Applications of Functionalized Quantum Dots in Bioanalysis,Imaging and Targeting Delivery

HE Dongxiu,WANG Danxia,QUAN Wenjie,YU Cuiyun

(Institute of Pharmacy & Pharmacology,Department of Pharmacy,University of South China,Hengyang,421001,China)

·博士笔谈·

ApplicationsofFunctionalizedQuantumDotsinBioanalysis,ImagingandTargetingDelivery

HE Dongxiu*,WANG Danxia,QUAN Wenjie,YU Cuiyun

(Institute of Pharmacy & Pharmacology,Department of Pharmacy,University of South China,Hengyang,421001,China)

Quantum dots (QDs),fluorescen nanomaterials,have exceptional optical properties.Functionalized QDs that include QDs and targeting moieties have been considered to have the potential as novel molecular probes and suited for a number of biomedical researches,which plays an important role in biomedicine.In recent years,the functionalized QDs have exhibited an important role in biomedical research and applications,especially in the field of bioanalysis,imaging and targeting delivery.

Functionalized quantum dots; applications; bioanalysis; bioimaging; targeting delivery

1 Introduction

Nanoparticles that interface with biological systems have recently attracted great attention of biomedical researchers due to their widespread applications in biomedical applications[1-5].Functional nanoparticles,one of the cutting-edge materials of the twenty-first century,are considered to have the potential as novel molecular tools for biomedical research,which plays a critical role in biomedicine.One major merit of using functional nanoparticles is that one can control and tailor properties in a very predictable manner to meet the needs of specific biomedical application.

Quantum dots (QDs) are semiconductor inorganic nanomaterials ranging from 1～10 nm.QDs have shown great potential interest to biomedical scientists because of their unique advantages over traditional fluorescent dyes,such as broad excitation spectra,robust,narrow-band emission,size-tunable absorption and photo-luminescence spectra,exceptional photo-stability,high quantum yield,and versatility in surface modification[3].Over the past decade,QDs have been used in many different aspects of biomedical field.First used for cellular imaging,QDs later became useful tools for bioanalysis[1],imaging and targeting delivery[4].Functionalized QDs,bioconjugated with types of targeting ligands or drug/gene through selective binding to the receptors over-expressed on the cell surface,have the potential to considerably improve analytic sensitivity.Additionally,functionalized QDs can provide the excellent efficiency of fluorescence imaging and target delivery[6-7].Here,this article provides a brief review on the recent developments of functionalized QDs in the biomedical applications,especially in the field of bioanalysis,bioimaging and targeting delivery.

2 Bioanalytical applications

Bioanalysis has recently used to define analytical techniques used in the quantification and characterization of biologicals.Analysis of drugs,forensic science,biomarkers,clinical chemistry and therapeutic drug monitoring have also belonged to the concept of bioanalysis[8].For successful analytic methods,there are two main aspects for obtaining satisfactory sensitivity and reproducibility.The first is to exploit highly efficient signal-transduction labels.The other is to adopt a simple,sensitive signal-transduction method.Functionalized QDs can produce a high analytical signal (luminescence,electrochemical or electrochemiluminescence).Additionally,functionalized QDs can offer high sensitivity and selectivity in bioassays[9].Herein,functionalized QDs have generated increasingly widespread applications in pharmaceutical analysis[10-21],biomarkers detection[22]and other important analyses including ATP[23]and toxins[24].

2.1 Pharmaceutical analysis applications

Quantification of pharmaceuticals plays an important role for the purposes of defining their pharmaceutics or minimizing drug safety risk.The fluorescent labeling is one of the most important methods of modern pharmaceutical analysis as a nonradioactive labeling technique.Now the new-type fluorescent quantum dots may have better application in the pharmaceutical analysis because functionalized QDs overcome the disadvantage of the traditional fluorescent dyes.

Alibolandietal.[10]developed the electrogenerated chemiluminescent method for the sensitive and selective determination of chloramphenicol based on the functionalized QDs generating an efficient,stable signal during potential cycling or pulsing.Their results suggested that the presented method was also well qualified for the detection of chloramphenicol in milk with a limit of detection of 0.2 ppb.And,several researches recently also suggested that functionalized QDs can be used for the quantification of d-penicillamine in pharmaceutical formulations[11]and heparin[12]with satisfactory limit of detection and limit of quantification.

