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Generation of a Library of Non-Toxic Quantum Dots for Cellular Imaging and siRNA Delivery
Advanced Materials
Abstract
The development of non-toxic quantum dots and further investigation of their composition-dependent cytotoxicity in a high-throughput manner have been critical challenges for biomedical imaging and gene delivery. Herein, we report a rapid sonochemical synthetic methodology for generating a library of highly biocompatible ZnS-AgInS(2) (ZAIS) quantum dots for cellular imaging and siRNA delivery.
... Additional surface coatings are required for the generation of water dispersible QDs followed by subsequent conjugation via biotin-avidin interactions. In overcoming cytotoxicity associated with Cd-, Te-, and Se-based QDs, the development of I-III-VI 2 -based QDs, such as AgInS 2 , CuInS 2 , and ZnS-AgInS 2 (ZAIS) QDs, serves to be the next step in the generation of nontoxic QDs; however, the synthesis of such QDs encompasses certain shortcomings including high reaction temperature, inadequate control over growth rates, long reaction times, complex procedures, and complications associated with high-throughput synthesis (Subramaniam et al. 2012). Addressing the above shortcomings, Subramaniam et al. have recently developed a novel sonochemical approach for high-throughput synthesis of a biocompatible library of ZAIS QDs (Subramaniam et al. 2012). ...
... In overcoming cytotoxicity associated with Cd-, Te-, and Se-based QDs, the development of I-III-VI 2 -based QDs, such as AgInS 2 , CuInS 2 , and ZnS-AgInS 2 (ZAIS) QDs, serves to be the next step in the generation of nontoxic QDs; however, the synthesis of such QDs encompasses certain shortcomings including high reaction temperature, inadequate control over growth rates, long reaction times, complex procedures, and complications associated with high-throughput synthesis (Subramaniam et al. 2012). Addressing the above shortcomings, Subramaniam et al. have recently developed a novel sonochemical approach for high-throughput synthesis of a biocompatible library of ZAIS QDs (Subramaniam et al. 2012). The application of ultrasound irradiation in sonochemical synthesis holds several advantages including rapid reaction rates in controllable conditions, generation of QDs with uniform shape and narrow size distributions, and high-purity synthesis at ambient temperatures. ...
... The application of ultrasound irradiation in sonochemical synthesis holds several advantages including rapid reaction rates in controllable conditions, generation of QDs with uniform shape and narrow size distributions, and high-purity synthesis at ambient temperatures. In contrast to size dependence exhibited in CdSe and CdTe QDs, the optical properties of ZAIS QDs are composition dependent as emission wavelengths are controlled by varying the concentrations of each precursor element; this offers the potential for QD emissions at near UV range, a property unattainable with size dependent CdSe/CdTe QDs (Subramaniam et al. 2012). Characterization of these ZAIS QDs has demonstrated comparable quantum yields to CdSe/CdTe QDs, high stability at ambient temperatures, significantly improved biocompatibility at high concentrations, strong fluorescence inside cells, and successful siRNA delivery upon conjugation to siRNA via PEI (Subramaniam et al. 2012). ...
Although viral vectors comprise the majority of gene delivery vectors, their various safety, production, and other practical concerns have left a research gap to be addressed. The non-viral vector space encompasses a growing variety of physical and chemical methods capable of gene delivery into the nuclei of target cells. Major physical methods described in this chapter are microinjection, electroporation, and ballistic injection, magnetofection, sonoporation, optical transfection, and localized hyperthermia. Major chemical methods described in this chapter are lipofection, polyfection, gold complexation, and carbon-based methods. Combination approaches to improve transfection efficiency or reduce immunological response have shown great promise in expanding the scope of non-viral gene delivery.
... Nanomaterials composed of less toxic materials represent a new and more environmentally friendly approach to the detection of explosive chemicals [2,[6][7][8][9][10][11]. Our group [12] and others [13][14][15][16] have recently explored the synthesis and applications of less toxic QDs composed of more environmentally friendly metals. To this end, we recently demonstrated the application of zinc silver indium sulfide (ZAIS) and related QDs for the application of metal detection [12]. ...
... The most significant advantage and novelty of this manuscript, is the relatively lower toxicity of AIS QDs in comparison to those nanomaterials based on Cd and or Pb. There have been several reports that detail the reduced toxicity of ZnAgInS 2 (ZAIS), CuInS 2 /ZnS, and ZnSe QDs for biomedical research and imaging studies [14,17,18]. Recent studies have reported, via cytotoxicity assays, that ZAIS QDs showed a significantly improved biocompatibility in comparison to the CdSe/ZnS QDs [14]. ...
... There have been several reports that detail the reduced toxicity of ZnAgInS 2 (ZAIS), CuInS 2 /ZnS, and ZnSe QDs for biomedical research and imaging studies [14,17,18]. Recent studies have reported, via cytotoxicity assays, that ZAIS QDs showed a significantly improved biocompatibility in comparison to the CdSe/ZnS QDs [14]. Further studies will be needed to address the long-term toxicity effects of AIS QDs, but based on these results we believe our cadmium free AIS QDs to be a less toxic than cadmium based nanomaterials and represent a possible alternative to nanomaterials that use heavy metals with known negative environmental effects [19]. ...
AgInS2 (AIS) quantum dots (QDs) were synthesized via a thermal decomposition reaction with dodecylamine as the ligand to help stabilize the QDs. This reaction procedure is relatively easy to implement, scalable to large batches (up to hundreds of milligrams of QDs are produced), and a convenient method for the synthesis of chalcogenide QDs. Metal powders of AgNO3 and In(NO3)3, were used as the metal precursors while diethyldithiocarbamate was used as the sulfur source. The AIS QDs were characterized via transmission electron microscopy, atomic force microscopy, and energy dispersive x-ray spectroscopy. As an application for these less toxic nanomaterials, we demonstrate the selective detection of Trinitrotoluene (TNT) at concentrations as low as 6 micromolar (μM) and without the functionalization of a ligand that is specifically designed to interact with TNT molecules. We also demonstrate a simple approach to patterning the AIS QDs onto filter paper, for the detection of TNT molecules by eye. Collectively, the ease of the synthesis of the less toxic AIS QDs, and the ability to detect TNT molecules by eye suggest an attractive route to highly sensitive and portable substrates for environmental monitoring, chemical warfare agent detection, and other applications.
... Also, because of their electrostatic binding properties, nanohybrid ligands can bind negatively charged genes. Most commonly, polycations are the most common carriers of genetic information, and a range of PEI-modified inorganic NPs was created to assess their effectiveness as gene carriers [150,161,197]. Boyer et al. used the "grafting onto" technique to functionalize Fe 2 O 3 NPs with P (OEG-A) and P (DMAEA) functionalized NPs to address protein adsorption issues caused by polycation positive charge [9]. ...
... It is extremely difficult to use QDs for cell and in vivo imaging because of the toxicity of heavy metal ions associated with them [166]. Lee et al. used ultrasound (US) irradiation to create a collection of nontoxic ZnxS-AgyIn1-yS2 QDs by means of enhanced optical (PL) features that were also nontoxic, according to their findings [161]. Regardless of To minimize cytotoxicity, QDs can be coated with polymer, BSA, or silica before hybridization [99,190,207]. ...
A great deal of interest has been drawn to organic and inorganic nanohybrids because of their advantageous properties and potential uses in the healthcare industry, among others. A significant amount of time and effort was expended on the design and fabrication of adaptable nanohybrids. This research discusses organic and inorganic nanohybrids formed from nanoparticles and polymeric substances as the subject of this research, which discusses their design, characteristics, and biomedical applications. Following that, we will talk about how nanohybrids work and what they are capable of, including things like self-assembling nanohybrids and those made from organic and inorganic components. On the following page, you will find examples of nanohybrids in use for ultrasound as well as medicine and imaging-guided therapy. The promise of sustainably grown nanohybrids, with their limitations and recommended research opportunities, are discussed in the last section.
... Ternary group I-III-VI QDs, such as AgInS 2 QDs, are deemed better candidates as they contain no highly toxic elements. The AgInS 2 /ZnS QDs showed significantly improved biocompatibility (less cytotoxic, 95% cell viability) in both brain tumor cells and stem cells at high concentrations in comparison with that of the CdSe/ZnS QDs, which were found to be cytotoxic at even low concentrations [22]. Thus, we used heavy metal-free AgInS 2 /ZnS QDs in this study. ...
... The concentration-dependent cytotoxicity of the water-soluble hfQDs was assessed in cancer cells for a cell proliferation assay (Fig. 2(c)). Cell viability using the QDs is higher than using CdSe/ZnS QDs in human brain tumor cells (U87 glioblastoma cell line) and human bone-marrow-derived mesenchymal stem cells (hMSCs) [22]. Human colon cancer cells (HCT116) were chosen as an MMP-expressed group and human breast cancer cells (MCF7) for the negative control. ...
Early detection of structural or molecular changes in dysplastic epithelial tissues is crucial for cancer screening and surveillance. Multi-targeting molecular endoscopic fluorescence imaging may improve noninvasive detection of precancerous lesions in the colon. Here, we report the first clinically compatible, wide-field-of-view, multi-color fluorescence endoscopy with a leached fiber bundle scope using a porcine model. A porcine colon model that resembles the human colon is used for the detection of surrogate tumors composed of multiple biocompatible fluorophores (FITC, ICG, and heavy metal-free quantum dots (hfQDs)). With an ex vivo porcine colon tumor model, molecular imaging with hfQDs conjugated with MMP14 antibody was achieved by spraying molecular probes on a mucosa layer that contains xenograft tumors. With an in vivo porcine colon embedded with surrogate tumors, target-to-background ratios of 3.36 ± 0.43, 2.70 ± 0.72, and 2.10 ± 0.13 were achieved for FITC, ICG, and hfQD probes, respectively. This promising endoscopic technology with molecular contrast shows the capacity to reveal hidden tumors and guide treatment strategy decisions.
... Compared with traditional CdSe/ZnS QDs, ZNXS-Agyin1-YS2 (ZAIS) QDs synthesized by acoustic chemical synthesis method showed lower cytotoxicity and phototoxicity when transfected into hMSCs and human brain tumor cells by changing the concentration of organomaterial precursor elements and retaining strong fluorescence in the cytoplasm. When ZAIS was used as a gene carrier for siRNA, the mRNA knockdown efficiency was up to 80% [122]. ...
