26 research outputs found
Efficacy versus Toxicity - The Ying and Yang in Translating Nanomedicines
Nanomedicine, as a relatively new offshoot of nanotechnology, has presented vast opportunities in biomedical research for developing novel strategies to treat diseases. In the past decade, there has been a significant increase in in vitro and preclinical studies addressing the benefits of nanomedicines. In this commentary, we focus specifically on the efficacy- and toxicity-related translational challenges of nanocarrier-mediated systems, and briefly discuss possible strategies for addressing such issues at in vitro and preclinical stages. We address questions related specifically to the balance between toxicity and efficacy, a balance that is expected to be substantially different for nanomedicines compared to that for a free drug. Using case studies, we propose a ratiometric assessment tool to quantify the overall benefit of nanomedicine as compared to free drugs in terms of efficacy and toxicity. The overall goal of this commentary is to emphasize the strategies that promote the translation of nanomedicines, especially by learning lessons from previous translational failures of other drugs and devices, and to apply these lessons to critically assess data at the basic stages of nanomedicinal research
Molecular-receptor-specific, non-toxic, near-infrared-emitting Au cluster-protein nanoconjugates for targeted cancer imaging
Molecular-receptor-targeted imaging of folate receptor positive oral carcinoma cells using folic-acid-conjugated fluorescent Au25 nanoclusters (Au NCs) is reported. Highly fluorescent Au25 clusters were synthesized by controlled reduction of Au+ ions, stabilized in bovine serum albumin (BSA), using a green-chemical reducing agent, ascorbic acid (vitamin-C). For targeted-imaging-based detection of cancer cells, the clusters were conjugated with folic acid (FA) through amide linkage with the BSA shell. The bioconjugated clusters show excellent stability over a wide range of pH from 4 to 14 and fluorescence efficiency of ~5.7% at pH 7.4 in phosphate buffer saline (PBS), indicating effective protection of nanoclusters by serum albumin during the bioconjugation reaction and cell-cluster interaction. The nanoclusters were characterized for their physico-chemical properties, toxicity and cancer targeting efficacy in vitro. X-ray photoelectron spectroscopy (XPS) suggests binding energies correlating to metal Au 4f7/2˜83.97 eV and Au 4f5/2~87.768 eV. Transmission electron microscopy and atomic force microscopy revealed the formation of individual nanoclusters of size ~1 nm and protein cluster aggregates of size ~8 nm. Photoluminescence studies show bright fluorescence with peak maximum at ~674 nm with the spectral profile covering the near-infrared (NIR) region, making it possible to image clusters at the 700-800 nm emission window where the tissue absorption of light is minimum. The cell viability and reactive oxygen toxicity studies indicate the non-toxic nature of the Au clusters up to relatively higher concentrations of 500 µg ml-1. Receptor-targeted cancer detection using Au clusters is demonstrated on FR+ve oral squamous cell carcinoma (KB) and breast adenocarcinoma cell MCF-7, where the FA-conjugated Au25 clusters were found internalized in significantly higher concentrations compared to the negative control cell lines. This study demonstrates the potential of using non-toxic fluorescent Au nanoclusters for the targeted imaging of cancer
Differential nano-bio interactions and toxicity effects of pristine versus functionalized graphene
We report the effect of carboxyl functionalization of graphene in pacifying its strong hydrophobic interaction with cells and associated toxic effects. Pristine graphene was found to accumulate on the cell membrane causing high oxidative stress leading to apoptosis, whereas carboxyl functionalized hydrophilic graphene was internalized by the cells without causing any toxicity
Radiofrequency ablation of drug-resistant cancer cells using molecularly targeted carboxyl-functionalized biodegradable graphene
Luminescent quantum clusters of gold in bulk by albumin-induced core etching of nanoparticles: metal ion sensing, metal-enhanced luminescence, and biolabeling
The synthesis of a luminescent quantum cluster (QC) of gold with a quantum yield of ~4 % is reported. It was synthesized in gram quantities by the core etching of mercaptosuccinic acid protected gold nanoparticles by bovine serum albumin (BSA), abbreviated as AuQC@BSA. The cluster was characterized and a core of Au38 was assigned tentatively from mass spectrometric analysis. Luminescence of the QC is exploited as a "turn-off" sensor for Cu2+ ions and a "turn-on" sensor for glutathione detection. Metal-enhanced luminescence (MEL) of this QC in the presence of silver nanoparticles is demonstrated and a ninefold maximum enhancement is seen. This is the first report of the observation of MEL from QCs. Folic acid conjugated AuQC@BSA was found to be internalized to a significant extent by oral carcinoma KB cells through folic acid mediated endocytosis. The inherent luminescence of the internalized AuQC@BSA was used in cell imaging