Besides the detection of small molecule drugs,functionalized QDs have also been proved to have prospect for sensitive detection of biomacromolecular drugs,such as protein[13-15],enzyme[16-17],DNA[19],small interfering RNA(siRNA)[20]and carbohydrate[21].Montoro Bustos et al demonstrated for the first time that the streptavidin modified CdSe/ZnS QDs was applied to the sequential quantification of five proteins (transferrin,complement C3,apolipoprotein A1,transthyretin and apolipoprotein A4) at different concentration levels in human serum samples[13].Huangxian Ju team designed the facile electrochemiluminescent method for sensitive dynamic monitoring of carbohydrate expression on living cells by combining the specific recognition of lectin to carbohydrate groups with the functionalized CdSe QDs[21].

2.2 Biomarkers detection applications

The detection of biomarkers is important and useful for screening and early diagnosis of disease,disease stage forecasting,and clinical management[25].Especially,tumor markers assays play a critical role in the cancer diagnosis if a set of tumor markers can be quantified and statistically differentiated between carcinoma cells and normal cell.Functionalized QDs have recently attracted increasingly widespread applications in biomarkers detection[22,25-27 ].

Liuetal.[22]reported on a disposable micro-device suitable for sandwich-type electrochemiluminescence (ECL) detection of prostate specific antigen (PSA).Taking advantage of dual-amplification effects of the Pt/Au and ZnO quantum dots dotted carbon nanotube (ZnO@CNT),this immunosensor could detect the PSA quantitatively,in the range of 0.001～500 ng/mL,with a low detection limit of 0.61 pg/mL.

Functionalized QDs were synthesized by Tang and his colleagues through formation of PAMAM dendrimer with CdS,ZnS and PbS.These functionalized QDs were used for a novel multiplexed stripping voltammetric immunoassay for simultaneous detection of three biomarkers (CA 125,CA 15-3,and CA 19-9)[28].

3 Biomedical imaging applications

Noninvasive imaging and minimally invasive in vivo biomedical imaging techniques are especially valuable tools in the arsenal of clinical diagnosis.Many types of biomedical imaging(e.g.,magnetic resonance imaging,optical fluorescence) are available.Whichever is bioimaging technique,its continuous development relies mainly on the improvement of corresponding contrast agents.The photochemical stability and high fluorescence intensity of QDs make them become the ideal contrast agents in practical clinical diagnosis application.Recently,functionalized QDs,conjugated with various targeting moieties,have been wide used for biomedical fluorescence imaging[6,29-36].

3.1 In vitro imaging application

One of the most advancing applications of functionalized QDs is in vitro imaging of cancer.Many research groups applied functionalized QDs for in vitro fluorescence imaging of cancer cells derived from ovarian carcinoma[6],melanoma[30],hepatocellular carcinoma[31],breast cancer[32],pancreatic cancer[33],glioblastoma[34],ovarian epidermoid carcinoma[35]and lung adenocarcinoma[36].

Zhangetal.[32]found that QDs conjugated with anti-type 1 insulin-like growth factor receptor (IGF1R) is a promising candidate for targeting and imaging in breast cancer cells.The key in this targeting was the detection of up-regulated IGF1R in MCF-7 breast cancer cells by QD-anti-IGFR1 conjugate.

Yong and coworkers[33]selectively detected human pancreatic cancer cells using QDs conjugated with anti-Claudin-4 antibody and anti-prostate stem cell antigen (anti-PSCA).These conjugates were recognized by the membrane proteins Claudin-4 and PSCA which are over-expressed in both primary and metastatic pancreatic cancer cells.

Kawashimaetal.[35]also explored intermolecular interactions involved in the lateral propagation of cell-signaling by EGFR single-molecules in human ovarian epidermoid carcinoma cells (A431) using nanocomposites loaded CdSe/ZnS QDs.Kawashima found that CHO and A431 cells were efficiently labeled by QD-EGF conjugates due to the specific binding of EGF to EGFR.

