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Wound infections, especially those caused by pathogenic bacteria, present a considerable public health concern due to associated complications and poor therapeutic outcomes. Herein, we developed antibacterial nanoparticles, namely, PGTP, by coordinating guanidine derivatives with a porphyrin-based sonosensitizer. The synthesized PGTP nanoparticles, characterized by their strong positive charge, effectively disrupted the bacterial biosynthesis process through charge interference, demonstrating efficacy against both Gram-negative and Gram-positive bacteria. Additionally, PGTP nanoparticles generated reactive oxygen species under ultrasound stimulation, resulting in the disruption of biofilm integrity and efficient elimination of pathogens. RNA-seq analysis unveiled the detailed mechanism of wound healing, revealing that PGTP nanoparticles, when coupled with ultrasound, impair bacterial metabolism by interfering with the synthesis and transcription of amino acids. This study presents a novel approach to combatting wound infections through ultrasound-driven charge-interfering therapy, facilitated by advanced antibacterial nanomaterials.

The rapid progress in the development of COVID-19 mRNA vaccines during the initial year of the pandemic has highlighted the significance of lipid nanoparticles in therapeutic delivery. Various lipid types have been investigated for the effective delivery of mRNA, each with unique functions and versatile applications. These range from their use in cancer immunotherapy and gene editing to their role in developing vaccines against infectious diseases. Nonetheless, continued exploration of novel lipids and synthetic approaches is necessary to further advance the understanding and expand the techniques for optimizing mRNA delivery. In this work, new lipids derived from FDA-approved soybean oil are facilely synthesized and these are employed for efficient mRNA delivery. EGFP and Fluc mRNA are used to evaluate the delivery efficacy of the lipid formulations both in vitro and in vivo. Furthermore, organ-specific targeting capabilities are observed in certain formulations, and their outstanding performance is demonstrated in delivering Cre mRNA for gene editing. These results showcase the potential of soybean oil-derived lipids in mRNA delivery, offering utility across a broad spectrum of bioapplications., (© 2023 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Dual-energy computed tomography (DECT) is a commonly used imaging technique for detecting and diagnosing liver cancer. Currently, it is performed using clinically approved iodinated small molecule contrast agents (CAs). However, these iodinated CAs have several drawbacks, including sub-optimal contrast generation and contra-indication in patients with renal insufficiency. Herein, we synthesized tungsten-based CAs ( i.e. , WO 3- x NPs) with excellent biocompatibility and investigated their effectiveness in DECT imaging. WO 3- x NPs significantly enhanced the contrast between liver tumors and normal liver tissues as indicated by in vivo DECT imaging. Furthermore, WO 3- x NPs exhibited excellent biocompatibility and minimal systemic toxicity. This study introduces a novel class of CAs for DECT and presents a promising method for accurate early diagnosis of liver tumors.

The process of transcatheter arterial chemoembolization is characterized by the ability to accurately deliver chemotherapy drugs with minimal systemic side effects and has become the standard treatment for unresectable intermediate hepatocellular carcinoma (HCC). However, this treatment option still has much room for improvement, one of which may be the introduction of nanomaterials, which exhibit unique functions and can be applied to in vivo tumor imaging and therapy. Several biodegradable and multifunctional nanomaterials and nanobeads have recently been developed and applied in the locoregional treatment of hepatocellular cancer. This review explores recent developments and findings in relation to micro-nano medicines in transarterial therapy for HCC, emerging strategies to improve the efficacy of delivering nano-based medicines, and expounding prospects for clinical applications of nanomaterials., (© 2023. The Author(s).)

During cerebral ischemia-reperfusion (I-R) injury, the infiltration of monocyte/macrophages (M o /M φ ) into the ischemic penumbra causes inflammatory damage but also regulates tissue repair in the penumbra. The regulation and balance of M o /M φ polarization is considered as a potential therapeutic target for treating cerebral I-R injury. Herein, these findings demonstrate that glabridin (Gla)-loaded nanoparticles (i.e., NP Gla -5k) can effectively inhibit M1-polarization and enhance M2-polarization of M o /M φ . Positron emission tomography (PET) imaging shows that NP Gla -5k can selectively accumulate in the spleen following intravenous injection. Spleen-targeted Cy5-NP Gla -5k can co-localize with peripheral macrophages in the penumbra at 24 h after tail-vein injection. Interestingly, NP Gla -5k treatment can reduce inflammatory damage, protect dying neurons, and improve nervous system function. The protective effect of spleen-targeted NP Gla -5k against cerebral I-R injury in mice encourages an exploration of their use for clinical treatment of patients with cerebral I-R injury., (© 2022 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

