nan Nurunnabi

In Vivo Biodistribution and Toxicology of Carboxylated Graphene Quantum Dots

Photoluminescent graphene quantum dots (GQDs) have fascinating optical and electronic properties with numerous promising applications in biomedical engineering. In this work, we first studied the in vivo biodistribution and the potential toxicity of carboxylated photoluminescent GQDs. KB, MDA-MB231, A549 cancer cells, and MDCK normal cell line were chosen as in vitro cell culture models to examine the possible adverse effects of the carboxylated photoluminescent GQDs. The carboxylated GQDs are desirable for increased aqueous solubility. All cancer cells efficiently took up the carboxylated GQDs. No acute toxicity or morphological changes were noted in either system at the tested exposure levels. A long-term in vivo study revealed that the GQDs mainly accumulated in liver, spleen, lung, kidney, and tumor sites after intravenous injection. To reveal any potential toxic effect of the GQDs on treated mice, serum biochemical analysis and histological evaluation were performed. The toxicity results from serum biochemistry and complete blood count study revealed that the GQDs do not cause appreciable toxicity to the treated animals. Finally, we observed no obvious organ damage or lesions for the GQDs treated mice after 21 days of administration at 5 mg/kg or 10 mg/kg dosages. With adequate studies of toxicity, both in vitro and in vivo, photoluminescent GQDs may be considered for biological application.

Surface Coating of Graphene Quantum Dots Using Mussel-Inspired Polydopamine for Biomedical Optical Imaging

Because of the superiority of GQDs (graphene quantum dots) in biomedical imaging, in terms of biocompatibility and toxicity of semiconductor quantum dots, GQDs bring new opportunities for the diagnosis and detection of diseases. In this study, we synthesized photoluminescent (PL) graphene quantum dots (GQDs) through a simple exfoliation and oxidation process, and then coated them with polydopamine (pDA) for enhanced stability in water and low toxicity in vivo. From the results, the GQDs coated with pDA showed an excellent stability of PL intensity. It showed that the PL intensity of noncoated GQDs in PBS solution rapidly decreased with time, resulting in a 45% reduction of the PL intensity for 14 days of incubation in PBS solution. After coating with polydopamine, PL intensities of polydopamine-coated GQDs was maintained more stably for 14 days compared with uncoated GQDs. We have observed the in vitro and in vivo biocompatibility of pDA-coated GQDs in nude mice. The overall observation revealed that pDA-coated GQDs could be used as a long-term optical imaging agent as well as a biocompatible drug carrier.

Bioapplication of graphene oxide derivatives: drug/gene delivery, imaging, polymeric modification, toxicology, therapeutics and challenges

Due to the wide range and various applications of graphene in multidisciplinary fields, such as electronics, solar cells, biomedicine, bioengineering, drug delivery, gene delivery and semiconductors, graphene and its derivatives have attracted most significant interest of diverse group of scientists in the last decades. Besides numerous applications in electrical and mechanical fields, their non-invasive biomedical imaging properties allow their wide-spread biological applications. Optical imaging probes play a pivotal role in early cancer detection, image based surgery, disease diagnosis and cellular imaging. Graphene has been widely studied in drug delivery systems due to its unique features and comparatively less/non-toxic properties in biological systems, thus promoting graphene quantum dots as potential organic optical imaging agents to substitute toxic cadmium or tellurium quantum dots. Many groups have also focused on different polymeric modification strategies to enhance the biocompatibility as well as the applications of graphene. In this review, we have summarized recent advances in graphene-based applications, and focused on the relation between chemical structure and polymeric modification with bio-safety issues. The lack of adequate biosafety studies and understanding of the interaction between graphene derivatives and biomolecules has hindered their progress in biomedical and biological applications. To proceed with biological applications of graphene derivatives, such as the development of graphene-based therapeutics and drug delivery systems, the research community must understand how graphene derivatives interact with cell lines and how they accumulate into cells. We also need to learn the fate of graphene derivatives in vivo once it invasively enters into a biological system.

Photoluminescent graphene nanoparticles for cancer phototherapy and imaging.

