Nanoparticles As Contrast Agents for In-Vivo Bioimaging: Current Status and Future Perspectives
Total Page:16
File Type:pdf, Size:1020Kb
Anal Bioanal Chem (2011) 399:3–27 DOI 10.1007/s00216-010-4207-5 REVIEW Nanoparticles as contrast agents for in-vivo bioimaging: current status and future perspectives Megan A. Hahn & Amit K. Singh & Parvesh Sharma & Scott C. Brown & Brij M. Moudgil Received: 18 August 2010 /Accepted: 7 September 2010 /Published online: 6 October 2010 # Springer-Verlag 2010 Abstract Nanoparticle-based contrast agents are quickly mography (PET), computed tomography (CT), ultrasound becoming valuable and potentially transformative tools for (US), and photoacoustic imaging (PAI). Clinical and preclin- enhancing medical diagnostics for a wide range of in-vivo ical applications of NPs are identified for a broad spectrum of imaging modalities. Compared with conventional molecular- imaging applications, with commentaries on the future scale contrast agents, nanoparticles (NPs) promise improved promise of these materials. Emerging technologies, for abilities for in-vivo detection and potentially enhanced example multifunctional and theranostic NPs, and their targeting efficiencies through longer engineered circulation potential for clinical advances are also discussed. times, designed clearance pathways, and multimeric binding capacities. However, NP contrast agents are not without Keywords Nanoparticles . In-vivo imaging . Clinical . issues. Difficulties in minimizing batch-to-batch variations Characterization . Multifunctional . Theranostic and problems with identifying and characterizing key physicochemical properties that define the in-vivo fate and transport of NPs are significant barriers to the introduction of Introduction new NP materials as clinical contrast agents. This manuscript reviews the development and application of nanoparticles and Noninvasive imaging and minimally invasive in-vivo bio- their future potential to advance current and emerging clinical imaging techniques are valuable tools in the arsenal of clinical bioimaging techniques. A focus is placed on the application of diagnostics. Many types of bioimaging are available, span- solid, phase-separated materials, for example metals and ning from techniques that enable whole-organism anatomical metal oxides, and their specific application as contrast agents imaging (e.g., magnetic resonance imaging, MRI) to others for in-vivo near-infrared fluorescence (NIRF) imaging, that provide specific molecular imaging (e.g., optical fluores- magnetic resonance imaging (MRI), positron emission to- cence) at subcellular resolution. Such tools are expected to be pivotal for advancing early-stage cancer diagnosis, guided stem cell therapies, drug delivery, pathogen detection, gene Published in the special issue Nanomaterials for Improved Analytical therapy, image-guided surgery, and cancer staging [1], in Processes with Guest Editors Miguel Valcárcel and Bartolomé M. addition to many other clinically relevant procedures, Simonet. diagnostics, and therapies. : : : M. A. Hahn (*) P. Sharma S. C. Brown B. M. Moudgil Nanoparticles (NPs) are a class of materials generally Particle Engineering Research Center, University of Florida, ranging in size from 1 to 100 nm that are emerging as 205 Particle Science and Technology Building, potentially powerful probes for in-vivo imaging in medical P.O. Box 116135, Gainesville, FL 32611, USA e-mail: mhahn@perc.ufl.edu and biological diagnostics. Several NP-based contrast : agents have been developed to overcome issues that plague A. K. Singh B. M. Moudgil conventional contrast agents; improvements in chemical Department of Materials Science and Engineering, and photostability of NP fluorophores, and contrast agent University of Florida, 205 Particle Science and Technology Building, detection limits, have been demonstrated in a broad array of P.O. Box 116135, Gainesville, FL 32611, USA imaging modalities. The ideal NP agent must fulfill a preferred over electrostaticincorporated interactions: on DNA, to RNA, abinding. and NP Therestealth is for a long circulationnanomaterial plethora times with is of minimal nonspecific Regardless often entities of composition, required that surfacethe to functionalization can of development enable the be ofadvancement targeting biomarkers in and based achieving on specific NP molecular constructs. targetingcancers and is metastases). effects of disrupteddetermining molecular treatment processes effectiveness,detection (e.g., and rather malignant characterization than ofvivo disease the imaging development modalities. end and Thereaccuracy. is Table a highity, desire for SNR, earlier penetrationwhich include depth spatial and/or inimaging temporal technique tissue, has resolution, its sensitiv- cancer and own advantages and quantitative and otherwhich