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Theranostic nanotechnologies: moving beyond imaging drug localization? “Both preclinical and clinical advances of drug delivery and imaging agents are expected to facilitate the development of theranostic nanotechnologies.” Keywords: drug delivery n imaging n nanoparticles n prognostics n therapeutics

Theranostic nanotechnologies are nanoparticles that are capable of both delivering a therapeutic and imaging agent [1–7]. Typically, the imaging properties are associated with either an imaging molecule or the intrinsic imaging properties of a nanomaterial. These nanotechnologies are of two types: n First-generation theranostic nanotechnologies, which combine both therapeutic and imaging modalities to image the localization of the drug-delivery vehicle;

First-generation theranostic nanotechnologies Imaging the localization of drugs into tissues is necessary for noninvasively determining the distribution of pharmacological response to the drug, including efficacy and toxicity. The stateof-the-art related to monitoring treatment efficacy and disease progression is accomplished via imaging the tumor size and determining the presence of tumor markers in either blood or tumor tissue. These indirect and invasive approaches cannot provide immediate feedback if the drug is delivered to the tumor. The complexity and heterogeneity of the patient’s tumors at different disease stages requires the use of noninvasive procedures to determine where the drug is actually delivered to improve patient treatment [7]. Because some formulations of nanoparticle drug-delivery systems and imaging agents are now US FDA approved, it is logical to combine both modalities to develop theranostic

nanotechnologies. The two main approaches involve the use of an established imaging agent to deliver drugs or an established drug-delivery nanoparticle to integrate an imaging agent. For example, the intrinsic properties of the imaging agent can be used to trace the nanoparticle drug-delivery system. In this approach, iron oxide nanoparticles are co-encapsulated with a therapeutic agent into a liposome [8]. After administration, theranostic liposomes accumulate into tissues and MRI is used to determine localization of the liposome loaded with the therapeutic agent [9]. In addition to the use of these first-generation theranostic nanotechnologies for imaging drug localization, image-guided therapy can be applied at a specific site [5,10,11]. The theranostic drug agent is first delivered in a nontoxic form; upon accumulation in the tissues, the imaging signal increases and an external trigger (visible light, ultrasound, magnetic field oscillation) is aimed at the specific site to activate the drug’s toxicity. This first-generation theranostic approach for imaging the localization of drugs into tissues can also spatially control the drug activation of toxins, photosensitizers and siRNA to prevent off-target toxicity, a procedure that is critical for delivering very toxic drugs that can damage surrounding tissues. There are many lipid-based or polymer-based nanoparticles that can be combined with imaging agents such as gold nanoparticles, quantum dots, iron oxide nanoparticles, and silica nanoparticles [7]. However, this approach is advantageous as the nanoparticles can be easily prepared, with a high drug-loading capability and prolonged release of the therapeutic agent. This approach is also deficient as during the process the size of nanoparticles greatly increases, a heterogeneous encapsulation of the imaging agent occurs, along with aggregations that affect the imaging properties. To offset these problems, imaging agents such as gold nanoparticles, quantum dots, iron

10.4155/TDE.13.136 © 2014 Future Science Ltd

Ther. Deliv. (2014) 5(2), 97–100

Second-generation theranostic nanotechnologies, which provide quantitative data including prognostics. In this editorial, we discuss theranostic nanotechnologies in the context of therapeutic and imaging functions, emphasizing their successful use to date and challenges for advancing that use in the future. n

Frank Alexis Author for correspondence: Department of Bioengineering, Clemson University, Clemson, SC 29631, USA Tel.: +1 864 656 5003 E-mail: [email protected]

Jeffrey N Anker Department of Chemistry, Center for Optical Materials Science & Engineering, & Environmental Toxicology Program, Clemson University, Clemson, SC 29634, USA

ISSN 2041-5990

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Editorial | Alexis & Anker oxide nanoparticles, silica nanoparticles, carbon nanotubes and nanobubbles can be functionalized either with or without polymers to deliver drugs. This functionalized approach is advantageous as the nanoparticles required are quite small and can hold a homogeneous drug load. However, this approach is deficient in that only a small amount of drugs can be loaded into the nanoparticles; the drugs are rapidly released with the possible decrease in the activity of chemically modified drugs. Despite the preclinical development of many first-generation theranostic agents, concerns about biodegradation, toxicity, tissue depth penetration, cost and stability have hindered the progress towards developing these agents into clinical applications [7]. Although this first generation of theranostic nanotechnologies has indeed validated the proof-of-concept of localization of drugs into tissues, the information remains only qualitative. Second-generation theranostic nanotechnologies There are numerous second-generation theranostic nanotechnologies that can provide quantitative information about tumor microenvironment (pH, oxygen, temperature, proteases and so forth) and drug release kinetics. The rationale for noninvasively collecting quantitative measurements of drug dose and/or release kinetics is based on the critical need to monitor treatment progress and adjust the therapeutic regimen accordingly. Considering that therapeutic agents are not active when encapsulated and active upon release from the drug-delivery system, any quantitative data differentiating the encapsulated and released drugs can indicate the dose delivered to the cells or tissues. Administering radiolabeled drugs and then using PET, single photon emission tomography or radiology to measure the total drug accumulation are current methods for quantifying drug concentrations. None of these methods, however, can distinguish between free (active) or encapsulated drugs (nonactive), which is critical for accurately determining the efficacy of treatments.