Graphene-based nanomaterials are of great interest in a wide range of applications in electronics, the environment, and energy as well as in biomedical and bioengineering. Their unique properties make them generally applicable as prognostic, diagnostic, and therapeutic agents in cancer. In this work, we focused on photodynamic and photothermal therapeutic properties of our previously synthesized carboxylated photoluminescent graphene nanodots (cGdots). The cGdots are ∼5 nm in diameter and excited at 655 nm. Our findings reveal that, upon laser irradiation by near-infrared (wavelength 670 nm) sensitizer, electrons of the cGdots starts to vibrate and form electron clouds, thereby generating sufficient heat (>50 °C) to kill the cancer cells by thermal ablation. The generation of singlet oxygen also occurs due to irradiation, thus acting similarly to pheophorbide-A, a well-known photodynamic therapeutic agent. The cGdots kills MDA-MB231 cancer cells (more than 70%) through both photodynamic and photothermal effects. The cGdots were equally effective in the in vivo model of MDA-MB231 xenografted tumor-bearing mice also as observed for 21 days. The cGdot was intravenously injected, and the tumor was irradiated by laser, resulting in final volume of tumor was ∼70% smaller than that of saline-treated tumor. It indicates that the growth rate of cGdot-treated tumor was slower compared to saline-treated tumor. The synthesized cGdots could enable visualization of tumor tissue in mice, thereby illustrating their use as optical imaging agents for detecting cancer noninvasively in deep tissue/organ. Collectively, our findings reveal that multimodal cGdots can be used for phototherapy, through photothermal or photodynamic effects, and for noninvasive optical imaging of deep tissues and tumors simultaneously.

Oral delivery of taurocholic acid linked heparin-docetaxel conjugates for cancer therapy.

We have synthesized taurocholic acid (TCA) linked heparin-docetaxel (DTX) conjugates for oral delivery of anticancer drug. The ternary biomolecular conjugates formed self-assembly nanoparticles where docetaxel was located inside the core and taurocholic acid was located on the surface of the nanoparticles. The coupled taurocholic acid in the nanoparticles had enhanced oral absorption, presumably through the stimulation of a bile acid transporter of the small intestine. The oral absorption profile demonstrated that the concentration of the conjugates in plasma is about 6 fold higher than heparin alone. An anti-tumor study in MDA-MB231 and KB tumor bearing mice showed significant tumor growth inhibition activity by the ternary biomolecular conjugates. Ki-67 histology study also showed evidence of anticancer activity of the nanoparticles. Finally, noninvasive imaging using a Kodak Molecular Imaging System demonstrated that the nanoparticles were accumulated efficiently in tumors. Thus, this approach for oral delivery using taurocholic acid in the ternary biomolecular conjugates is promising for treatment of various types of cancer.

A photosensitizer-conjugated magnetic iron oxide/gold hybrid nanoparticle as an activatable platform for photodynamic cancer therapy

A multifunctional nanomedicine combining magnetic resonance imaging (MRI) and photodynamic therapy (PDT) functionalities is a promising integrated platform that allows for targeted drug delivery, noninvasive monitoring of therapeutic responses, and simultaneous cancer diagnosis and treatment. A hybrid nanoparticle (NP) system with a core/shell-structured magnetic iron oxide/gold (Fe3O4/Au) NP and a photosensitizer (PS)-conjugated heparin surface layer is investigated as a novel multifunctional carrier in PDT. A thiolated heparin-pheophorbide a (PhA) conjugate (H-PhA), which is a macromolecular PS, is synthesized and introduced onto the NP surface through a gold-thiol interaction. The photoactivity of the PhA moieties on the NP surface is significantly suppressed by the quenching effect of the Fe3O4/Au NP. However, their photoactivity can be restored in a glutathione (GSH)-rich intracellular environment, which allows GSH-mediated switchable photoactivity in the hybrid NP system. As a result, marked phototoxicity and strong fluorescence signals are observed in NP-treated A549 cells under light irradiation. In an animal tumor model, Fe3O4/Au/H-PhA NPs are efficacious in photodynamic cancer treatment and exhibit prolonged circulation characteristics, enhanced tumor specificity, and higher therapeutic efficacy compared with free PhA. In addition, in vitro MRI studies reveal that the NPs could potentially serve as MRI contrast agents in cancer diagnosis and may be used to monitor the photodynamic treatment response used to accurately guide light irradiation. The present findings show that the Fe3O4/Au/H-PhA NP is a promising nanomedicine platform in PDT and cancer diagnosis.

Oral Delivery of Near-Infrared Quantum Dot Loaded Micelles for Noninvasive Biomedical Imaging

The purpose of this study is to design, develop, and characterize an optical imaging agent for oral administration. The hydrophobic, nanosized (7 nm), near-infrared (NIR) quantum dots (QDs) have been loaded into deoxycholic acid (DOCA) conjugated low molecular weight heparin (LMWH) micelles. The QD-loaded LMWH-DOCA (Q-LHD) nanoparticles have been characterized by electrophoretic light scattering (ELS) and a transmission electron microscope (TEM) which shows the average particle size was 130-220 nm in diameter. The Q-LHD nanoparticles also show the excellent stability in different pH conditions, and the release profile demonstrates the slow release of QDs after 5 days of oral administration. Concfocal laser microscopic scanning images show that the Q-LHD nanoparticles penetrate the cell membrane and are located inside the cell membrane. The real time pharmacokinetics studies show the absorption, distribution, metabolism, and elimination profile of Q-LHD nanoparticles, observed by the Kodak molecular imaging system (KMIS). This study has demonstrated that the orally administered Q-LHD nanoparticles are absorbed in the small intestine through the bile acid transporter and eliminated through the kidneys.