Mesenchymal stem cells (MSCs) are promising seed cells for neural regeneration therapy owing to their plasticity and accessibility. They possess several inherent characteristics advantageous for the transplantation-based treatment of neurological disorders, including neural differentiation, immunosuppression, neurotrophy, and safety. However, the therapeutic efficacy of MSCs alone remains unsatisfactory in most cases. To improve some of their abilities, many studies have employed genetic engineering to transfer key genes into MSCs. Both viral and nonviral methods can be used to overexpress therapeutic proteins that complement the inherent properties. However, to date, different modes of gene transfer have specific drawbacks and advantages. In addition, MSCs can be functionalized through targeted gene modification to facilitate neural repair by promoting neural differentiation, enhancing neurotrophic and neuroprotective functions, and increasing survival and homing abilities. The methods of gene transfer and selection of delivered genes still need to be optimized for improved therapeutic and targeting efficacies while minimizing the loss of MSC function. In this review, we focus on gene transport technologies for engineering MSCs and the application of strategies for selecting optimal delivery genes. Further, we describe the prospects and challenges of their application in animal models of different neurological lesions to broaden treatment alternatives for neurological diseases.
... 10−12 These QDs could eventually replace Cd-and Pb-based nanocrystals in some applications as light emitters, including sensitized solar cells and solar concentrators, 13−15 hydrogen production, 16 and cellular imaging studies. 17,18 The optical properties of ternary and quaternary QDs depend on size and chemical composition and differ in many aspects from those of binary II−VI, III−V, and IV−VI QDs. 19,20 While high-quality binary QDs exhibit relatively narrow and symmetrically shaped emission bands and lifetimes in the shorter nanosecond range, AIS, CIS, and ZAIS QDs show broad PL bands, large Stokes shifts, and PL lifetimes of a few hundred nanoseconds, which indicate the involvement of intragap levels in their PL. ...
... Embedding more than one enzyme in gelatin has also been explored as a suitable strategy for biosensor fabrication [18]. Nanotechnology amplification processes have enhanced the intensity of the imaging signal and can lead to ultrasensitive assays [19,20]. The combination of biopolymer and nanotechnology provides inherent miniaturization, high sensitivity and is cost-effective for sensor and imaging technology [21,22]. ...
The bio-nanohybrid gelatin protein/cadmium sulfide (Gel/CdS) quantum dots (QDs) have been designed via a facile one-pot strategy. The amino acids group of gelatin chelate Cd2+ and grow CdS QDs without any agglomeration. The 1H NMR spectra indicate that during the above process there are no alterations of the gelatin protein structure conformation and chemical functionalities. The prepared Gel/CdS QDs were characterized and their potential as a system for cellular imaging and the electrochemical sensor for hydrogen peroxide (H2O2) detection applications were investigated. The obtained results demonstrate that the developed Gel/CdS QDs system could offer a simple and convenient operating strategy both for the class of contrast agents for cell labeling and electrochemical sensors purposes.
... In vitro experiment also confirmed that pDNA could be released from the derived composite and it is a promising material for targeted gene delivery. In another study, Subramaniam et al. [68] carried out the removal of oncogene genes in brain tumour cell line (U87) using SiRNA. For effective delivery of the SiRNA, they are conjugated to AgInS 2 -ZnS (ZAIS) QDs using PEI. ...
Semiconductor nanomaterials, also known as quantum dots (QDs), have gained significant interest due to their outstanding optical properties with potential biological and biomedical applications. However, the presence of heavy toxic metals such as Cd, Pb, and Hg in conventional QDs have been a major challenge in their applications. Therefore, it is imperative to seek a viable alternative that will be non-toxic and have similar optical properties as the conventional QDs. Ternary I–III–VI QDs have been found to be suitable alternatives. Their optical properties are tunable and have emissions in the near-infrared region. These properties make them useful in a wide range of biological applications. Hence, this review focuses on the recent progress in the use of ternary QDs in Forster resonance energy transfer (FRET), nanomedical applications such as drug and gene delivery. It also discusses the biophotonic application of ternary I–III–VI QDs in optical imaging, biosensing, and multimodal imaging. Furthermore, we looked at the pharmacokinetics and biodistribution of these QDs, and their toxicity concerns. Finally, we looked at the current status, challenges, and future directions in the application of these ternary QDs.
... Over last few years a diversity of Cd-free QDs have been synthesized from materials including indium phosphide (InP) [4,6,7], copper indium sulfide (CuInS 2 ) [8][9][10][11][12][13][14][15], silver indium sulfide (AgInS 2 ) [16][17][18][19][20], ZAISe (Zn-Ag-In-Se) [21], doped Zn chalcogenides [22,23], graphene [24], silicon [25], indium arsenide (InAs) [26][27][28][29], zinc selenide (ZnSe) [30] and gallium arsenide (GaAs) [31]. ...
This work reports the design, manufacturing and numerical simulation approach of a 6-pixel (4.5mm2/pixel) electroluminescent quantum dot light emitting device (QLED) based on CuInS2/ZnS quantum dots as an active layer. Following a conventional thin-film deposition multilayer approach, the QLED device was fabricated. In addition, the electrical I-V curve was measured for each pixel independently, observing how the fabrication process and layer thickness have an influence in the shape of the plot. This experimental device fabricated, enabled us to create a computational model for the QLED based on the Transfer Hamiltonian approach to calculate the current density J(mA/cm2), the band diagram of the system, and the accumulated charge distribution. Besides, it is worth highlighting that the simulator allows the possibility to study the influence of different parameters of the QLED structure like the junction capacitance between the distinct multilayer set. Specifically, we found that Anode-HIL interface capacitance has a greater influence in the I-V plot shape. That junction capacitance plays an important role in the current increase and the QLED turn-on value when a forward voltage is applied to the device. Thanks to the simulator, that influence could be put under control by the selection of the optimal thickness and transport layers during the experimental fabrication process. This work is remarkable since it achieves to fit simulation and experiment results in an accurate way for electroluminescent QLED devices; particularly the simulation of the device current, which is critical when designing the automotive electronics to control these new nanotechnology lighting devices in the future.
... However, for effectiveness in bio-medical applications it is necessary for QDs to have a high QY, to be water dispersible and to be biocompatible. Several studies have shown that the use of hydrophilic ligands as sulphur sources such as dodecanethiol [27], l-Cysteine [63] and diethyldithiocarbonate [64] have produced water soluble ternary QDs with good QY suitable for biomedical applications. ...
Semiconductor nanoparticles also known as quantum dots (QDs) have continued to receive more attention from researchers due to their unique optical, magnetic and photo physical properties which made them useful as biomedical materials, solar cells, catalyst etc. However, ternary I–III–VI QDs have shown to be a safer alternative to the binary II–VI or IV–VI QDs due to the absent of heavy toxic elements such as Cd and Pb. Cancer management and therapy in Africa has been bedevilled by a lot of challenges such as inaccurate diagnosis and ineffective therapeutic methods. Therefore, the need to develop an appropriate approach for cancer detection and treatment is of paramount importance. Tunable optical properties and absorption in the near infra-red region of the ternary QDs makes them useful as fluorescent probes in cancer detection and treatment. They have the ability to detect specific cancer cells including those that are not easily detected by modern imaging technique. Also, properties such as non-bleaching, stability, water solubility etc. made them a desirable fluorophore when compared to conventional dyes. Most cancer drugs suffer from inherent shortcomings such as limited absorption, insolubility and aggregation. However, these shortcomings can be overcome when these drugs are applied in form of conjugated systems. The use of QDs as conjugates has revolutionise the treatment of cancer in the 21st century. This review provides information about the synthesis strategies, optical properties, hydrophilization and bioconjugation of ternary I–III–VI QDs. Furthermore, we described the various biomedical applications in biosensors, bioimaging, drug delivery and phototherapeutic techniques. Finally, we looked at the challenges and future perspective of these QDs in cancer management.
... They conducted an in vivo delivery experiment targeting human prostate cancer in mice and demonstrated enhanced permeability and retention [69]. While the toxicity of Cd contained in QDs is a concern, non-toxic QDs based on materials including Zn, Ag, and In are also under investigation [70]. ...
A variety of engineered nanoparticles, including lipid nanoparticles, polymer nanoparticles, gold nanoparticles, and biomimetic nanoparticles, have been studied as delivery vehicles for biomedical applications. When assessing the efficacy of a nanoparticle-based delivery system, in vitro testing with a model delivery system is crucial because it allows for real-time, in situ quantitative transport analysis, which is often difficult with in vivo animal models. The advent of tissue engineering has offered methods to create experimental models that can closely mimic the 3D microenvironment in the human body.
This review paper overviews the types of nanoparticle vehicles, their application areas, and the design strategies to improve delivery efficiency, followed by the uses of engineered microtissues and methods of analysis. In particular, this review highlights studies on multicellular spheroids and other 3D tissue engineering approaches for cancer drug development. The use of bio-engineered tissues can potentially provide low-cost, high-throughput, and quantitative experimental platforms for the development of nanoparticle-based delivery systems.
... 80% siRNA mediated knockdown of EGFP mRNA was observed in U87 cells genetically modified for GFP expression. Similar results could also be expected from stem cells, and these QDs could be explored as a viable option for simultaneous delivery and imaging probe in stem cells [89]. ...
Stem cell based regenerative medicine holds exceptional therapeutic potential and hence the development of efficient techniques to enhance control over the rate of differentiation has been the focus of active research. One of the strategies to achieve this involves delivering siRNA into stem cells and exploiting the RNA interference (RNAi) mechanism. Transport of siRNA across the cell membrane is a challenge due to its anionic property, especially in primary human cells and stem cells. Moreover, naked siRNA incites immune responses, may cause off-target effects, exhibits low stability and is easily degraded by endonucleases in the bloodstream. Although siRNA delivery using viral vectors and electroporation have been used in stem cells, these methods demonstrate low transfection efficiency, cytotoxicity, immunogenicity, events of integration and may involve laborious customization. With the advent of nanotechnology, nanocarriers which act as novel gene delivery vehicles designed to overcome the problems associated with safety and practicality are being developed. The various nanomaterials that are currently being explored and discussed in this review include liposomes, carbon nanotubes, quantum dots, protein and peptide nanocarriers, magnetic nanoparticles, polymeric nanoparticles, etc. These nanodelivery agents exhibit advantages such as low immunogenic response, biocompatibility, design flexibility allowing for surface modification and functionalization, and control over the surface topography for achieving the desired rate of siRNA delivery and improved gene knockdown efficiency. This review also includes discussion on siRNA co-delivery with imaging agents, plasmid DNA, drugs etc. to achieve combined diagnostic and enhanced therapeutic functionality, both for in vitro and in vivo applications.
