Design considerations for tumour-targeted nanoparticles (original) (raw)
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Quantum Dots: An Optimistic Approach to Novel Therapeutics
Nanotechnology is a multidisciplinary field and has achieved breakthroughs in bioengineering, molecular biology, diagnostics, and therapeutics. Targeted delivery of therapeutic agents has the potential to localize drugs to a specific tissue as a mechanism to enhance treatment efficacy and abrogate side effects. The successful nanoparticle mediated delivery includes the ability to target specific tissues and cell types (primary & secondary targeting) and escape from the uptake by the reticuloendothelial system (RES). The feasibility of in vivo targeting of peptides has recently been achieved by using semiconductor quantum dots (Qdots). Qdots are small (<10 nm) inorganic nanocrystals that possess unique luminescent properties; their fluorescence emission is stable and tuned by varying the particle size or composition. It has been found that ZnS-capped CdSe Qdots coated with a lung-targeting peptide accumulate in the lungs of mice after i.v. injection, whereas two other peptides specifically direct Qdots to blood vessels or lymphatic vessels in tumors. Adding polyethylene glycol to the Qdot coating slows down opsonization and prevents nonselective accumulation of Qdots in RES. These results encourage the construction of more complex nanostructures with capabilities such as disease sensing and feedback regulated drug delivery. This work is expected to address the formidable challenges encountered in the field of drug targeting, and opens up new vistas in future development of a promisingly active and site-specific delivery system.
Effect of ligand nature on the kinetics and the bio-distribution of quantum dots in mice
The meeting of nano-materials with biology has produced a new generation of technologies that can profoundly impact biomedical research. The NIR emitting window (650-900 nm) is appealing for in vivo optical imaging because of the low tissue absorption and scattering in this wavelength range. The design of high-quality NIRemitting quantum dots, with outstanding optical properties in comparison to organic dyes, should therefore lead to novel contrast agents with improved performance. Quantum dot growth is controlled by the coordination of hydrophobic ligands. Hence, they have to be transferred in water and conveniently coated before their use in vivo. Several coating strategies are developed. In this paper we report the coating of commercial ITK705-amino particles with methoxy-terminated PEG of different chain length and their in vivo behaviour. Fluorescence imaging studies indicate that the speed of first pass extraction of the coated quantum dots towards the liver depends strongly o...
Quantum dots as a platform for nanoparticle drug delivery vehicle design
Advanced Drug Delivery Reviews, 2013
Nanoparticle-based drug delivery (NDD) has emerged as a promising approach to improving upon the efficacy of existing drugs and enabling the development of new therapies. Proof-of-concept studies have demonstrated the potential for NDD systems to simultaneously achieve reduced drug toxicity, improved bio-availability, increased circulation times, controlled drug release, and targeting. However, clinical translation of NDD vehicles with the goal of treating particularly challenging diseases, such as cancer, will require a thorough understanding of how nanoparticle properties influence their fate in biological systems, especially in vivo. Consequently, a model system for systematic evaluation of all stages of NDD with high sensitivity, high resolution, and low cost is highly desirable. In theory, this system should maintain the properties and behavior of the original NDD vehicle, while providing mechanisms for monitoring intracellular and systemic nanocarrier distribution, degradation, drug release, and clearance. For such a model system, quantum dots (QDots) offer great potential. QDots feature small size and versatile surface chemistry, allowing their incorporation within virtually any NDD vehicle with minimal effect on overall characteristics, and offer superb optical properties for real-time monitoring of NDD vehicle transport and drug release at both cellular and systemic levels. Though the direct use of QDots for drug delivery remains questionable due to their potential long-term toxicity, the QDot core can be easily replaced with other organic drug carriers or more biocompatible inorganic contrast agents (such as gold and magnetic nanoparticles) by their similar size and surface properties, facilitating translation of well characterized NDD vehicles to the clinic, maintaining NDD imaging capabilities, and potentially providing additional therapeutic functionalities such as photothermal therapy and magneto-transfection. In this review we outline unique features that make QDots an ideal platform for nanocarrier design and discuss how this model has been applied to study NDD vehicle behavior for diverse drug delivery applications.
Quantum Dots and their Potential Role in Cancer Theranostics
Critical Reviews in Therapeutic Drug Carrier Systems, 2015
The emergence of cancer nanomedicine is the result of fruitful advances in the fields of nanotechnology, bioimaging, formulation development, and molecular biology. Quantum dots (QDs) are the luminescent nanocrystals (NCs) that provide a multifunctional platform for imaging the biosystems following controlled delivery of therapeutic drugs, proteins, peptides, oligonucleotides, and genes. These engineered fluorescent probes with integrated imaging and carrier functionalities have become excellent tools for molecular diagnostics and delivery of therapeutics molecules. Flexible surface chemistry, unique optical properties, high sensitivity, and multiplexing capabilities of QDs certainly make them a most promising tool for personalized medicine. This review focuses on state-of-art advances in synthesizing QDs and highlights the approaches used for functionalization of QDs with desired ligands for targeted carriage to specific sites. Discussed is the role of QDs in antitumor therapy through drug delivery and gene delivery and the recently emerged photodynamic therapy (PDT). We also endeavor to critically address the major impediments in the clinical development of these multifunctional nanoplatforms, with a special focus on plausible advancements for the near future.