In recent years, there have been significant innovations in the development of nanoparticle-based vaccines and vaccine delivery systems. For the purposes of both design and evaluation, these nanovaccines are imaged using the wealth of understanding established around medical imaging of nanomaterials. An important insight to the advancement of the field of nanovaccines can be given by an analysis of the design rationale of an imaging platform, as well as the significance of the information provided by imaging. Nanovaccine imaging strategies can be categorized by the imaging modality leveraged, but it is also worth understanding the superiority or convenience of a given modality over others in a given context of a particular nanovaccine. The most important imaging modalities in this endeavor are optical imaging including near-infrared fluorescence imaging (NIRF), emission tomography methods such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) with or without computed tomography (CT) or magnetic resonance (MR), the emerging magnetic particle imaging (MPI), and finally, multimodal applications of imaging which include molecular imaging with magnetic resonance imaging (MRI) and photoacoustic (PA) imaging. One finds that each of these modalities has strengths and weaknesses, but optical and PET imaging tend, in this context, to be currently the most accessible, convenient, and informative modalities. Nevertheless, an important principle is that there is not a one-size-fits-all solution, and that the specific nanovaccine in question must be compatible with a particular imaging modality. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease., (© 2022 Wiley Periodicals LLC.)

Adoptive cell therapy by natural cells for drug delivery has achieved encouraging progress in cancer treatment over small-molecule drugs. Macrophages have a great potential in antitumor drug delivery due to their innate capability of sensing chemotactic cues and homing toward tumors. However, major challenge in current macrophage-based cell therapy is loading macrophages with adequate amounts of therapeutic, while allowing them to play a role in immunity without compromising cell functions. Herein, a potent strategy to construct a macrophage-mediated drug delivery platform loaded with a nanosphere (CpG-ASO-Pt) (CAP) composed of functional nucleic acid therapeutic (CpG-ASO) and chemotherapeutic drug cisplatin (Pt) is demonstrated. These CAP nanosphere loaded macrophages (CAP@M) are employed not only as carriers to deliver this nanosphere toward the tumor sites, but also simultaneously to guide the differentiation and maintain immunostimulatory effects. Both in vitro and in vivo experiments indicate that CAP@M is a promising nanomedicine by macrophage-mediated nanospheres delivery and synergistically immunostimulatory activities. Taken together, this study provides a new strategy to construct a macrophage-based drug delivery system for synergistic chemo-/gene-/immuno-therapy., (© 2022 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

In the field of nanomedicine, there is a tendency of matching designed nanomaterials with a suitable type of orthotopic cancer model, not just a casual subcutaneous one. Under this condition, knowing the specific features of the chosen cancer model is the priority, then introducing a proper therapy strategy using designed nanomaterials. Here, the Fenton chemistry is combined with zinc peroxide nanoparticles in the treatment of orthotopic liver cancer which has a "chemical factory" including that liver is the main place for iron storage, metabolism, and also the main metabolic sites for the majority of ingested substances, guaranteeing customized and enhanced chemodynamic therapy and normal liver cells protection as well. The good results in vitro and in vivo can set an inspiring example for exploring and utilizing suitable nanomaterials in corresponding cancer models, ensuring well-fitness of nanomaterials for disease and satisfactory therapeutic effect., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Theranostic nanoparticles hold the potential to greatly improve cancer management by providing personalized medicine. Although many theranostic nanoconstructs have been successful in preclinical studies, clinical translation is still hampered by their limited targeting capability and lack of successful therapeutic efficacy. We report the use of novel ultrasmall porous silica nanoparticles (UPSN) with enhanced in vivo pharmacokinetics such as high target tissue accumulation (12% ID/g in the tumor) and evasion from the reticuloendothelial system (RES) organs. Herein, UPSN is conjugated with the isotopic pair 90/86 Y, enabling both noninvasive imaging as well as internal radiotherapy. In vivo PET imaging demonstrates prolonged blood circulation and excellent tumor contrast with 86 Y-DOTA-UPSN. Tumor-to-muscle and tumor-to-liver uptake values were significantly high (12.4 ± 1.7 and 1.5 ± 0.5, respectively), unprecedented for inorganic nanomaterials. 90 Y-DOTA-UPSN significantly inhibits tumor growth and increases overall survival, indicating the promise of UPSN for future clinical translation as a cancer theranostic agent.