... Nanoparticle (NP)-based delivery carriers are increasingly recognized as a promising approach to cross biological barriers, including nanoformulations of NPs with siRNA (termed siRNA nanomedicines) created by electrostatic interaction, entrapment, or conjugation [20]. To date, different types of NPs have been widely developed as carriers for siRNA delivery ( Figure 2): polymeric (such as micelles [21], nanogels [22], linear chains [23], dendrimers [24], and polymersomes [25], etc.), inorganic (such as gold NPs [26], quantum dots [27], and silica NPs [28], etc.), liposome- [29] and, very recently, exosome- [30] and DNA nanostructure-based carriers [31], as well as hybrids that integrate the advantages of different materials [32]. With the addition of delivery carriers and nanoformulation surface modification or engineering, naked siRNA can be endowed with the ability to cross existing barriers (Table 2), improving its potential for treating brain diseases. ...
Small interfering RNA (siRNA)-based gene silencing technology has demonstrated significant potential for treating brain-associated diseases. However, effective and safe systemic delivery of siRNA into the brain remains challenging because of biological barriers such as enzymatic degradation, short circulation lifetime, the blood-brain barrier (BBB), insufficient tissue penetration, cell endocytosis, and cytosolic transport. Nanotechnology offers intriguing potential for addressing these challenges in siRNA brain delivery in conjunction with chemical and biological modification strategies. In this review, we outline the challenges of systemic delivery of siRNA-based therapy for brain diseases, highlight recent advances in the development and engineering of siRNA nanomedicines for various brain diseases, and discuss our perspectives on this exciting research field for siRNA-based therapy towards more effective brain disease therapy.
... ZnS, silica) to prevent leaching of toxic elements [75], or using biocompatible elements to generate non-toxic QDs (e.g. CuInS 2 , ZnS-AgInS 2 ) [76]. ...
There is a growing interest in developing effective tools to better probe the central nervous system (CNS), to understand how it works and to treat neural diseases, injuries and cancer. The intrinsic complexity of the CNS has made this a challenging task for decades. Yet, with the extraordinary recent advances in nanotechnology and nanoscience, there is a general consensus on the immense value and potential of nanoscale tools for engineering neural systems. In this review, an overview of specialized nanomaterials which have proven to be the most effective tools in neuroscience is provided. After a brief background on the prominent challenges in the field, a variety of organic and inorganic-based nanomaterials are described, with particular emphasis on the distinctive properties that make them versatile and highly suitable in the context of the CNS. Building on this robust nano-inspired foundation, the rational design and application of nanomaterials can enable the generation of new methodologies to greatly advance the neuroscience frontier.
... Luminescent materials like quantum dots (QDs) and metal nanoclusters have attracted considerable attention in recent years for their unique optical properties that make them suitable for applications in cellular imaging [1], solar cells [2] and chemical sensors [3]. These unique optical properties are adjustable according to the nanoparticle size [4]. ...
A new 'turn-on' Förster resonance energy transfer (FRET) nanosensor for l-tryptophan based on molecularly imprinted quantum dots (QDs) is proposed. The approach combines the advantages of the molecular imprinting technique, the fluorescent characteristics of the QDs and the energy transfer process. Silica-coated CdTe QDs were first synthesized and then molecularly imprinted using a sol–gel process without surfactants. The final composite presents stable fluorescence which increases with the addition of l-tryptophan. This 'turn-on' response is due to a FRET mechanism from the l-tryptophan as donor to the imprinted QD as acceptor. QDs are rarely applied as acceptors in FRET systems. The nanosensor shows selectivity towards l-tryptophan in the presence of other amino acids and interfering ions. The l-tryptophan nanosensor exhibits a linear range between 0 and 8 µM concentration, a detection limit of 350 nM and high selectivity. The proposed sensor was successfully applied for the detection of l-tryptophan in saliva. This novel sensor may offer an alternative approach to the design of a new generation of imprinted nanomaterials for the recognition of different analytes.
... The emission wavelengths of ZAIS QDs redshifted with increasing x. Subramaniam et al. 171 demonstrated a facile room-temperature sonochemical approach for rapid synthesis of a series of Zn x S−Ag y In 1−y S 2 (ZAIS) QDs of varied composition. The QD PL was tuned from blue to red (480−700 nm) by changing the cation composition (x and y). ...
This review summarizes recent progress in the design and applications of cadmium-free quantum dots (Cd-free QDs), with an emphasis on their role in biophotonics and nanomedicine. We first present the features of Cd-free QDs and describe the physics and emergent optical properties of various types of Cd-free QDs whose applications are discussed in subsequent sections. Selected specific QD systems are introduced, followed by the preparation of these Cd-free QDs in a form useful for biological applications, including recent advances in achieving high photoluminescence quantum yield (PL QY) and tunability of emission color. Next, we summarize biophotonic applications of Cd-free QDs in optical imaging, photoacoustic imaging, sensing, optical tracking, and photothermal therapy. Research advances in the use of Cd-free QDs for nanomedicine applications are discussed, including drug/gene delivery, protein/peptide delivery, image-guided surgery, diagnostics, and medical devices. The review then considers the pharmacokinetics and biodistribution of Cd-free QDs and summarizes current studies on the in vitro and in vivo toxicity of Cd-free QDs. Finally, we provide perspectives on the overall current status, challenges, and future directions in this field.
... Breast carcinoma cells: BT474 [33,192] HeLa and HeLaS3 [34,44] Colon from human (supraclavicular lymph node metastasis): Lovo cell lines [44] Human liver cancer cells: Hep-G2 [44,193] Human breast cancer cells: MDA-MB-435-GFP ( ␣v3 integrin +) and MCF-7; [42,194] Adenocarcinomic human alveolar basal epithelial cells: A549-GFP ( ␣v3 integrin −) [194] Human osteosarcoma cells: Saos-2 cells [38] Mouse embryonic fibroblast cells: NIH3T3 [34] In vivo study on Flank xenograft tumor of C6 glioma cells in mice [43] Magnetic nanotubes (MNTs) answer to an external magnetic field imaging application encapsulation drugs modulated by inner surface functionalization [67] Carbon [195] HeLa-derived MAGI cells [195] Pancreatic cell line: MiaPaCa2-HRE cells with an HIF-1␣/luciferase reporter [199] HeLa(CCL-2.2);(); [49,[197][198][199] Human lung carcinoma cells: A549 (CCL-185) [196] [208] of nanoparticles have been explored. Here we report some examples of most commonly used nanovectors. ...
Conventional chemotherapeutics have been employed in cancer treatment for decades due to their efficacy in killing the malignant cells, but the other side of the coin showed off-target effects, onset of drug resistance and recurrences. To overcome these limitations, different approaches have been investigated and suicide gene therapy has emerged as a promising alternative. This approach consists in the introduction of genetic materials into cancerous cells or the surrounding tissue to cause cell death or retard the growth of the tumor mass. Despite promising results obtained both in vitro and in vivo, this innovative approach has been limited, for long time, to the treatment of localized tumors, due to the suboptimal efficiency in introducing suicide genes into cancer cells. Nanoparticles represent a valuable non-viral delivery system to protect drugs in the bloodstream, to improve biodistribution, and to limit side effects by achieving target selectivity through surface ligands. In this scenario, the real potential of suicide genes can be translated into clinically viable treatments for patients. In the present review, we summarize the recent advances of inorganic nanoparticles as non-viral vectors in terms of therapeutic efficacy, targeting capacity and safety issues. We describe the main suicide genes currently used in therapy, with particular emphasis on toxin-encoding genes of bacterial and plant origin. In addition, we discuss the relevance of molecular targeting and tumor-restricted expression to improve treatment specificity to cancer tissue. Finally, we analyze the main clinical applications, limitations and future perspectives of suicide gene therapy.
Rapid development of nanotechnology in less than two decades has led to the evolution of novel DNA and RNA delivery systems for gene therapy, which has become a significant technique for the advancement of genetic engineering. The treatment of genetic disorders has been promising, and recently, a wide variety of nanomaterials including carbon nanotubes, chitosan‐based nanoparticles, dendrimers, gold nanoparticles, inorganic nanoparticles, peptide‐based nanoparticles, protein and liposomes are being investigated as vectors for gene delivery. These vectors are used to target cells, and each type of vector has their own advantages and limitations. A major area of focus in this chapter will be the use of nanoparticles as nonviral carriers for gene delivery purposes considering their favorable characteristics, such as their nanometric size, high surface to volume ratio, stability, ability to undergo surface modifications, encapsulate nucleic acids and release them inside target cells, and lack of immunogenicity. We have summarized the advantages of immune response, design flexibility and effective biological system with low cytotoxicity along with few demerits discussed in a table format. Further, in this chapter, we have focused on the application of nanoparticles in gene therapy. Each type of nanoparticles has been elaborately discussed based on their structure, function, and successful implementation in different gene therapy purposes for the treatment of various diseases. We have also covered the treatments referring to some considerable studies and experiments done in vitro and in vivo . Toxic effects and potential hazards of nanoparticles, in addition to the ethical issues, have also been discussed with regard to gene therapy.
In2S3/AgInS2/TiO2 nanotube arrays (NTAs) were successfully prepared by a two-step anodization of titanium followed by a successive ionic layer absorption and reaction (SILAR) procedure. In2S3/AgInS2/TiO2 NTAs exhibited a high photocatalytic activity with the photoinduced open circuit potential drop up to 950 mV and current density drop of up to 30 µA·cm⁻² under visible light. Therefore, In2S3/AgInS2/TiO2 NTAs can provide higher photoelectrochemical cathodic protection under visible light compared with pristine TiO2 NTAs 304 stainless steel.