Protein Nanomedicine Exerts Cytotoxicity toward CD34<sup>+</sup> CD38<sup>–</sup> CD123<sup>+</sup> Leukemic Stem Cells
The efficacy of protein-vorinostat
nanomedicine (NV) is demonstrated
in leukemic stem cells (LSC) isolated from refractory acute myeloid leukemia (AML) patient samples, where
it successfully ablated both CD34<sup>+</sup> CD38<sup>–</sup> CD123<sup>+</sup> LSC and non-LSC “leukemic blast”
compartments, without inducing myelosuppression or hemotoxicity. Besides,
NV also exerted excellent synergistic lethality against leukemic bone
marrow cells (BMC) at lower concentrations (0.1 μM) in combination
with DNA methyltransferase (DNMT) inhibitor, decitabine. Considering
the extermination of resilient LSC and synergism with decitabine,
NV shows promise for clinical translation in the setting of a more
tolerable and effective epigenetic targeted therapy for leukemia
Green Synthesis of Anisotropic Gold Nanoparticles for Photothermal Therapy of Cancer
Nanoparticles
of varying composition, size, shape, and architecture
have been explored for use as photothermal agents in the field of
cancer nanomedicine. Among them, gold nanoparticles provide a simple
platform for thermal ablation owing to its biocompatibility in vivo.
However, the synthesis of such gold nanoparticles exhibiting suitable
properties for photothermal activity involves cumbersome routes using
toxic chemicals as capping agents, which can cause concerns in vivo.
Herein, gold nanoparticles, synthesized using green chemistry routes
possessing near-infrared (NIR) absorbance facilitating photothermal
therapy, would be a viable alternative. In this study, anisotropic
gold nanoparticles were synthesized using an aqueous route with cocoa
extract which served both as a reducing and stabilizing agent. The
as-prepared gold nanoparticles were subjected to density gradient
centrifugation to maximize its NIR absorption in the wavelength range
of 800–1000 nm. The particles also showed good biocompatibility
when tested in vitro using A431, MDA-MB231, L929, and NIH-3T3 cell
lines up to concentrations of 200 μg/mL. Cell death induced
in epidermoid carcinoma A431 cells upon irradiation with a femtosecond
laser at 800 nm at a low power density of 6 W/cm<sup>2</sup> proved
the suitability of green synthesized NIR absorbing anisotropic gold
nanoparticles for photothermal ablation of cancer cells. These gold
nanoparticles also showed good X-ray contrast when tested using computed
tomography (CT), proving their feasibility for use as a contrast agent
as well. This is the first report on green synthesized anisotropic
and cytocompatible gold nanoparticles without any capping agents and
their suitability for photothermal therapy
Biocompatible Magnetite/Gold Nanohybrid Contrast Agents via Green Chemistry for MRI and CT Bioimaging
Magnetite/gold (Fe<sub>3</sub>O<sub>4</sub>/Au) hybrid
nanoparticles
were synthesized from a single iron precursor (ferric chloride) through
a green chemistry route using grape seed proanthocyanidin as the reducing
agent. Structural and physicochemical characterization proved the
nanohybrid to be crystalline, with spherical morphology and size ∼35
nm. Magnetic resonance imaging and magnetization studies revealed
that the Fe<sub>3</sub>O<sub>4</sub> component of the hybrid provided
superparamagnetism, with dark T<sub>2</sub> contrast and high relaxivity
(124.2 ± 3.02 mM<sup>–1</sup> s<sup>–1</sup>).
Phantom computed tomographic imaging demonstrated good X-ray contrast,
which can be attributed to the presence of the nanogold component
in the hybrid. Considering the potential application of this bimodal
nanoconstruct for stem cell tracking and imaging, we have conducted
compatibility studies on human Mesenchymal Stem Cells (hMSCs), wherein
cell viability, apoptosis, and intracellular reactive oxygen species
(ROS) generation due to the particle–cell interaction were
asessed. It was noted that the material showed good biocompatibility
even for high concentrations of 500 μg/mL and up to 48 h incubation,
with no apoptotic signals or ROS generation. Cellular uptake of the
nanomaterial was visualized using confocal microscopy and prussian
blue staining. The presence of the nanohybrids were clearly visualized
in the intracytoplasmic region of the cell, which is desirable for
efficient imaging of stem cells in addition to the cytocompatible
nature of the hybrids. Our work is a good demonstrative example of
the use of green aqueous chemistry through the employment of phytochemicals
for the room temperature synthesis of complex hybrid nanomaterials
with multimodal functionalities