3.2 In vivo imaging application

3.2.1 Tumor imaging application The basic principles underlying in vitro targeting of cancer cells can be applied in vivo.However,in vivo applications of functionalized QDs are more complicated and challenging.One main challenge for in vivo imaging using the functionalized QDs is their biodistribution and pharmacokinetics.Chenetal[38].have monitored the dynamic distribution of CdHgTe/SiO2 nanocomposites in vivo by near infrared fluorescence imaging system.Another main challenge for in vivo targeting and imaging is the fluorescence emitting property of the functionalized QDs.Visible emitting QDs provide poor signal to background ratio in deep tissue and when imaging targets in small animals[29].While NIR QDs offer several advantages for the non-invasive visualization of living tissues because of its deeper photon penetration,low absorption and scattering.So,functionalized NIR QDs are considered to have the potential as novel probe for carcinoma imaging[39-42].

Carcinoma cell labeling or tracking in living organisms was monitored efficiently and sensitively by functionalized QDs,which may provide tools to locate tumors and metastases or map tumor margins during surgery.

It was demonstrated that functionalized QDs can represent excellent tool for new tumor vessel imaging[41-42]or multimodal molecular imaging of angiogenesis[43].

3.2.2 Lymph node imaging Lymphatic metastasis is one of the main metastatic pathways of most cancers and determines the prognoses of those cancers to a large extent.The sentinel lymph node (SLN),which can reflect the status of group lymph nodes accurately,is defined as the first lymph node (LN) to receive the lymphatic drainage and metastasis of the primary tumor[44].Compared with the sentinel lymph node biopsy technique,lymph node mapping (LNM) should identify LNs more readily than SLNs.Several studies on the detection of SLN using functionalized QDs have been reported[37,44-45].The initial research of the SLN mapping in vivo using NIR emitting QDs have been reported by Kim and coworkers[44].

Sietal[45].demonstrated that functionalized QDs are excellent tracers for intraoperative LNM.SLN detection using functionalized QDs only takes a few minutes after injection,which greatly simplifies surgical procedures.Wu Q and Chu MQ recently reported that the sensitivity in SLN mapping has greatly been enhanced by using self-illuminating QDs[46].

3.3.3 Vasculature imaging Vasculature,consisting of blood vessels and lymphatic drainage systems,is vital to life and participates in many pathological processes,including metastasis and tumorigenesis.In vivo real-time visualization of the vasculature has great potential to improve our understanding of vasculature related physiological and pathological processes and to advance clinical diagnostics and therapy[47].NIR-emitting QDs can be finely tuned in size and shape to modulate pharmacokinetics and tissue distribution,and they could be useful in in vivo real-time visualization of tissue blood flow in the nude mouse[47]or in living pulmonary edema mouse[48].It has also been reported that lymphatic drainage from the eye present in mice by visualizing the trajectory of the CdSe/ZnS QDs coated with carboxylic acids once injected into the eyes of 17 live mice[49].

4 Targeting delivery applications

Targeting delivery by nanoparticles or nanocapsules offers a promising approach to improving upon the efficacy of existing drugs and enabling the development of new therapies.QDs are newer luminescent nanoparticles with rich surface chemistry and unique optical properties that make them useful as visualization probes or carriers for traceable targeting delivery applications without the need for external dyes[50-51].

4.1 Targeting drug delivery applications

By directly noncovalent coupling or covalent coupling drug molecules to the QDs surface,drug-conjugated QDs can be delivered to specific sites and subsequently release drug molecules from the QDs surface in response to local biological conditions such as pH or the presence of enzymes.Several research groups have demonstrated the integration of therapeutic antibody[52]or drug molecules[53]with functionalized QDs for targeting drug delivery in vitro and in vivo.Xuetal.[52]demonstrated for the first time that the nanocomposite comprising of QDs and anti-GRP78 scFv could be efficiently internalized by cancer cells,thus upregulate phophosphate-AKT-ser473 and possess biological anti-tumor activity by inhibition of breast cancer growth in a xenograft model.Functionalized QDs,fibrinogen (fib) coated CdTe/ZnTe and paclitaxel (PTX),can target MCF-7 cells and effectively deliver PTX towards breast cancer cells via the α5β1-integrins[53].Chakravarthyetal.[54]found that doxorubicin (Dox) can be effectively released from the nanocomposites loaded CdSe/CdS/ZnS QDs and Dox and accumulated in the cell nucleus.They also demonstrated that the functionalized QDs can provide targeted macrophage-selective therapy for the treatment of pulmonary disease.Furthermore,Jeyadevia’s study revealed that using TGA-CdTe QDs as nanocarrier of quercetin could enhance the anti-arthritic effect of quercetin even at a lower concentration of the drug in rheumatic complications[55].