Inorganic nanoparticles (NPs) have a tunable shape, size, surface morphology, and unique physical properties like catalytic, magnetic, electronic, and optical capabilities. Unlike inorganic nanomaterials, organic polymers exhibit excellent stability, biocompatibility, and processability with a tailored response to external stimuli, including pH, heat, light, and degradation properties. Nano-sized assemblies derived from inorganic and polymeric NPs are combined in a functionalized composite form to import high strength and synergistically promising features not reflected in their part as a single constituent. These new properties of polymer/inorganic functionalized materials have led to emerging applications in a variety of fields, such as environmental remediation, drug delivery, and imaging. This review spotlights recent advances in the design and construction of polymer/inorganic functionalized materials with improved attributes compared to single inorganic and polymeric materials for environmental sustainability. Following an introduction, a comprehensive review of the design and potential applications of polymer/inorganic materials for removing organic pollutants and heavy metals from wastewater is presented. We have offered valuable suggestions for piloting, and scaling-up polymer functionalized nanomaterials using simple concepts. This review is wrapped up with a discussion of perspectives on future research in the field.
I–III–VI-based quantum dots have received tremendous attention over the past decade due to their excellent properties such as composition tunable fluorescence across the visible and near infrared region, low toxicity, high photostability, longer excited-state lifetime, etc. These salient features presented them as a potential candidate and safer alternative to the conventional cadmium based binary QDs for several biomedical and analytical applications. In this chapter, we have provided some fundamental concepts of imaging techniques and cancer therapy and summarized recent advances of the use of I–III–VI QDs as a fluorescent probe in these techniques. Furthermore, we also focused on the application of these fluorescent QDs in in vitro and in vivo cancer imaging as well as their utilization with other imaging contrast agents for multimodal imaging of tumor/organ. In addition, recent investigations on the phototherapeutic and drug delivery applications using these QDs for cancer treatment are also provided. The comprehensive collection of research works based on the application of these ternary QDs for bioimaging and therapy are provided in a tabular form.
Nanodimensional metal sulfides are a developing class of low-cost materials with potential applications in areas as wide-ranging as energy storage, electrocatalysis, and imaging. An attractive synthetic strategy, which allows careful control over stoichiometry, is the single source precursor (SSP) approach in which well-defined molecular species containing preformed metal-sulfur bonds are heated to decomposition, either in the vapor or solution phase, resulting in facile loss of organics and formation of nanodimensional metal sulfides. By careful control of the precursor, the decomposition environment and addition of surfactants, this approach affords a range of nanocrystalline materials from a library of precursors. Dithiocarbamates (DTCs) are monoanionic chelating ligands that have been known for over a century and find applications in agriculture, medicine, and materials science. They are easily prepared from nontoxic secondary and primary amines and form stable complexes with all elements. Since pioneering work in the late 1980s, the use of DTC complexes as SSPs to a wide range of binary, ternary, and multinary sulfides has been extensively documented. This review maps these developments, from the formation of thin films, often comprised of embedded nanocrystals, to quantum dots coated with organic ligands or shelled by other metal sulfides that show high photoluminescence quantum yields, and a range of other nanomaterials in which both the phase and morphology of the nanocrystals can be engineered, allowing fine-tuning of technologically important physical properties, thus opening up a myriad of potential applications.
A series of barriers including poor drug solubility, stability, biocompatibility, bioavailability and pharmacokinetics, distribution to normal tissues, hemorheological flow limitations, multidrug resistance (MDR), and metastasis compromise cancer therapeutic effects. Nanotechnologies provide potential solutions to address these problems by taking advantage of distinct mechanisms of action of multiple therapeutics/modalities. In this regard, hybrid nanomaterials hold great promise for tremendous potential applications. In cancer diagnosis and therapy, a combination of the unique physical and chemical properties of two or more classes of nanomaterials can be used to produce versatile new categories of nanomaterials for gene/drug delivery, immunotherapy, molecular diagnostic, and bio-imaging. Such nanoplatforms of hybrid materials expand the functionality of single-component systems by synergistically killing of target tumor tissues and cells. This review will elaborate on current advances in the design/development, biomedical applications, and therapeutic advantages of state-of-the-art organic-inorganic hybrid nanomaterials used in cancer theranostics. We believe that this class of hybrid nanotechnology might provide new prospects for clinical therapy and management of cancer.
The RNA interference (RNAi) technique is based on the molecular mechanisms of the interference of endogenous RNA. Small interfering RNA (siRNA) is considered as a novel nucleic acid tool for the treatment of a diverse category of diseases like genetic diseases, viral diseases, and cancers. Despite the diversity of siRNA in disease therapy, there are still a few challenges, including the design of a proper delivery system as well as systemic administration that limits the clinical translation of siRNA for cancer therapeutics. The development of delivery carriers for nucleic acid moieties like plasmid DNA and antisense oligonucleotides have cleared the path for in vivo delivery of siRNA. In the present chapter, we elaborate on the mechanism of RNAi and its applications in disease therapy with special emphasis on nanoparticle-mediated siRNA delivery in different cancer types. Further, we discuss challenges, barriers, and toxicity.
A semiconducting molecule containing a thiol anchor group, namely 2-(5-mercaptothien-2-yl)-8-(thien-2-yl)-5-hexylthieno[3,4-c]pyrrole-4,6-dione (abbreviated as D-A-D-SH), was designed, synthesized, and used as a ligand in nonstoichiometric quaternary nanocrystals of composition Ag1.0In3.1Zn1.0S4.0(S6.1) to give an inorganic/organic hybrid. Detailed NMR studies indicate that D-A-D-SH ligands are present in two coordination spheres in the organic part of the hybrid: (i) inner in which the ligand molecules form direct bonds with the nanocrystal surface and (ii) outer in which the ligand molecules do not form direct bonds with the inorganic core. Exchange of the initial ligands (stearic acid and 1-aminooctadecane) for D-A-D-SH induces a distinct change of the photoluminescence. Efficient red luminescence of nanocrystals capped with initial ligands (λmax = 720 nm, quantum yield = 67%) is totally quenched and green luminescence characteristic of the ligand appears (λmax = 508 nm, quantum yield = 10%). This change of the photoluminescence mechanism can be clarified by a combination of electrochemical and spectroscopic investigations. It can be demonstrated by cyclic voltammetry that new states appear in the hybrid as a consequence of D-A-D-SH binding to the nanocrystals surface. These states are located below the nanocrystal LUMO and above its HOMO, respectively. They are concurrent to deeper donor and acceptor states governing the red luminescence. As a result, energy transfer from the nanocrystal HOMO and LUMO levels to the ligand states takes place, leading to effective quenching of the red luminescence and appearance of the green one.
Surface modification of titanium implants by siRNA is quite efficient for improving implant osseointegration. Loading siRNA onto their surface is a crucial factor for siRNA-functionalized implants to realize their biological function. Direct binding of siRNA to implants has low siRNA binding and releasing rate, so usually it needs to be mediated by vectors. Polymeric, nonmaterial-mediated and lipid-based vectors are types of non-viral vectors which are commonly used for delivering siRNA. Three major methods of loading process, namely simple physical adsorption, layer-by-layer assembly and electrodeposition, are also summarized. A brief introduction, the basic principle and the general procedure of each method are included. The loading efficiency, which can be measured both qualitatively and quantitatively, together with gene knockdown efficiency, cytotoxicity assay and osteogenesis of the three methods are compared. A good many applications in osteogenesis have also been described in this review.
Ternary and quaternary chalcopyrite-type nanocrystals of MIMIIIE2 and MIMIIIZnE2 type (MI = Ag, Cu; MIII = In, Fe; E = S, Se) and their core/shell structures have attracted a huge interest in the past decade because they combine size- and composition-tunable optical and electronic properties without relying on toxic elements such as Cd and Pb. These materials had been primarily studied as light harvesters in solar cell applications. However, in form of colloidal nanocrystals, they exhibit remarkable photoluminescence properties in the visible and near infrared range. At the same time, the underlying emission mechanisms are distinctly different from those occurring in binary semiconductor quantum dots. Several models have been developed to explain the origin of the observed phenomena, in particular the line width broadening, large Stokes shift and long photoluminescence lifetimes. This review first focusses on the current understanding of the optical properties of the title compounds. Next, an overview of the main synthesis methods is given, both in organic solvents and in the aqueous phase. In the second part, the surface chemistry and ligand exchange procedures are discussed. Finally, organic/inorganic hybrids of chalcopyrite nanocrystals with electroactive molecules are presented as well as their use in photovoltaics.
Advancement in miniaturization in recent years has enabled high-throughput, in-parallel, rapid, and precise operations in modern medical and biological research. Although numerous biomimetic devices have been inspired by nature cues, the artificial gadgets still cannot be on a par with their natural counterparts. Caenorhabditis elegans (C. elegans), the smallest multi-cellular model animal, has become a popular platform for drug screening, biosensing, genetic engineering, neuroscience, developmental biology, and so forth since its first debut made by Sydney Brenner nearly five decades ago. The nematode C. elegans features small size, transparency body, fully sequenced genomes, high genetic similarity with humans, short life cycle, and simple neural network. The combination of C. elegans and microchip can prompt promising uses in some aspects. To cope with the new demands, the scientific community has endeavored great efforts to meet all sorts of worm maneuvers, such as sorting, immobilization, long-term imaging, confined culture, and biomechanics. The proposed manipulation repertoire then leads to realizations of a wide applications. Examples may include drug screening for pharmaceutics, point-of-care testing (POCT) for diseases, and fundamental research. Although worms-on-a-chip (WoC) appears to remain in its infancy stage of development, intensive research has gradually unveiled novel possibilities in many potential fields. This chapter aims to introduce the current development of WoCs and provides examples according to their categories. Pros and cons will be addressed in the end. Some practical uses will also be suggested for the future prospects.