“The complexity and heterogeneity of the patient’s tumors at different disease stages requires the use of noninvasive procedures to determine where the drug is actually delivered to improve patient treatment.” There are few methods that have been developed to quantitatively determine the 98

Ther. Deliv. (2014) 5(2)

concentrations of free and encapsulated drugs. The first involves co-encapsulating a contrast imaging agent and a drug with the same release kinetics. The second involves fluorescent quenching via nanomaterials with advanced imaging properties to reduce the background signal and enhanced sensitivity. One such method for co-encapsulating theranostic nanotechnologies entails the use of liposomes that encapsulate both a drug (doxorubicin) and gadoliniumdiethylene triamine pentaacetic acid complex imaging agent [12]. However, co-encapsulating the imaging and therapeutic agents requires balancing the content of both agents into the nanoparticle for theranostic applications. MRI is particularly useful as a theranostic imaging modality because it is not limited by imaging depth and it can deliver gadolinium-diethylene (FDA approved) at safe doses. Optical imaging methods are widely used for quantitatively measuring the results of in vitro studies because they are sensitive and provide submicron resolution images. However, these methods are limited in that the optical light through the tissue and autofluorescence backgrounds dramatically reduces the imaging resolution in vivo, which requires minimally invasive methods to apply light in deep tissues [7]. Upconversion nanoparticles that can convert longer near-infrared wavelength light to visible light and drug release can be quantified by measuring the return of luminescent intensity from the NPs when the drug is released [13]. The advantages of upconversion theranostic nanotechnologies are low tissue autofluorescence, deeper tissue penetration of excitation wavelengths, and lower light scattering. We recently developed a radioluminescent theranostic nanotechnology [14,15], in which we converted x-ray energy into visible light, which differs from traditional upconversion nanoparticles in that we used radiation energy as the excitation source. The drug release in vitro can be quantified by measuring the return of luminescent intensity from the nanoparticles when the drug is released. The benefit of our system for measuring drug release is that x-rays can penetrate soft tissues better than near-infrared light without any background autofluorescence [16]. In addition, the limited width of the focused x-ray beam makes it possible to generate high-resolution images in deep tissues, in contrast to fluorescence excitation, in which the excitation beam scatters at a width close to the tissue depth. Visible light emission, unfortunately, still limits the use of radioluminescent theranostic nanotechnologies. future science group

Theranostic nanotechnologies: moving beyond imaging drug localization? Despite the preclinical development of many such second-generation theranostic agents, concerns of biodegradation, toxicity, cost and stability still remain challenges to the development for clinical applications. Preclinical & clinical challenges The instability, inability to provide quantitative data, biodegradation, and high toxicity still hinders the preclinical development of viable theranostic nanotechnologies. Significant low-dose toxicity, associated with the surface properties, shape, impurities and composition of nanomaterials, prohibits the long-term response of cells and tissues to these materials [7]. Ideally, theranostic nanotechnologies should not be toxic at doses required for drug delivery and imaging. They should also be either excreted or degraded upon completing their therapeutic and diagnostic function to limit their interactions with the biological environment. However, preliminary toxicology data of encapsulated quantum dots and silicon nanoparticles in primates indicated no evidence of toxicity within 90 days, which suggests a possible clinical translation [17]. Gold, iron-based, and manganese or gadolinium-loaded theranostic nanotechnologies also demonstrate good biocompatibility. Gold nanoshells and iron nanoparticles are expected to form the basis for developing new iron-based theranostic nanotechnologies due to their clinical success as imaging agent [18]. Although gold, iron-based, and manganeseloaded theranostic nanotechnologies have shown good tissue depth penetration, none of these

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methods differentiate between encapsulated and free drug release. They are all also quite expensive. In addition, drugs activated by visible light (photosensitive) are currently used for the head and neck, and in melanoma and prostate cancers, making the logical use of optimal imaging theranostic nanotechnologies for these applications [19]. While other optical imaging theranostic nanotechnologies have limited deep tissue applications, they can provide quantitative for superficial tissues (e.g., the head and neck, and in melanoma and prostate cancers). There are many theranostic nanotechnologies, all of which have their inherent advantages and limitations; some are particularly useful as drug delivery systems and others are more suitable as imaging agents. Both preclinical and clinical advances of drug delivery and imaging agents are expected to facilitate the development of theranostic nanotechnologies. These new theranostic nanotechnologies must also meet the regulatory requirements that will emerge from their development before they can be used in the clinic [20]. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t­estimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Theranostic nanotechnologies: moving beyond imaging drug localization?

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