 4T1 breast cancer cells. Further, the tumor localization studies on orthotopic breast cancer models revealed that Au-CRC-TRC-NPs could selectively accumulate at primary and secondary tumors as confirmed by in vivo live imaging followed by ex vivo tissue imaging and HPLC studies. These preclinical results throw light on their feasibility as a better tumor targetable nanomedicine for RF-assisted breast treatment modalities.

Near-Infrared Heptamethine Cyanine Based Iron Oxide Nanoparticles for Tumor Targeted Multimodal Imaging and Photothermal Therapy

Near-infrared fluorescent (NIRF) imaging modality holds great promise for tumor detection and offers several advantages of bioimaging, such as high tissue penetration with less background scattering. The disadvantage of NIRF bioimaging is that it has very low spatial resolution. Thus, the combination of NIRF with magnetic resonance imaging (MRI) is a good option because MRI can provide anatomical information with a higher resolution. Heptamethine cyanine dye (MHI-148) has been reported to have tumor-targeting capability which was used here as the NIRF agent. DSPE-SPION nanoparticles were synthesized by the solvent hydration method and conjugated with MHI-148 dye to form a MRI/NIRF dual imaging probe. The size and charge of the MHI-DSPE-SPION were found to be about 84 ± 6 nm and 3.7 mV by DLS & Zeta Potential analysis. In vivo MRI of the SCC7 tumor showed an enhanced accumulation of MHI-DSPE-SPION, peaking at day 1, compared to 4 hrs with the control DSPE-SPION. An in vivo photothermal tumor reduction study was done on the SCC7 tumor of BALB/c nude mice. Tumor reduction study showed complete tumor removal after 8 days. In conclusion, MHI-DSPE-SPION can be used as a cancer theranostics material because it provides MRI-optical imaging capabilities and the photothermal therapy (PTT) effect.

Effectiveness of Losartan-Loaded Hyaluronic Acid (HA) Micelles for the Reduction of Advanced Hepatic Fibrosis in C3H/HeN Mice Model

Advanced hepatic fibrosis therapy using drug-delivering nanoparticles is a relatively unexplored area. Angiotensin type 1 (AT1) receptor blockers such as losartan can be delivered to hepatic stellate cells (HSC), blocking their activation and thereby reducing fibrosis progression in the liver. In our study, we analyzed the possibility of utilizing drug-loaded vehicles such as hyaluronic acid (HA) micelles carrying losartan to attenuate HSC activation. Losartan, which exhibits inherent lipophilicity, was loaded into the hydrophobic core of HA micelles with a 19.5% drug loading efficiency. An advanced liver fibrosis model was developed using C3H/HeN mice subjected to 20 weeks of prolonged TAA/ethanol weight-adapted treatment. The cytocompatibility and cell uptake profile of losartan-HA micelles were studied in murine fibroblast cells (NIH3T3), human hepatic stellate cells (hHSC) and FL83B cells (hepatocyte cell line). The ability of these nanoparticles to attenuate HSC activation was studied in activated HSC cells based on alpha smooth muscle actin (α-sma) expression. Mice treated with oral losartan or losartan-HA micelles were analyzed for serum enzyme levels (ALT/AST, CK and LDH) and collagen deposition (hydroxyproline levels) in the liver. The accumulation of HA micelles was observed in fibrotic livers, which suggests increased delivery of losartan compared to normal livers and specific uptake by HSC. Active reduction of α-sma was observed in hHSC and the liver sections of losartan-HA micelle-treated mice. The serum enzyme levels and collagen deposition of losartan-HA micelle-treated mice was reduced significantly compared to the oral losartan group. Losartan-HA micelles demonstrated significant attenuation of hepatic fibrosis via an HSC-targeting mechanism in our in vitro and in vivo studies. These nanoparticles can be considered as an alternative therapy for liver fibrosis.

A Hyaluronic Acid-Conjugated Gadolinium Hepatocyte-Specific T1 Contrast Agent for Liver Magnetic Resonance Imaging.

PurposeIn this study, we synthesized hyaluronic acid-conjugated gadolinium (HA-diethylene triamine pentaacetic acid (DTPA)-Gd) and evaluated as hepatocyte-specific magnetic resonance imaging (MRI) contrast agent for the diagnosis of hepatic metastasis.ProceduresWe conducted Fourier transform (FT)-IR analysis to determine the conjugation of HA and DTPA and performed cell viability assays using NIH3T3 and FL83B cell lines. We also conducted T1-weighted MRI of HA-DTPA-Gd and gadoxetic acid to compare the paramagnetic properties of both.ResultsHA-DTPA-Gd had a higher efficiency in liver MRI compared with the commercially available liver-specific contrast agent (p < 0.001). HA-DTPA-Gd, which possessed a higher T1 relaxivity, showed excellent capability for the diagnosis of hepatic metastasis through an in vivo MRI study in comparison with gadoxetic acid (p < 0.001).ConclusionBased on this study, we believe that HA-DTPA-Gd has promising potential for use as a contrast agent for liver MRI of hepatic metastases.