Preparation, characterization, in vitro drug release and biological studies of curcumin loaded dextran sulphate–chitosan nanoparticles

Nanoformulation of curcumin, (a low molecular weight hydrophobic drug) was prepared by using dextran sulphate and chitosan. The developed nanoparticles were characterized by Dynamic Light Scattering measurements (DLS), Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM), Fourier Transform Infrared Spectroscopy (FT-IR), X-ray Diffraction (XRD) and Differential Thermal Analysis (DTA). The prepared system showed an average size of 200-220 nm with a zeta potential value of -30 mV and showed ∼74% drug entrapment efficiency. In vitro drug release studies showed a controlled and pH dependent curcumin release over a period of one week. The cytocompatibility of bare nanoparticles was verified by MTT assay; cellular internalisation of curcumin loaded nanoparticles was confirmed by fluorescent imaging and quantified spectrophotometrically, anticancer activity of curcumin loaded nanoparticles was proved by MTT assay and reconfirmed by apoptosis assay (FACS). The results showed preferential killing of cancer cells compared to normal cells by the curcumin-loaded nanoparticles. Thus the developed curcumin loaded nanoformulation could be a promising candidate in cancer therapy

Biostable and bioreducible polymersomes for intracellular delivery of doxorubicin

To minimize the premature drug release of nanocarriers, we have developed chemically cross-linked bioreducible polymersomes (CLPMs) that can specifically release the drug inside cancer cells. Polymersomes were prepared using poly(ethylene glycol)-b-poly(lysine)-b-poly(caprolactone), a biocompatible triblock copolymer. To chemically cross-link the polymersomes, the primary amine of the triblock copolymer was reacted with a disulfide-containing cross-linker. Doxorubicin (DOX) was chosen as a model anti-cancer drug, and was effectively encapsulated into the CLPMs. The drug-loaded polymersomes greatly retarded the release of DOX under physiological conditions (pH 7.4), whereas the release rate of DOX increased remarkably in the presence of 10 mM glutathione, mimicking an intracellular environment. Microscopic observation showed that DOX-loaded CLPMs could effectively deliver the drug into an intracellular level of SCC7 cancer cells, leading to high cytotoxicity. These observations suggest that CLPMs are promising nanocarriers for intracellular DOX delivery

Nanoparticles based on quantum dots and a luminol derivative: implications for in vivo imaging of hydrogen peroxide by chemiluminescence resonance energy transfer

Overproduction of hydrogen peroxide is involved in the pathogenesis of inflammatory diseases such as cancer and arthritis. To image hydrogen peroxide via chemiluminescence resonance energy transfer in the near-infrared wavelength range, we prepared quantum dots functionalized with a luminol derivative

Hypoxia-responsive polymeric nanoparticles for tumor-targeted drug delivery

Hypoxia is a condition found in various intractable diseases. Here, we report self-assembled nanoparticles which can selectively release the hydrophobic agents under hypoxic conditions. For the preparation of hypoxia-responsive nanoparticles (HR-NPs), a hydrophobically modified 2-nitroimidazole derivative was conjugated to the backbone of the carboxymethyl dextran (CM-Dex). Doxorubicin (DOX), a model drug, was effectively encapsulated into the HR-NPs. The HR-NPs released DOX in a sustained manner under the normoxic condition (physiological condition), whereas the drug release rate. remarkably increased under the hypoxic condition. From in vitro cytotoxicity tests, it was found the DOX-loaded HR-NPs showed higher toxicity to hypoxic cells than to normoxic cells. Microscopic observation showed that the HR-NPs could effectively deliver DOX into SCC7 cells under hypoxic conditions. In vivo biodistribution study demonstrated that HR-NPs were selectively accumulated at the hypoxic tumor tissues. As consequence, drug-loaded HR-NPs exhibited high anti-tumor activity in vivo. Overall, the HR-NPs might have a potential as nanocarriers for drug delivery to treat hypoxia-associated diseases. (C) 2013 Elsevier Ltd. All rights reserved