This chapter describes the potential of multifunctional nanobiodevices in combination with quantum dots (QDs) to meet the requirements of diagnostic and theranostic systems. Nanobiodevices are primed to be powerful tools to provide the basis for the detection of small amounts of samples and simple operation. QDs can be utilized in these devices as bio-probes or labels for biological imaging of single molecules and cells. They have developed into new formats of biosensing to push the limits of detection. QDs has been also demonstrated to construct a multifunctional nanoplatform for stem cell transplantation and labeling with diagnostic and therapeutic modalities. The potential clinical applications of QDs have been expanded by the development of considerably low cytotoxicity QDs that do not include cadmium or selenium, as well as the development of longwave fluorescence QDs with strong permeability into the body. It provides the promising applications and further perspectives on future regenerative medicine.
Aims
In this review, we summarize the rational design and versatile applications of organic/inorganic hybrid gene carriers as multifunctional delivery systems.
Discussion
Organic/inorganic nanohybrids with both organic and inorganic components in one nanoparticle have attracted intensive attention due to their favorable properties. Particularly, nanohybrids comprising of cationic polymers and inorganic nanoparticles are considered promising candidates as multifunctional gene delivery systems. In this review, we begin with the introduction of gene delivery and gene carriers to show the motivation of fabrication of nanohybrids as multifunctional carriers. Then, the construction strategies and morphology effect of organic/inorganic hybrid gene carriers were summarized and discussed. Both sections provide valuable information for the design and synthesis of hybrid gene carriers with superior properties. Finally, the application of nanohybrids as multifunctional gene carriers is overviewed. Diverse therapies and versatile imaging‐guided therapies have been achieved through the rational design of nanohybrids. In addition to the simple combination of functions of organic and inorganic components, it is believed that performances arising from the synergistic effect of both components are more intriguing.
Conclusion
All these information might offer guidance for the understanding of organic/inorganic nanohybrids as multifunctional gene delivery systems.
The presented research is focused on the synthesis of alloyed Ag-In-Zn-S colloidal nanocrystals from a mixture of simple metal precursors such as AgNO3, InCl3, zinc stearate combined with 1-dodecanethiol (DDT), 1-octadecene (ODE), and sulfur dissolved in oleylamine (OLA). In particular, the focus is on the effect of the solvent (ODE vs 1,2-dichlorobenzene (DCB)) and the type of sulfur precursor (S/OLA vs S/n-octylamine (OCA)) on the metal precursors reactivates and on the chemical composition, crystal structure, and luminescent properties of the resulting nanocrystals. The replacement of ODE by DCB as a solvent lowers the reactivity of metal precursors and results in a 3-fold decrease of the photoluminescence quantum yields (Q.Y.) values (from 67% to 21%). This negative effect can be fully compensated by the use of S/OCA as a source of sulfur instead of S/OLA (Q.Y. increases from 21% to 64%). NMR studies of the isolated organic phase indicate that the S/OLA precursor generates two types of ligands being products of (Z)-1-amino-9-octadecene (OLA) hydrogenation. These are "surface bound" 1-aminooctadecane (C18H37NH2) and crystal bound, i.e., alkyl chain covalently bound to the nanocrystal surface via surfacial sulfur (C18H37-NH-S crystal). Highly luminescent Ag-In-Zn-S nanocrystals exhibit a cation-enriched (predominantly indium) surface and are stabilized by a 1-aminooctadecane ligand, which shows more flexibility than OLA. These investigations were completed by hydrophilization of nanocrystals obtained via exchange of the primary ligands for 11-mercaptoundecanoic acid, (MUA) with only a 2-fold decrease of photoluminescence Q.Y. in the most successful case (from 67% to 31%). Finally, through ligand exchange, an electroactive inorganic/organic hybrid was obtained, namely, Ag-In-Zn-S/7-octyloxyphenazine-2-thiol, in which its organic part fully retained its electrochemical activity.
Organic/inorganic nanohybrids have attracted widespread interests due to their favorable properties and promising applications in biomedical areas. Great efforts have been made to design and fabricate versatile nanohybrids. Among different organic components, diverse polymers offer unique avenues for multifunctional systems with collective properties. This review focuses on the design, properties, and biomedical applications of organic/inorganic nanohybrids fabricated from inorganic nanoparticles and polymers. We begin with a brief introduction to a variety of strategies for the fabrication of functional organic/inorganic nanohybrids. Then the properties and functions of nanohybrids are discussed, including properties from organic and inorganic parts, synergistic properties, morphology-dependent properties, and self-assembly of nanohybrids. After that, current situations of nanohybrids applied for imaging, therapy, and imaging-guided therapy are demonstrated. Finally, we discuss the prospect of organic/inorganic nanohybrids and highlight the challenges and opportunities for the future investigations.
There is a recent demand in development of luminescent materials for visualizations of latent fingerprints (LFPs) for achieving enhanced security. Also recently there has been a new research trend on developments of 2D materials from non-layered semiconductors with strong luminescence properties in the visible region. The conventional growth process of luminescent materials limits its capacity of tuning the structure and light emission efficiency. However, multi-atom doping provides an additional degree of freedom to tune the basic morphologies and optical properties of luminescent semiconductors by controlling the defect levels. Here, by a simple chemical technique multi-atom (Cu and Mn) doped rarely reported 2D nanosheets of zinc sulphide (ZnS) have been grown. Thus a stable high fluorescence efficiency of ~62% in the visible region has been realized for visualization of LFPs. Further near-white light emission has been demonstrated by coating the synthesized materials with a suitable doping concentration on a commercially available UV-LED chip. The proposed technique may be utilized further to build-up other 2D nanostructured materials for multifunctional applications in solid state lighting, LFPs and in forensic sciences.
Microscopy allows for the characterization of small objects invisible to the naked eye, a technique that, since its conception, has played a key role in the development across nearly every field of science and technology. Given the nanometer size of the materials explored in the field of nanotechnology, the contributions of modern microscopes that can visualize these materials are indispensable, and the ever-improving technology is paramount to the future success of the field. This chapter will focus on four fundamental areas of microscopy used in the field of nanotechnology including fluorescence microscopy (Sect. 3.1), particle tracking and photoactivated localization microscopy (Sect. 3.2), quantum dots and fluorescence resonance energy transfer (Sect. 3.3), and cellular MRI and PET labeling (Sect. 3.4). The functionality, as well as the current and recommended usage of each given imaging system, will be discussed.
Among the advantages of multicomponent nanocrystals is the possibility to adjust their electronic and optical properties with composition as well as size. However, the synthesis of multicomponent nanocrystals is challenging due to the presence of several metal precursors in the reaction mixture. This review takes I-III-VI semiconductor materials as an example class of multicomponent nanocrystals to highlight the underestimated importance of composition, which can affect the electronic and optical properties of nanocrystals as much as size. We discuss synthetic strategies, which enable the composition control, and show that the ability to separately choose nanocrystal size and nanocrystal composition can be beneficial for many optoelectronic and bio-medical applications.
Cancer treatment still faces a lot of obstacles such as tumor heterogeneity, drug resistance and systemic toxicities. Beyond the traditional treatment modalities, exploitation of RNA interference (RNAi) as an emerging approach has immense potential for the treatment of various gene-caused diseases including cancer. The last decade has witnessed enormous research and achievements focused on RNAi biotechnology. However, delivery of small interference RNA (siRNA) remains a key challenge in the development of clinical RNAi therapeutics. Indeed, functional nanomaterials play an important role in siRNA delivery, which could overcome a wide range of sequential physiological and biological obstacles. Nanomaterial-formulated siRNA systems have potential applications in protection of siRNA from degradation, improving the accumulation in the target tissues, enhancing the siRNA therapy and reducing the side effects. In this review, we explore and summarize the role of functional inorganic–organic hybrid systems involved in the siRNA therapeutic advancements. Additionally, we gather the surface engineering strategies of hybrid systems to optimize for siRNA delivery. Major progress in the field of inorganic–organic hybrid platforms including metallic/non-metallic cores modified with organic shells or further fabrication as the vectors for siRNA delivery is discussed to give credit to the interdisciplinary cooperation between chemistry, pharmacy, biology and medicine.
One way to limit the negative effects of anti-tumor drugs on healthy cells is targeted therapy employing functionalized drug carriers. Here we present a biocompatible and stable nanoconjugate of transferrin anchored to Ag-In-Zn-S quantum dots modified with 11-mercaptoundecanoic acid (Tf-QD) as a drug carrier versus typical anticancer drug, doxorubicin. Detailed investigations of Tf-QD nanoconjugates without and with doxorubicin by fluorescence studies and cytotoxic measurements showed that the biological activity both the transferrin and doxorubicin was fully retained in the nanoconjugate. In particular, the intercalation capabilities of free doxorubicin versus ctDNA remained essentially intact upon its binding to the nanoconjugate. In order to evaluate these capabilities, we studied the binding constant of doxorubicin attached to Tf-QD with ctDNA as well as the binding site size on the ctDNA molecule. The binding constant slightly decreased compared to that of free doxorubicin while the binding site size, describing the number of consecutive DNA lattice residues involved in the binding, increased. It was also demonstrated that QD alone and in the form of nanoconjugate with Tf were not cytotoxic towards human non-small cell lung carcinoma (H460 cell line) and the tumor cell sensitivity of the DOX-Tf-QD nanoconjugate was comparable to that of doxorubicin alone.
Currently, the method of choice to test for the presence of chromium in water is to submit samples to a lab for testing. In this work, we present a simple field ready test that is selective for the presence of chromium at concentrations of 100 ppb or greater. The EPA maximum contaminant limit (MCL) for total chromium is 100 ppb. This test uses a simple on/off fluorescent screening employing the use of silver indium sulfide (AgInS2) quantum dots. These quantum dots were impregnated into cotton pads to simplify field testing without the need for solvents or other liquid chemicals to be present. The change in fluorescence is instant and can be readily observed by eye with the use of a UV flashlight.
Nano-sized quantum dots (QDs) exhibit uniquely optical properties that are tunable with different sizes and shapes. QDs can emit narrow symmetric bands under a wide excitation range, possess anti-photobleaching stability, and be bio-functionalized on the large surface area. Therefore, QDs are attractive vectors for imaging-guided therapy. Small-interfering RNA (siRNAs)-based therapeutics hold great potential to target a large part of the currently undruggable genes, but overcoming the lipid bilayer to deliver siRNA into cells has remained a major challenge to solve for widespread development of siRNA therapeutics. In this mini-review, we focus on theranostic QD/siRNA assembles for enhancing delivery of siRNA and facilitating evaluation of therapeutic efficacy via imaging of QDs, with special attention to carbonaceous QDs for delivery of siRNA.