4.2 Targeting gene delivery applications

Gene therapy has emerged as a powerful strategy for disease treatment over the past several decades because of the genetic link associated with tumor development and progression.The delivery of nucleic acid therapeutics to down-regulate or replace mutated genes,and to silence unexpected gene expression,is becoming an attractive approach to suppressing tumor cell growth and invasion.There have been intensive efforts to develop safe and efficient gene delivery carriers to provide high transfection efficiency at the desired target.

Besides the delivery of small molecule drugs,QDs have also been proved to have prospect for delivery of more intricate genes,such as small interfering RNA (siRNA).The short and double-stranded therapeutic siRNA works by silencing the expression of unwanted,disease-causing genes.Nevertheless,free forms of them owe high negative charge and are easy to degrade in body environment.Thus,in order to achieve optimal function in physiological conditions,they must be delivered via conbination with cationic nanocariers.Because of appropriately surface functionalized with cationic moieties,functionalized QDs are good choices of siRNA carriers as they not only render these genetic drugs with physiological stability and target specificity,but also the entire nanocomposites can be optically traced.Therefore,functionalized QDs were specifically designed to overcome barriers in siRNA delivery such as siRNA protection,cellular penetration,endosomal release,carrier unpacking,intracellular transport and gene silencing.Lietal.[56]confirmed that QDs could efficiently delivery siRNA into HeLa cells and silence a target gene,and the functionalized QDs could also be used as fluorescence probes,allowing real-time tracking and localization of QDs during delivery and transfection in vivo.More importantly,functionalized QDs have been demonstrated to deliver an active siRNA to knockdown EGFRvIII receptors in human glioma cells,and subsequently monitor the resulting down-regulated signaling pathway with high efficiency[57],suggesting that QDs could be designed to deliver gene to a specified target cell type.

5 Summary

Real-time bioanalysis and imaging,visual tracking and targeting delivery have been hot topics in life science fields.Current investigation of functionalized QDs in vitro and in vivo has offered less invasive imaging,visual tracking and drug delivery.However,up to date functionalized QDs clinical applications have been limited due to side-effects.Various non-toxic elements QDs such as silica,zinc,sulfur and copper have been explored with recent developments in the preparation and characterization techniques of QDs.The emergence of nanocomposites including QDs,targeting moieties,and other materials enabled to improve imaging and targeting delivery applications because of their better biocompatibility,lower toxicity and longer circulation time in vivo,which were better applied for biomedical applications.

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功能化量子点在生物分析，生物成像和靶向运输中的应用

贺冬秀，王丹霞，全文捷，喻翠云

(南华大学药物药理研究所药学系，湖南 衡阳 421001)

贺冬秀，博士，副教授，硕士生导师。主要研究方向为生物分析、分子影像与分子探针。主持完成和在研湖南省自然科学基金项目、湖南省中医药管理局重点课题等课题。在《中国科学》、《J Pharm Biomed Anal》等期刊发表科研论文20余篇。

量子点是一类具有优良光学特性的荧光纳米材料。量子点与靶向配体结合形成功能化量子点。功能化量子点被认为是潜在的、新颖的分子探针，适合于一系列生物医学研究。近年来，功能化量子点在生物医学的应用和研究领域，特别是在生物分析，生物成像和靶向运输等方面发挥着重要作用。

功能化量子点； 应用； 生物分析； 生物成像； 靶向运输

10.15972/j.cnki.43-1509/r.2015.05.001

date：2015-08-30；

date2015-9-11

SupportedFundingNational Natural Science Foundation of China (81471777,81102409) and Natural Science Foundation of Hunan province (13JJ6096).

*Correspondingauthor1025165380@qq.com.

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