Bioreducible Carboxymethyl Dextran Nanoparticles for Tumor-Targeted Drug Delivery

Bioreducible carboxymethyl dextran (CMD) derivatives are synthesized by the chemical modification of CMD with lithocholic acid (LCA) through a disulfide linkage. The hydrophobic nature of LCA allows the conjugates (CMD-SS-LCAs) to form self-assembled nanoparticles in aqueous conditions. Depending on the degree of LCA substitution, the particle diameters range from 163 to 242 nm. Doxorubicin (DOX), chosen as a model anticancer drug, is effectively encapsulated into the nanoparticles with high loading efficiency (>70%). In vitro optical imaging tests reveal that the fluorescence signal of DOX quenched in the bioreducible nanoparticles is highly recovered in the presence of glutathione (GSH), a tripeptide capable of reducing disulfide bonds in the intracellular compartments. Bioreducible nanoparticles rapidly release DOX when they are incubated with 10 m M GSH, whereas the drug release is greatly retarded in physiological buffer (pH 7.4). DOX-loaded bioreducible nanoparticles exhibit higher toxicity to SCC7 cancer cells than DOX-loaded nanoparticles without the disulfide bond. Confocal laser scanning microscopy observation demonstrate that bioreducible nanoparticles can effectively deliver DOX into the nuclei of SCC7 cells. In vivo biodistribution study indicates that Cy5.5-labeled CMD-SS-LCAs selectively accumulate at tumor sites after systemic administration into tumor-bearing mice. Notably, DOX-loaded bioreducible nanoparticles exhibit higher antitumor efficacy than reduction-insensitive control nanoparticles. Overall, it is evident that bioreducible CMD-SS-LCA nanoparticles are useful as a drug carrier for cancer therapy

Intracellularly Activatable Nanovasodilators To Enhance Passive Cancer Targeting Regime

Conventional cancer targeting with nanoparticles has been based on the assumed enhanced permeability and retention (EPR) effect. The data obtained in clinical trials to date, however, have rarely supported the presence of such an effect. To address this challenge, we formulated intracellular nitric oxide-generating nanoparticles (NO-NPs) for the tumor site-specific delivery of NO, a well-known vasodilator, with the intention of boosting EPR. These nanoparticles are self-assembled under aqueous conditions from amphiphilic copolymers of poly­(ethylene glycol) and nitrated dextran, which possesses inherent NO release properties in the reductive environment of cancer cells. After systemic administration of the NO-NPs, we quantitatively assessed and visualized increased tumor blood flow as well as enhanced vascular permeability than could be achieved without NO. Additionally, we prepared doxorubicin (DOX)-encapsulated NO-NPs and demonstrated consequential improvement in therapeutic efficacy over the control groups with considerably improved DOX intratumoral accumulation. Overall, this proof of concept study implies a high potency of the NO-NPs as an EPR enhancer to achieve better clinical outcomes

Light-induced reactive-oxygen-species-(ros-) mediated activation of self-assembled nanoplatforms for on-demand drug delivery

Significant research efforts have been devoted to the development of multifunctional nanoplatforms that can efficiently target and deliver therapeutic/diagnostic agents to diseased sites. In recent years, the use of internal or external stimuli to trigger drug release in a controlled or programmed fashion is emerging as a promising approach to the design and fabrication of smart drug carriers. Among various stimuli, light as an external source of energy has become a powerful tool for realizing precise drug delivery because it not only allows remote and accurate control of drug release but can also be easily focused into specific pathological areas such as tumor. Recently, the photosensitized cascade generation of reactive oxygen species (ROS) and cleavage of an ROS-sensitive linker have been utilized as a trigger to facilitate drug release at desired target sites. This book chapter highlights recent progress in the light-induced ROS-mediated activation of various self-assembled nanoassemblies for on-demand drug delivery. © 2019 American Chemical Society. All rights reserved.11Nscopu