This report presents the fabrication of bifunctional magnetic and fluorescent microneedles (µNDs) made of a ternary mixture of magnetic nanoparticles (NPs), quantum dots (QDs), and polyelectrolyte. The assembly relies on the electrostatic complexation of negatively charged NPs with positively charged polymer strands and is controlled by the charge ratio between the nanoparticle building blocks and the polymer mortar. The resulting 1D objects can be actuated using an external magnetic field and can be imaged using fluorescence microscopy, thanks to the fluorescent and superparamagnetic properties inherited from their NP constituents. Using a combination of core and surface characterizations and a state-of-the-art image analysis algorithm, the dependence of the brightness and length on the ternary composition is thoroughly investigated. In particular, statistics on hundreds of µNDs with a range of compositions show that the µNDs have a log-lormal length distribution and that their mean length can be robustly tuned in the 5–50 µm range to match the relevant length scales of various applications in micromixing, bioassays or biomechanics.
Surface modified and bioconjugated quantum dots (QDs) compromise interminable outlook to advance biomedical applications. In this regard, particularly I-III-VI QDs, are of a specific interest for biosensor, multimodal imaging, chemotherapy and for phototherapy as a whole theranostics application. Such surface modification used us to manage the physico-chemical properties, biocompatibility, and pharmacological properties. This review is anticipated to provide an introduction to novices about I-III-VI type QDs concerning to synthesis, optical properties, surface modification, bioconjugation, and accordingly formulate them for applications in biosensors, biological imaging, drug delivery, photothermal therapy and photodynamic therapy. We also highlight introducing magnetic metals and nanoparticles to these QDs for multimodal imaging applications and addressed to eliminate toxicity related issues. Finally, we summarize and give a short outlook on future directions of I-III-VI based QDs biomedical applications.
Stem cell therapy plays a large role in regenerative medicine for many diseases such as lung and liver diseases, as the regeneration of these organs is very difficult.1-3 Indeed, stem cell therapy using somatic stem cells, progenitor cells, and mature cells differentiated from stem cells has been applied in clinical practice.4,5 Therefore, the detection and diagnosis of the behavior, accumulation and engraftment of transplanted stem cells in vivo are essential for ensuring the safety and maximum therapeutic effect of stem cell transplantation. However, in vivo imaging modalities for detecting transplanted stem cells are not sufficient at present.6-8 A number of modalities, such as ultrasonic diagnostics, roentgen diagnosis, X-ray computed tomography (CT),9 magnetic resonance imaging (MRI),10 positron emission computerized-tomography (PET),11 and single-photon emission computed tomography (SPECT),12 have been implemented in clinical practice. However, these modalities are meant to be used to diagnose tissues and organs, so the highly sensitive detection of transplanted stem cells using such techniques is very difficult. Fluorescence imaging is expected to contribute to the development of stem cell transplantation, as fluorescence imaging can detect transplanted stem cells at the cellular level.13-15 However, the detection and diagnosis of transplanted stem cells in vivo using conventional fluorescent probes such as fluorescent proteins and organic fluorescent probes is almost impossible due to the inhibition caused by the autofluorescence and scattering/absorbance derived from the body. 16,17 Recently, quantum dots (QDs) with entirely different fluorescent properties from conventional fluorescent probes have received focus as a potential solution to these problems. QDs achieved super-high resolution, super-high sensitivity, super-long duration, energy savings, and low costs and were first applied to 4K/8K displays in 2013.18 Our groups have explored stem cell labeling using QDs and in vivo fluorescence imaging of transplanted stem cells, demonstrating in vivo imaging diagnostic techniques for transplanted stem cells by measuring the fluorescence of QDs. In this review, we report the QD types available for stem cells, the methods of stem cell labeling using QDs, in vivo fluorescence imaging systems, and in vivo fluorescence imaging data of transplanted stem cells labeled with QDs, focusing largely on findings from recent papers. The future prospects for the application of QDs to regenerative medicine, including stem cell therapy, will also be discussed.
Nanomedicine as a discipline is unique in that its application requires a wide spectrum of skills and knowledge. As molecular nanotechnology and molecular biology evolved into the nanomedicine of today, so it is important to accept that the terms nano and molecular both deal with manipulations at the same scale. The roots of nanomedicine could arguably be traced to the advances in combinatorial chemistry and polymer therapeutics that paved the way for the rational design of small molecules and the emergence of techniques to improve therapeutic index. Nanostructured materials also have potential therapeutic applications by themselves. Lipid-based liquid crystalline nanoparticles, for example, are emerging as a novel, nontoxic, and highly effective drug delivery platform, particularly for lipo-philic drugs. The first nanoscale delivery systems, liposomes, were described in the 1960s but have subsequently undergone a number of key developments that paved the way for the evolution of modern nanoparticle formulations.
Nanoscale materials have been explored extensively as agents for therapeutic and diagnostic (i.e., theranostic) applications. Research efforts have shifted from exploring new materials in vitro to designing materials that function in more relevant animal disease models, thereby increasing potential for clinical translation. Current interests include non-invasive imaging of diseases, biomarkers, and targeted delivery of therapeutic drugs. Here, some general design considerations of advanced theranostic materials and challenges of their use, from both diagnostic and therapeutic perspectives, are discussed. Common classes of nanoscale biomaterials, including magnetic nanoparticles, quantum dots, upconversion nanoparticles, mesoporous silica nanoparticles, carbon-based nanoparticles, and organic dye-based nanoparticles, have demonstrated potential for both diagnosis and therapy. Variations such as size control and surface modifications can modulate biocompatibility and interactions with target tissues. The need for improved disease detection and enhanced chemotherapeutic treatments, together with realistic considerations for clinically translatable nanomaterials, will be key driving factors for theranostic agent research in the near future.
Magnetic/fluorescent barcodes, which combine quantum dots (QDs) and superparamagnetic nanoparticles in micrometer-sized host microspheres, are promising for automatic high-throughput multiplexed biodetection applications and “point of care” biodetection. However, the fluorescence intensity of QDs sharply decreases after addition of magnetic nanoparticles (MNPs) due to absorption by MNPs, and thus, the encoding capacity of QDs becomes more limited. Furthermore, the intrinsic toxicity of cadmium-based QDs, the most commonly used QD in barcodes, has significant risks to human health and the environment. In this work, to alleviate fluorescence quenching and intrinsic toxicity, cadmium-free NIR-emitting CuInS2/ZnS QDs and Fe3O4 MNPs are successfully incorporated into poly(styrene-co-maleic anhydride) microspheres by using the Shirasu porous glass membrane emulsification technique. A “single-wavelength” encoding model is successfully constructed to guide the encoding of NIR QDs with wide emission spectra. Then, a “single-wavelength” encoding combined with size encoding is used to produce different optical codes by simply changing the wavelength and the intensity of the QDs as well as the size of the barcode microspheres. 48 barcodes are easily created due to the greatly reduced energy transfer between the NIR-emitting QDs and MNPs. The resulting bifunctional barcodes are also combined with a flow cytometer using one laser for multiplexed detection of five tumor markers in one test. Assays based on these barcodes are significantly more sensitive than non-magnetic and traditional ELISA assays. Moreover, validating experiments also show good performance of the bifunctional barcodes-based suspension array when dealing with patient serum samples. Thus, magnetic/fluorescent barcodes based on NIR-emitting CuInS2/ZnS QDs are promising for multiplexed bioassay applications.
We demonstrated a convenient, flexible and modular synthetic approach for preparation of a small library of DNA-encapsulated supramolecular nanoparticles SNPs superset DNA and RGD-SNPs superset DNA with different sizes and RGD target ligand coverage for targeted gene delivery.
Although stem cells hold great potential for the treatment of many injuries and degenerative diseases, several obstacles must be overcome before their therapeutic application can be realized. These include the development of advanced techniques to understand and control functions of microenvironmental signals and novel methods to track and guide transplanted stem cells. The application of nanotechnology to stem cell biology would be able to address those challenges. This review details the current challenges in regenerative medicine, the current applications of nanoparticles in stem cell biology and further potential of nanotechnology approaches towards regenerative medicine, focusing mainly on magnetic nanoparticle- and quantum dot-based applications in stem cell research.
Semiconductor quantum dots (QDs) are among the most promising emerging fluorescent labels for cellular imaging. However, it is unclear whether QDs, which are nanoparticles rather than small molecules, can specifically and effectively label molecular targets at a subcellular level. Here we have used QDs linked to immunoglobulin G (IgG) and streptavidin to label the breast cancer marker Her2 on the surface of fixed and live cancer cells, to stain actin and microtubule fibers in the cytoplasm, and to detect nuclear antigens inside the nucleus. All labeling signals are specific for the intended targets and are brighter and considerably more photostable than comparable organic dyes. Using QDs with different emission spectra conjugated to IgG and streptavidin, we simultaneously detected two cellular targets with one excitation wavelength. The results indicate that QD-based probes can be very effective in cellular imaging and offer substantial advantages over organic dyes in multiplex target detection.
The recent development of functional crystalline nanomaterials for therapeutics is described. In contrast to conventional therapeutic approaches, nanomaterial-based systems present novel therapeutic opportunities; for example, by allowing active agents to be site-specifically delivered and efficiently absorbed while offering fewer or reduced side effects. In addition, nanomaterials are generally amenable to surface functionalization and interior doping. These attributes provide the nanomaterials with tunable surface, optical, magnetic, thermal and mechanical properties that are important for applications ranging from controlled release of drugs to photothermal therapy. In this article, we seek to provide a conceptual framework for understanding nanomaterial-based therapeutics. We also attempt to highlight recent therapeutic applications involving some representative nanostructured materials. With improved control over the synthesis and functional characteristics of nanomaterials, the emergence of nanomaterial-based therapeutics will likely accelerate future medical research and improve patient care.