Ternary graphene quantum dot–polydopamine–Mn3O4 nanoparticles for optical imaging guided photodynamic therapy and T1-weighted magnetic resonance imaging

Imaging-guided therapy, which bridges treatment and diagnosis, plays an important role in overcoming the limitations of classical cancer therapy. To provide a more exact location of the tumor and to reduce side effects to normal tissues, a multifunctional probe was designed to serve as both an imaging agent and a therapeutic agent. Ternary hybrid nanoparticles comprised of visible red-responsive graphene, the T1-weighted magnetic resonance imaging (MRI) agent Mn3O4 and a mussel-inspired linker polydopamine. The conjugation of graphene to Mn3O4 through polydopamine enhanced the water solubility of Mn3O4, enabling an efficient uptake by cancer cells as well as tumor accumulation when the nanoparticles were intravenously administered into mice. These nanoparticles, when localized at a tumor site, exhibited low cytotoxicity in the dark, while light irradiation of the cancer cells transfected with the nanoparticles resulted in significant phototherapeutic effects, apparently by generating toxic reactive oxygen species. These nanoparticles also allowed excellent T1-weighted MR imaging in a human lung cancer xenograft model and were successfully used for combined visible red-imaging-guided photodynamic therapy and T1-weighted MRI.

Hybrid photoactive nanomaterial composed of gold nanoparticles, pheophorbide-A and hyaluronic acid as a targeted bimodal phototherapy

Modern cancer research is largely focused on the design and development of multifunctional nanomaterials for cancer therapy and diagnosis. In this study, we fabricated a theranostic nanomaterial known as a photomedicine that combines a photothermal therapy (PTT), gold nanoparticles (AuNPs), a photodynamic therapy (PDT), pheophorbide-A (PheoA), and a cancer-targeting agent, hyaluronic acid (HA); this photomedicine also acts as a bimodal phototherapy. The combination of AuNPs and PheoA exerts a synergistic effect on PTT and PDT when irradiated by a laser source with a specific excitation wavelength. When excited by an external laser source, the hybrid nanomedicine generates singlet oxygen from PheoA while simultaneously generating heat from the AuNP, thus demonstrating a higher efficacy than any of the individual agents. The presence of HA on the outer surface of the Au accelerates the cellular uptake of the nanomedicine through CD44 receptors and prevents nonspecific accumulation of the drug in non-cancerous cells. The multifunctional nanoparticles have a diameter of ∼70 nm and show constant stability in different conditions for up to a week of observation. In vitro and in vivo studies have demonstrated that multifunctional nanomaterials selectively target cells overexpressing CD44 receptor. In vitro photo-activity assays in the lung cancer cell line (A549) show that over 95% of the cells were dead upon laser irradiation. In brief, this newly developed nanomaterial rapidly accumulates in the tumor within 3 h of IV administration and inhibits tumor growth by 95% upon laser irradiation compared with a saline-treated tumor model observed for 24 days.

Intracellular delivery and activation of the genetically encoded photosensitizer Killer Red by quantum dots encapsulated in polymeric micelles

We have prepared polymeric micelle-encapsulating quantum dots (QDots) for delivering the optically activatable protein Killer Red (KR) as a plasmid to cancer cells. QDots absorb light at a lower wavelength and emit light at a higher wavelength in the cell cytoplasm, activating the expressed KR. Once activated, KR triggers the generation of reactive oxygen species (ROS). We prepared cadmium selenide (CdSe)/zinc sulphide (ZnS) QDots and evaluated their optical properties. Subsequently, we performed morphology studies, elemental analysis, thermogravimetric analysis (TGA), and measurements of particle size and surface charge of prepared QDots encapsulated in PHEA-g-PEG-bPEI (PPP-QDot). Cellular uptake of PPP-QDot and PPP-QDot/KR nanoparticles was confirmed using confocal microscopy, and the cellular toxicity and transfection efficiency associated with uptake of PPP-QDot/KR nanoparticles were analyzed. KR expression in normal cells and cancer cells was confirmed using confocal microscopy and Western blotting. Cellular morphologies before and after intracellular activation of KR were observed using phase contrast, fluorescence, and confocal microscopy. Cell fate after exposure to blue light-emitting diode lighting was determined using apoptosis staining and a cell proliferation assay, confirming a suppression in proliferation and a reduction in metabolic activity. We determined that ROS generation contributed to cellular damage after treatment with PPP-QDot/KR nanoparticles and blue light exposure.