limitations, disease is models. betterMRI) in Each suited a clinical toward type setting,techniques rather small of than are animal fluorescence in-vivo more imaging, imagingtarget, powerful and and for the safer sizeinformation on and humans desired, thickness (e.g., of thethe the contrast characteristics subject. agents Different of or the probes, is biological dependentin on the the drug type development of of cancer therapeutics. side effects time and money whileresponse diminishing to patient chemotherapy discomfort treatmentsguided and tumor in resection. real In-vivo time operatively imaging using could optical track tumor imagingimage that can a then tumorexample, aid a image- pre-operatively combination utilizing ofdevelopment, in-vivo MRI imaging and can and beimaging efficacy intra- used of to of geneadvantageous anti-cancer expression include drugs. in tumor vivo For imaging to for elucidate guidedimaging disease is surgery, complete. at low dosesmaterials and will be be suitable forin safely long-term quantitative the cleared imaging blood fromto-noise if the ratio, SNR) administered body and intravenously.antigen, after sufficiently cell, Ideally, long tissue) circulation with these good times have contrast quality high (high signal- sensitivityand have and programmed selectivity clearance mechanisms;and for and be it resistant the should to reticuloendothelial targetmeasurement; system it (e.g., (RES) should uptake, exhibittemperature limited nonspecific when binding thesedifferences conditions in areof solvent not local polarity, intendeddispersible in-vivo ionic for and environments strength, stable (i.e.,number and pH, resist of aggregation) not or in stringent be a variety requirements: affected it by 4 should be easily One area of research which has led to significant The performance of the bioimaging modality used, and Important areas in which NP-based contrast can prove — which would be an immensely powerful role 1 highlights the most commonly used in- ’ s surface, with covalent bonding — saving Table 1 Comparison of commonly used bioimaging techniques (adapted from Refs. [225] and [226]) Technique Typical NP label Signal measured Resolution Depth Sensitivity (moles Throughput Cost Main limitation of label detected) − NIRF QDs, dye-doped NPs, upconverting NPs, Light, particularly in the near-infrared 1–3mm <1cm 1012 High Low Poor depth penetration SWNTs and other carbon-based nanomaterials − − MRI Iron oxide NPs, Gd(III)-doped NPs, NP-based Alterations in magnetic fields 50 μm No limit 10 9–10 6 Low High Low sensitivity, cannot CEST and hyperpolarized probes (e.g., 129Xe) follow many labels − PET NPs incorporating radioisotopes (e.g., 18F, 11C, Positron from radionuclides 1–2 mm No limit 10 15 Low High Can detect only one 64Cu, 124I) radionuclide, requires radioactivity − SPECT NPs incorporating radioisotopes (e.g., 99mTc, 111In) γ-rays 1–2 mm No limit 10 14 Low High Requires radioactivity − CT Iodinated NPs, gold NPs, iron oxide-doped X-rays 50 μm No limit 10 6 Low High Poor resolution of soft nanomaterials tissues − US Microbubbles, nanoemulsions, silica NPs, Sound 50 μm Several cm 10 8 High Low Poor image contrast, polystyrene NPs works poorly in air-containing organs M.A. Hahn et al. − PAI Gold nanoshells, gold nanocages, gold nanorods, Sound 50 μm<5cm1012 High Low Information processing gold NPs, SWNTs, dye-doped NPs and machines still being optimized NP contrast agents for bioimaging 5 oligonucleotides (aptamers); peptides, proteins, peptidomi- thin tissue sections; the requirement for deeper penetra- metics, enzymes, antibodies, and antibody fragments; tion depths for most clinical applications is driving tumor cell receptors, for example folate and Her2, or fluorescence-based techniques into the NIR region ligands against particular antigens or epitopes; carbohy- (650–950 nm). In this NIR window, the absorption of drates; and agents to reduce the chance of an immunogenic water, hemoglobin, and lipids are at their minimum while response while increasing the circulation time in the blood, autofluorescence and tissue scatter are low, enabling and stealthily avoiding the RES and promoting dispersi- maximum light penetration; therefore, high SNRs and bility and solubility (e.g., poly(ethylene glycol) (PEG), sensitive detection limits result. Typically <1 cm, light polymers, phospholipids, dextran, latex). No matter what penetration depth depends on the type of tissue imaged: the surface moiety, its activity must not be altered once skin and muscle are more transparent than organs having anchored to the NP surface. lots of vasculature (e.g., liver and spleen) because of This review will focus on several principle types of absorption by hemoglobin. However, new advances in NPs currently affecting or with the ability to improve optical microscopy imaging