With their bright, photostable fluorescence, semiconductor quantum dots (QDs) show promise as alternatives to organic dyes for biological labeling. Questions about their potential cytotoxicity, however, remain unanswered. While cytotoxicity of bulk cadmium selenide (CdSe) is well documented, a number of groups have suggested that CdSe QDs are cytocompatible, at least with some immortalized cell lines. Using primary hepatocytes as a liver model, we found that CdSe-core QDs were indeed acutely toxic under certain conditions. Specifically, we found that the cytotoxicity of QDs was modulated by processing parameters during synthesis, exposure to ultraviolet light, and surface coatings. Our data further suggest that cytotoxicity correlates with the liberation of free Cd2+ ions due to deterioration of the CdSe lattice. When appropriately coated, CdSe-core QDs can be rendered nontoxic and used to track cell migration and reorganization in vitro. Our results provide information for design criteria for the use of QDs in vitro and especially in vivo, where deterioration over time may occur.
We report on the photoluminescence (PL) mechanisms and the nature of the related electronic states of AgInS2 quantum dots (QDs) synthesized via a metathesis reaction of metal complexes. A broad PL band with a large Stokes shift is apparent in the PL spectra of AgInS2 QDs whose average diameter is 2.6 nm. The characteristic decay behavior of the PL spectra and the peak shift of the PL band depending on the excitation intensity indicate that the PL is attributed to the donor−acceptor (DA) pair recombination. The binding energies of the donor and acceptor are estimated to be 100 and 220 meV. These values are derived from the temperature dependence of the PL intensity and an analysis of the spectral profile of the PL spectrum considering the DA pair recombination processes. Furthermore, we show that the phonon sidebands constitute the dominant contribution to the PL spectra because of the strong electron−phonon interaction of carriers trapped by these donors or acceptors.
A facile method for the synthesis of size- and shape-controlled CuInS2 semiconductor nanocrystals was developed by thermolysis of a mixed solution of CuAc, In(Ac)3 (molar ratio of CuAc to In(Ac)3 = 1:1) and dodecanethiol in noncoordinating solvent 1-octadecene (ODE) at 240 °C. CuInS2 nanoparticles with size of 2 to 5 nm and nanorods with aspect ratio of 1 to 3 were obtained by adjusting the reaction parameters such as temperature and time. The as-prepared nanoparticles were characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy, selected area electron diffraction spectroscopy, inductively coupled plasma atomic emission spectroscopy, UV−vis absorption, and photoluminescence (PL) spectroscopy. The nanoparticle solutions exhibit tunable absorption and PL spectra with the absorption edge ranging from 550 to 750 nm and PL emission peaks from 600 to 750 nm, indicating a strong size-dependent quantum confinement effect. Optical measurements of the CuInS2 nanoparticles demonstrated that their optical properties are related to donor−acceptor defects, size-dependent quantum confined effects, and surface defects. The PL decay curve of CuInS2 nanoparticles has a triple exponential characteristic with lifetimes of 4−12, 28−60, and 140−300 ns, respectively, and the PL emission with the longest lifetime (140−300 ns) occupied 40−80% of the PL emission of the samples. These results imply that the room-temperature PL emission of CuInS2 nanoparticles involves three types of recombination: band exciton recombination, surface-related recombination, and donor−acceptor defects recombination. Among them, the PL emission from donor−acceptor defects occupied a large amount.
Near-infrared (NIR) semiconductor quantum dots (QDs) represent promising fluorescent probes for biological and biomedical imaging. CuInSe2 is a good candidate for these applications due to its bandgap in the near-infrared and the reduced toxicity of its components compared to other NIR QD materials (CdTe, CdHgTe, PbS, etc.). Here we present a simple one-pot synthetic route without injection to make fluorescent sphalerite Cu−In−Se core and Cu−In−Se/ZnS core/shell QDs. We show that the photoluminescence (PL) of the resulting core QDs can be tuned from 700 nm to 1 μm depending on the QD size (from 2 to 5 nm in diameter). The optical and structural properties of these QDs are consistent with charge recombination via donor−acceptor levels instead of direct excitonic recombination. Finally, we show that the growth of a ZnS shell around these QDs increases their PL quantum yield substantially (up to 40−50% at 800 nm) and allows preservation of their PL properties after solubilization into water and in vivo, as demonstrated by detection of the regional lymph node in a mouse.
The properties of CuInS2 semi-conductor nanoparticles make them attractive materials for use in next-generation photovoltaics. We have prepared CuInS2 nanoparticles from single source precursors via microwave irradiation. Microwave irradiation methods have allowed us to increase
the efficiency of preparation of these materials by providing uniform heating and rapid reaction times. The synergistic effect
of varying thiol capping ligand concentrations as well as reaction temperatures and times resulted in fine control of nanoparticle
growth in the 3–5nm size range. Investigation of the photophysical properties of the colloidal nanoparticles were performed
using electronic absorption and luminescence emission spectroscopy. Qualitative nanoparticles sizes were determined from the
photoluminescence (PLE) data and compared to HRTEM images.
Multiple dysregulated pathways in tumors necessitate targeting multiple oncogenic elements by combining orthogonal therapeutic moieties like short-interfering RNAs (siRNA) and drug molecules in order to achieve a synergistic therapeutic effect. In this manuscript, we describe the synthesis of cyclodextrin-modified dendritic polyamines (DexAMs) and their application as a multicomponent delivery vehicle for translocating siRNA and anticancer drugs. The presence of β-cyclodextrins in our DexAMs facilitated complexation and intracellular uptake of hydrophobic anticancer drugs, suberoylanilide hydroxamic acid (SAHA) and erlotinib, whereas the cationic polyamine backbone allowed for electrostatic interaction with the negatively charged siRNA. The DexAM complexes were found to have minimal cytotoxicity over a wide range of concentrations and were found to efficiently deliver siRNA, thereby silencing the expression of targeted genes. As a proof of concept, we demonstrated that upon appropriate modification with targeting ligands, we were able to simultaneously deliver multiple payloads--siRNA against oncogenic receptor, EGFRvIII and anticancer drugs (SAHA or erlotinib)--efficiently and selectively to glioblastoma cells. Codelivery of siRNA-EGFRvIII and SAHA/erlotinib in glioblastoma cells was found to significantly inhibit cell proliferation and induce apoptosis, as compared to the individual treatments.
Carbon-protected iron cobalt nanoparticles (FeCo/C NPs) are synthesized using a hydrothermal approach. It is demonstrated that FeCo/C NPs can be used as highly sensitive magnetic resonance and Raman imaging probes. These FeCo/C NPs are then used for targeting tumor cells for combined siRNA and hyperthermia-based therapy, resulting in the significant inhibition of proliferation and induction of apoptosis in tumor cells.
CuInS(2)-ZnS alloyed nanocubes with high luminescence were synthesized through a solution-based diffusion method.
This work demonstrates the use of confocal Raman microscopy (CRM) to measure the dynamics of cellular uptake and localization of gold nanoparticles (GNP) with nanoscale resolution. This is important as nanoparticle cellular interactions are increasingly under investigation to support applications as diverse as drug delivery, gene transfection and a variety of heat and radiation based therapeutics. At the heart of these applications is a need to know the dynamics of nanoparticle cellular uptake and localization (i.e., cell membrane, cytoplasm or nucleus). This process can change dramatically based on size, charge, shape and ligand attached to the nanoparticle. While electron microscopy, atomic emission spectroscopy and histology can be used to assess cellular uptake, they are labor intensive and post-mortem and can miss critical dynamics of the process. For this reason investigators are increasingly turning to optically active nanoparticles that allow direct microscopic interrogation of uptake. Here we show that CRM adds to this evolving armamentarium as a fast, noninvasive, and label-free technique to dynamically study cellular uptake of GNPs with subcellular detail in cancer. Raman laser interaction with GNPs inside cells shows unique spectroscopic features corresponding to the intracellular localization of GNPs over 2 to 24 h at the membrane, cytoplasm or nucleus that are separately verified by histology (silver staining) and electron microscopy. These results show that CRM has the potential to facilitate high-throughput study of the dynamics and localization of a variety of GNPs in multiple cell types.
Quantum dots (QDs) conjugated with thiol-modified small interfering RNA (siRNA) were functionalized with thiol-modified RGD and HIV-Tat peptides. These multifunctional QDs were used for the targeted delivery and tracking of siRNA molecules for the knockdown of the EGFRvIII gene, which led to the down-regulation of the PI3K-Akt signaling pathway and the apoptosis of malignant brain cancer cells.
In this report we summarize the progress made in the past several years on the use of luminescent QDs to probe biological processes at the single molecule level. We start by providing a quick overview of the basic properties of semiconductor nanocrystals, including synthetic routes, surface-functionalization strategies, along with the main attributes of QDs that are of direct relevance to single molecule studies based on fluorescence detection. We then detail some valuable insights into specific biological processes gained using single QDs. These include progress made in probing biomolecular interactions, tracking of protein receptors both in vitro and in live cells, and single particle resonance energy transfer. We will also discuss the advantages offered and limitations encountered by single QD fluorescence as an investigative tool in biology.
Although uptake into cells is highly complex and regulated, heterogeneous particle collectives are usually employed to deliver small interfering RNA (siRNA) to cells. Within these collectives, it is difficult to accurately identify the active species, and a decrease in efficacy is inherent to such preparations. Here, we demonstrate the manufacture of uniform nanoparticles with the deposition of siRNA on gold in a layer-by-layer approach, and we further report on the cellular delivery and siRNA activity as functions of surface properties.
A method for the synthesis of nearly monodisperse CuInS(2) semiconductor nanocrystals (from <2 to 20 nm) was developed using generic and air-stable chemicals in a non-coordinating solvent. Such "greener" approaches also allowed the reaction temperatures to be below 200 degrees C. By introducing reactivity-controlling ligands for Cu, namely thiols, control of the Cu:In stoichiometric ratio in the nanocrystals was achieved. Amines were identified as catalytic reagents for the rapid oxidation of the CuInS(2) nanocrystals, which could be prevented by the formation of CuInS(2)/ZnS core/shell nanocrystals by a one-pot approach. CuInS(2)/ZnS core/shell nanocrystals also showed greatly improved optical properties, with photoluminescence quantum yield up to about 30% and an emission peak position tunable from 500 to 950 nm. The versatility of the synthetic strategy was demonstrated by extending it to the synthesis of AgInS(2) nanocrystals by simply replacing the copper salt by a silver salt.