Mechanisms of Quantum Dot Nanoparticle Cellular Uptake
Toxicological Sciences, 2009
Due to the superior photoemission and photostability characteristics, quantum dots (QD) are novel tools in biological and medical applications. However, the toxicity and mechanism of QD uptake are poorly understood. QD nanoparticles with an emission wavelength of 655 nm are ellipsoid in shape and consist of a cadmium/selenide core with a zinc sulfide shell. We have shown that QD with a carboxylic acid surface coating were recognized by lipid rafts but not by clathrin or caveolae in human epidermal keratinocytes (HEKs). QD were internalized into early endosomes and then transferred to late endosomes or lysosomes. In addition, 24 endocytic interfering agents were used to investigate the mechanism by which QD enter cells. Our results showed that QD endocytic pathways are primarily regulated by the G-proteincoupled receptor associated pathway and low density lipoprotein receptor/scavenger receptor, whereas other endocytic interfering agents may play a role but with less of an inhibitory effect. Lastly, low toxicity of QD was shown with the 20nM dose in HEK at 48 h but not at 24 h by the live/dead cell assay. QD induced more actin filaments formation in the cytoplasm, which is different from the actin depolymerization by cadmium. These findings provide insight into the specific mechanism of QD nanoparticle uptake in cells. The surface coating, size, and charge of QD nanoparticles are important parameters in determining how nanoparticle uptake occurs in mammalian cells for cancer diagnosis and treatment, and drug delivery.
Non-specific cellular uptake of surface-functionalized quantum dots
Nanotechnology, 2010
We report a systematic empirical study of nanoparticle internalization into cells via non-specific pathways. The nanoparticles were comprised of commercial quantum dots (QDs) that were highly visible under a fluorescence confocal microscope. Surface-modified QDs with basic biologically-significant moieties, e.g. carboxyl, amino, streptavidin were used, in combination with the surface derivatization with polyethylene glycol (PEG) in a range of immortalized cell lines. Internalization rates were derived from image analysis and a detailed discussion about the effect of nanoparticle size, charge and surface groups is presented. We find that PEG-derivatization dramatically suppresses the nonspecific uptake while PEG-free carboxyl and amine functional groups promote QD internalization. These uptake variations displayed a remarkable consistency across different cell types. The reported results are important for experiments concerned with cellular uptake of surface-functionalized nanomaterials, both when non-specific internalization is undesirable and also when it is intended for material to be internalized as efficiently as possible.
2015
Glyconanomaterials are of great interest for bio-imaging to understand biological processes, for instance metabolism, cell-cell or virus-cell interactions, gluconeogenesis, and cancer. Herein, we present a strategy for the biofunctionalization of fluorescent quantum dots (QDs) from continuous-flow reactor with carbohydrates. This flow reactor enables the reproducible synthesis of a large amount of QDs, with controlled surface functionalization. These QDs act as fluorescent biomarkers and as structural scaffolds for the presentation of glycoclusters to lectins, receptors and cells. Before the phase transfer into water takes place, the carbohydrates are covalently attached to an amphiphilic poly(isoprene)-bpoly(ethylene glycol) diblock copolymer (PI-b-PEG) using click-chemistry as previously described by us. These functionalized polymers are subsequently used for the encapsulation of the QDs under preservation of their unique optical properties in a continuous flow system. Binding of glycoconjugated QDs to the human cervical cancer cell line HeLa was characterized using confocal microscopy. Depending on the terminal group of the polymer (namely: D-maltose, D-glucose, carboxyl, and amine), the uptake of the functionalized QDs can be controlled and directed. Functionalization with maltose yields very high uptake in low incubation times and low concentrations. Although serum is known to inhibit the cellular response of artificial nanostructures, we observe reduced but significant cellular uptake of the maltose functionalized nanocontainers in serum containing media. This encapsulated materials have already been tested to be suitable for in vivo tumor targeting, due to their lack of toxicity as well as extraordinary stability. Though this method relies on highly reproducible continuous flow systems, which yield high amounts of well defined, functional, non-toxic and highly stable nanoparticles this method has extraordinary industrial, biological and medical relevance.
Quantum dots (QDs) are luminescent nanocrystals with rich surface chemistry and unique optical properties that make them useful as probes or carriers for traceable targeted delivery and therapy applications. QDs can be functionalized to target specific cells or tissues by conjugating them with targeting ligands. Recent advancement in making biocompatible QD formulations has made these nanocrystals suitable for in vivo applications. This review provides an overview of the preparation of QDs and their use as probes or carriers for traceable, targeted therapy of diseases in vitro and in vivo. More specifically, recent advances in the integration of QDs with drug formulations for therapy and their potential toxicity in vitro and in vivo are highlighted. The current findings and challenges for optimizing QD/drug formulations with respect to optimal size and stability, short-term and long-term toxicity, and in vivo applications are described. Lastly, we attempt to predict key trends in QD/drug formulation development over the next few years and highlight areas of therapy where their use may provide breakthrough results in the near future.
In vivo cancer targeting and imaging with semiconductor quantum dots
Nature Biotechnology, 2004
We describe the development of multifunctional nanoparticle probes based on semiconductor quantum dots (QDs) for cancer targeting and imaging in living animals. The structural design involves encapsulating luminescent QDs with an ABC triblock copolymer and linking this amphiphilic polymer to tumor-targeting ligands and drug-delivery functionalities. In vivo targeting studies of human prostate cancer growing in nude mice indicate that the QD probes accumulate at tumors both by the enhanced permeability and retention of tumor sites and by antibody binding to cancer-specific cell surface biomarkers. Using both subcutaneous injection of QD-tagged cancer cells and systemic injection of multifunctional QD probes, we have achieved sensitive and multicolor fluorescence imaging of cancer cells under in vivo conditions. We have also integrated a whole-body macro-illumination system with wavelengthresolved spectral imaging for efficient background removal and precise delineation of weak spectral signatures. These results raise new possibilities for ultrasensitive and multiplexed imaging of molecular targets in vivo. NATURE BIOTECHNOLOGY VOLUME 22 NUMBER 8 AUGUST 2004 969 © 2004 Nature Publishing Group http://www.nature.com/naturebiotechnology