Stimuli-Responsive Polymeric Nanomaterials for the Delivery of Immunotherapy Moieties: Antigens, Adjuvants and Agonists

Immunotherapy has been investigated for decades, and it has provided promising results in preclinical studies. The most important issue that hinders researchers from advancing to clinical studies is the delivery system for immunotherapy agents, such as antigens, adjuvants and agonists, and the activation of these agents at the tumour site. Polymers are among the most versatile materials for a variety of treatments and diagnostics, and some polymers are reactive to either endogenous or exogenous stimuli. Utilizing this advantage, researchers have been developing novel and effective polymeric nanomaterials that can deliver immunotherapeutic moieties. In this review, we summarized recent works on stimuli-responsive polymeric nanomaterials that deliver antigens, adjuvants and agonists to tumours for immunotherapy purposes

Biomedical applications for gas-stabilizing solid cavitation agents

For over a decade, advancements in ultrasound-enhanced drug delivery strategies have demonstrated remarkable success in providing targeted drug delivery for a broad range of diseases. In order to achieve enhanced drug delivery, these strategies harness the mechanical effects from bubble oscillations (i.e., cavitation) of a variety of exogenous cavitation agents. Recently, solid cavitation agents have emerged due to their capacity for drug-loading and sustained cavitation duration. Unlike other cavitation agents, solid cavitation agents stabilize gaseous bubbles on hydrophobic surface cavities. Thus, the design of these particles is crucial. In this Review, we provide an overview of the different designs for solid cavitation agents such as nanocups, nanocones, and porous structures, as well as the current status of their development. Considering the numerous advantages of solid cavitation agents, we anticipate further innovations for this new type of cavitation agent across a broad range of biomedical applications.NMRC (Natl Medical Research Council, S’pore)Accepted versio

Remote targeted implantation of sound-sensitive biodegradable multi-cavity microparticles with focused ultrasound

Ultrasound-enhanced drug delivery has shown great promise in providing targeted burst release of drug at the site of the disease. Yet current solid ultrasound-responsive particles are non-degradable with limited potential for drug-loading. Here, we report on an ultrasound-responsive multi-cavity poly(lactic-co-glycolic acid) microparticle (mcPLGA MP) loaded with rhodamine B (RhB) with or without 4′,6-diamidino-2-phenylindole (DAPI) to represent small molecule therapeutics. After exposure to high intensity focused ultrasound (HIFU), these delivery vehicles were remotely implanted into gel and porcine tissue models, where the particles rapidly released their payload within the frst day and sustained release for at least seven days. RhB-mcPLGA MPs were implanted with HIFU into and beyond the sub-endothelial space of porcine arteries without observable damage to the artery. HIFU also guided the location of implantation; RhB-mcPLGA MPs were only observed at the focus of the HIFU away from the direction of ultrasound. Once implanted, DAPI co-loaded RhB-mcPLGA MPs released DAPI into the arterial wall, staining the nucleus of the cells. Our work shows the potential for HIFUguided implantation of drug-loaded particles as a strategy to improve the local and sustained delivery of a therapeutic for up to two weeks.NMRC (Natl Medical Research Council, S’pore)Published versio

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

<div><p>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.</p></div

Effect of hepato-toxins in the acceleration of hepatic fibrosis in hepatitis B mice.

Chronic liver diseases such as hepatitis B viral (HBV) infection and liver fibrosis have been a major health problem worldwide. However, less research has been conducted owing to the lack of animal models. The key purpose of this study was to determine the effects of different hepatotoxins in HBV-affected liver. In this study, we successfully generated a combined liver fibrosis model by administering HBV 1.2 plasmid and thioacetamide/ethanol (TAA/EtOH). To our knowledge, this is the first study in which an increase in the liver fibrosis level is observed by the intraperitoneal administration of TAA and EtOH in drinking water after the hydrodynamic transfection of the HBV 1.2 plasmid in C3H/HeN mice. The HBV+TAA/EtOH group exhibited higher level of hepatic fibrosis than that of the control groups. The hepatic stellate cell activation in the TAA- and EtOH-administered groups was demonstrated by the elevation in the level of fibrotic markers. In addition, high levels of collagen content and histopathological results were also used to confirm the prominent fibrotic levels. We established a novel HBV mice model by hydrodynamic injection-based HBV transfection in C3H/HeN mice. C3H/HeN mice were reported to have a higher HBV persistence level than that of the C57BL/6 mouse model. All the results showed an increased fibrosis level in the HBV mice treated with TAA and EtOH; hence, this model would be useful to understand the effect of hepatotoxins on the high risk of fibrosis after HBV infection. The acceleration of liver fibrosis can occur with prolonged administration as well as the high dosage of hepatotoxins in mice

Confocal microscopy imaging of α-sma expression in hHSC cell.

<p>In HA micelle group, hHSC cells were incubated for 24 hours with HA micelle prior to 2 hour incubation with 1,000 nM of angiotensin 2. When angiotensin 2 is taken up by cells via angiotensin 1 receptor mechanism, expression of α-sma indicate the possible activation of HSC. In losartan group hHSC cells were incubated for 24 hours with 1,000nM losartan prior to 2 hour incubation with 1,000 nM of angiotensin 2. The angiotensin 1 receptors have been blocked by losartan which minimized expression of α-sma. In losartan-HA micelle group, hHSC cells were incubated for 24 hours with 1,000nM losartan-HA micelle prior to 2 hour incubation with 1,000 nM of angiotensin 2. Losartan-HA micelle helped in suppressing expression of α-sma more effectively. Blue color indicate DAPI stain.</p

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 T(2) 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

Lipo-MGN nanoparticle hypoxia attenuation-mediated single-dose radiotherapy- and pH/ROS-responsive T1 contrast magnetic resonance imaging in hepatocellular carcinoma

Abstract Tumor hypoxia is an important factor for developing resistance to radiation therapy (RT) and presents a bleak prognosis in cancer patients undergoing treatment for RT resistant hepatocellular carcinoma. Here, we present the synthesis of liposome-coated Mn3O4 (MGN) nanoparticles (Lipo-MGN) and investigation of their therapeutic potential with RT utilizing a HepG2 cancer model. According to in vitro research, Lipo-MGN effectively produced oxygen in the presence of H2O2 and significantly reduced the expression of HIF-1 in human HepG2 cells that were under hypoxic conditions. Lipo-MGN reversed the radio-resistance brought on by hypoxia and increased cell damage. When Lipo-MGN and RT were administered together in a HepG2 xenograft mice model, the tumor growth was delayed more than with RT alone. As determined by MR imaging, liposome-MGN also exhibited T1 contrast enhancement in tumor. According to these findings, Lipo-MGNs may increase the impact of RT by focusing tumor hypoxia. Hypoxic, radioresistant HepG2 cancer may be treated with Lipo-MGN in clinical studies