In this report, we evaluated the cytotoxicity of a series of quantum dots (QDs) directly synthesized in aqueous phase, i.e., thiols-stabilized CdTe, CdTe/CdS core-shell structured and CdTe/CdS/ZnS core-shell-shell structured QDs, with a variety of cell lines including K562 and HEK293T. We have demonstrated that the CdTe QDs are highly toxic for cells due to the release of cadmium ions. Epitaxial growth of a CdS layer reduces the cytotoxicity of QDs to a small extent. However, the presence of a ZnS outlayer greatly improves the biocompatibility of QDs, with no observed cytotoxicity even at very high concentration and long-time exposure in cells. Our systematic investigation clearly shows that the cytotoxicity of QDs can be modulated through elaborate surface coatings and that the CdTe/CdS/ZnS core-shell-shell structured QDs directly synthesized in aqueous phase are highly promising biological fluorescent probes for cellular imaging.
The use of semiconductor quantum dots (QDs) in biological sensing and labeling continues to grow with each year. Current and projected applications include use as fluorescent labels for cellular labeling, intracellular sensors, deep-tissue and tumor imaging agents, sensitizers for photodynamic therapy, and more recently interest has been sparked in using them as vectors for studying nanoparticle-mediated drug delivery. Many of these applications will ultimately require the QDs to undergo targeted intracellular delivery, not only to specific cells, but also to a variety of subcellular compartments and organelles. It is apparent that this issue will be critical in determining the efficacy of using QDs, and indeed a variety of other nanoparticles, for these types of applications. In this review, we provide an overview of the current methods for delivering QDs into cells. Methods that are covered include facilitated techniques such as those that utilize specific peptide sequences or polymer delivery reagents and active methods such as electroporation and microinjection. We critically examine the benefits and liabilities of each strategy and illustrate them with selected examples from the literature. Several important related issues such as QD size and surface coating, methods for QD biofunctionalization, cellular physiology and toxicity are also discussed. Finally, we conclude by providing a perspective of how this field can be expected to develop in the future.
Advances in imaging are enabling researchers to track more accurately the localization of macromolecules in cells.
Quantum dots (QDs), tiny light-emitting particles on the nanometer scale, are emerging as a new class of fluorescent probe for in vivo biomolecular and cellular imaging. In comparison with organic dyes and fluorescent proteins, QDs have unique optical and electronic properties: size-tunable light emission, improved signal brightness, resistance against photobleaching, and simultaneous excitation of multiple fluorescence colors. Recent advances have led to the development of multifunctional nanoparticle probes that are very bright and stable under complex in vivo conditions. A new structural design involves encapsulating luminescent QDs with amphiphilic block copolymers and linking the polymer coating to tumor-targeting ligands and drug delivery functionalities. Polymer-encapsulated QDs are essentially nontoxic to cells and animals, but their long-term in vivo toxicity and degradation need more careful study. Bioconjugated QDs have raised new possibilities for ultrasensitive and multiplexed imaging of molecular targets in living cells, animal models and possibly in humans.
The synthesis and characterization of ultrafine CuInS2 nanoparticles are described. Ultraviolet irradiation was used to decompose a molecular single source precursor, yielding organic soluble approximately 2 nm sized nanoparticles with a narrow size distribution. UV-vis absorption, 1H and 31P{1H} NMR, and fluorescence spectroscopies and mass spectrometry were used to characterize decomposition of the precursors and nanoparticle formation. The nanoparticles were characterized by high-resolution transmission electron microscopy (HRTEM), scanning electron microscopy energy dispersive X-ray spectroscopy, powder X-ray diffraction (XRD), electron diffraction, inductively coupled plasma analysis, UV-vis absorption spectroscopy, and fluorescence spectroscopy. They have a wurzite-type crystal structure with a copper-rich composition. The hypsochromic shift in their emission band due to quantum confinement effects is consistent with the size of the nanocrystals indicated in the HRTEM and XRD analyses.
Treatment of human diseases such as cancer generally involves the sequential use of diagnostic tools and therapeutic modalities. Multifunctional platforms combining therapeutic and diagnostic imaging functions in a single vehicle promise to change this paradigm. in particular, nanoparticle-based multifunctional platforms offer the potential to improve the pharmacokinetics of drug formulations, while providing attachment sites for diagnostic imaging and disease targeting features. We have applied these principles to the delivery of small interfering RNA (siRNA) therapeutics, where systemic delivery is hampered by rapid excretion and nontargeted tissue distribution. Using a PEGlyated quantum dot (QD) core as a scaffold, siRNA and tumor-homing peptides (F3) were conjugated to functional groups on the particle's surface. We found that the homing peptide was required for targeted internalization by tumor cells, and that siRNA cargo could be coattached without affecting the function of the peptide. Using an EGFP model system, the role of conjugation chemistry was investigated, with siRNA attached to the particle by disulfide cross-linkers showing greater silencing efficiency than when attached by a nonreducible thioether linkage. Since each particle contains a limited number of attachment sites, we further explored the tradeoff between number of F3 peptides and the number of siRNA per particle, leading to an optimized formulation. Delivery of these F3/siRNA-QDs to EGFP-transfected HeLa cells and release from their endosomal entrapment led to significant knockdown of EGFP signal. By designing the siRNA sequence against a therapeutic target (e.g., oncogene) instead of EGFP, this technology may be ultimately adapted to simultaneously treat and image metastatic cancer.
Long-term labeling of stem cells during self-replication and differentiation benefits investigations of development and tissue regeneration. We report the labeling of human mesenchymal stem cells (hMSCs) with RGD-conjugated quantum dots (QDs) during self-replication, and multilineage differentiations into osteogenic, chondrogenic, and adipogenic cells. QD-labeled hMSCs remained viable as unlabeled hMSCs from the same subpopulation. These findings suggest the use of bioconjugated QDs as an effective probe for long-term labeling of stem cells.
Nanoparticles of ZnS-AgInS2 solid solution (ZAIS) were synthesized by the thermal decomposition of (AgIn)xZn2(1-x)(S2CN(C2H5)2)4 precursors in a hot oleylamine solution. X-ray powder diffraction analyses revealed that the resulting nanoparticle powders were not a mixture of ZnS and AgInS2 but a ZnS-AgInS2 solid solution in which the fraction of ZnS was enlarged with a decrease in the value of x, that is, an increase in the content of Zn2+ in the precursors used. The energy gap of ZAIS nanoparticles could be controlled by the composition of solid solution. Intense emission was observed at room temperature, regardless of the kind of the particles, the peak wavelength of PL being blue-shifted from 720 to 540 nm with a decrease in the value of x. The highest quantum yield of ca. 24% was obtained for nanoparticles prepared with x = 0.86, which was much higher than the quantum yields reported for I-III-VI2-based semiconductor nanoparticles, such as CuInS2 and ZnS-CuInS2 solid solution.
We present a family of water-soluble quantum dots (QDs) that exhibit low nonspecific binding to cells, small hydrodynamic diameter, tunable surface charge, high quantum yield, and good solution stability across a wide pH range. These QDs are amenable to covalent modification via simple carbodiimide coupling chemistry, which is achieved by functionalizing the surface of QDs with a new class of heterobifunctional ligands incorporating dihydrolipoic acid, a short poly(ethylene glycol) (PEG) spacer, and an amine or carboxylate terminus. The covalent attachment of molecules is demonstrated by appending a rhodamine dye to form a QD-dye conjugate exhibiting fluorescence resonance energy transfer (FRET). High-affinity labeling is demonstrated by covalent attachment of streptavidin, thus enabling the tracking of biotinylated epidermal growth factor (EGF) bound to EGF receptor on live cells. In addition, QDs solubilized with the heterobifunctional ligands retain their metal-affinity driven conjugation chemistry with polyhistidine-tagged proteins. This dual functionality is demonstrated by simultaneous covalent attachment of a rhodamine FRET acceptor and binding of polyhistidine-tagged streptavidin on the same nanocrystal to create a targeted QD, which exhibits dual-wavelength emission. Such emission properties could serve as the basis for ratiometric sensing of the cellular receptor's local chemical environment.
Semiconductor quantum dots (QDs) are tiny light-emitting particles on the nanometer scale, and are emerging as a new class of fluorescent labels for biology and medicine. In comparison with organic dyes and fluorescent proteins, they have unique optical and electronic properties, with size-tunable light emission, superior signal brightness, resistance to photobleaching, and broad absorption spectra for simultaneous excitation of multiple fluorescence colors. QDs also provide a versatile nanoscale scaffold for designing multifunctional nanoparticles with both imaging and therapeutic functions. When linked with targeting ligands such as antibodies, peptides or small molecules, QDs can be used to target tumor biomarkers as well as tumor vasculatures with high affinity and specificity. Here we discuss the synthesis and development of state-of-the-art QD probes and their use for molecular and cellular imaging. We also examine key issues for in vivo imaging and therapy, such as nanoparticle biodistribution, pharmacokinetics, and toxicology.
We report the rational design of multifunctional nanoparticles for short-interfering RNA (siRNA) delivery and imaging based on the use of semiconductor quantum dots (QDs) and proton-absorbing polymeric coatings (proton sponges). With a balanced composition of tertiary amine and carboxylic acid groups, these nanoparticles are specifically designed to address longstanding barriers in siRNA delivery such as cellular penetration, endosomal release, carrier unpacking, and intracellular transport. The results demonstrate dramatic improvement in gene silencing efficiency by 10-20-fold and simultaneous reduction in cellular toxicity by 5-6-fold, when compared directly with existing transfection agents for MDA-MB-231 cells. The QD-siRNA nanoparticles are also dual-modality optical and electron-microscopy probes, allowing real-time tracking and ultrastructural localization of QDs during delivery and transfection. These new insights and capabilities represent a major step toward nanoparticle engineering for imaging and therapeutic applications.
We report the synthesis of a size series of copper indium selenide quantum dots (QDs) of various stoichiometries exhibiting photoluminescence (PL) from the red to near-infrared (NIR). The synthetic method is modular, and we have extended it to the synthesis of luminescent silver indium diselenide QDs. Previous reports on QDs luminescent in the NIR region have been primarily restricted to binary semiconductor systems, such as InAs, PbS, and CdTe. This work seeks to expand the availability of luminescent QD materials to ternary I-III-VI semiconductor systems.
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