Advances in technology and nanomedicine have led to the development of nanoparticles that can be activated for multimodal imaging of cancer, where a stimulus induces a material modification that enhances image contrast. Multimodal imaging using nanomaterials with this capability can combine the advantages and overcome the limitations of any single imaging modality. When designed with stimuli-responsive abilities, the target-to-background ratio of multimodal imaging nanoprobes increases because specific stimuli in the tumor enhance the signal. Several aspects of the tumor microenvironment can be exploited as an internal stimulus response for multimodal imaging applications, such as the pH gradient, redox processes, overproduction of various enzymes, or combinations of these. In this review, design strategies are discussed and an overview of the recent developments of internally responsive multimodal nanomaterials is provided. Properly implementing this approach improves noninvasive cancer diagnosis and staging as well as provides a method to monitor drug delivery and treatment response., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hepatic ischemia-reperfusion injury (IRI), which mainly results from excessive reactive oxygen species (ROS) generated by a reperfusion burst of oxygen, has long been a major cause of liver dysfunction and failure after surgical procedures. Here, a monodispersed hydrophilic carbohydrate-derived nanoparticle (C-NP) was synthesized as a nanoantioxidant that could effectively prevent hepatic IRI. The spherical C-NPs had a size of ∼78 ± 11.3 nm covered with polar surface groups. They were well dispersible in water with good colloidal stability, nontoxicity, and good ROS scavenging capability. The C-NPs also exhibited good circulation lifetime, effective delivery to liver, and gradual degradability with an ability to assist the IRI group maintaining a normal and healthy liver status. The pathology mechanism of C-NPs in hepatic IRI was confirmed to be scavenging of excessive ROS by C-NPs. The effective therapeutic treatment of C-NPs in living animals revealed a great potential in clinical prevention for hepatic IRI.

It is important for antitumor drugs to accumulate at the tumor site and penetrate deeply to play a role in treatment. However, it is difficult for the drugs to reach the destination on account of the complex tumor microenvironment such as elevated tumor interstitial fluid pressure (IFP) and solid stress. Here, we report a type of nanocarrier composed entirely of Camellia oleifera protein (COP), which could lower tumor IFP and solid stress. Its physicochemical properties, cellular uptake, in vitro cytotoxicity and tumor perfusion, biodistribution, and in vivo antitumor efficiency were evaluated. It was found that COP NPs had good cellular uptake ability and cytocompatibility. When loading doxorubicin, COP NPs showed an in vitro concentration-dependent cytotoxicity. Importantly, the tumor IFP and solid stress were greatly reduced after injecting COP NPs into tumor-bearing mice, leading to more drug accumulating in the tumor and a longer survival time for tumor-bearing mice. Therefore, our study provided a new strategy to improve the tumor microenvironment and to achieve better antitumor efficiency.

The chirality of nanoparticles directly influences their transport and biological effects under physiological conditions, but the details of this phenomenon have rarely been explored. Herein, chiral GSH-anchored selenium nanoparticles (G@SeNPs) are fabricated to investigate the effect of their chirality on their transport and antioxidant activity. G@SeNPs modified with different enantiomers show opposite handedness with a tunable circular dichroism signal. Noninvasive positron emission tomography imaging clearly reveals that 64 Cu-labeled l-G@SeNPs experience distinctly different transport among the major organs from that of their d-and dl-counterparts, demonstrating that the chirality of the G@SeNPs influences the biodistribution and kinetics. Taking advantage of the strong homologous cell adhesion and uptake, l-G@SeNPs have been shown here to effectively prevent oxidation damage caused by palmitic acid in insulinoma cells., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Nanocarriers are employed to deliver photosensitizers for photodynamic therapy (PDT) through the enhanced penetration and retention effect, but disadvantages including the premature leakage and non-selective release of photosensitizers still exist. Herein, we report a 1 O 2 -responsive block copolymer (POEGMA-b-P(MAA-co-VSPpaMA) to enhance PDT via the controllable release of photosensitizers. Once nanoparticles formed by the block copolymer have accumulated in a tumor and have been taken up by cancer cells, pyropheophorbide a (Ppa) could be controllably released by singlet oxygen ( 1 O 2 ) generated by light irradiation, enhancing the photosensitization. This was demonstrated by confocal laser scanning microscopy and in vivo fluorescence imaging. The 1 O 2 -responsiveness of POEGMA-b-P(MAA-co-VSPpaMA) block copolymer enabled the realization of self-amplified photodynamic therapy by the regulation of Ppa release using NIR illumination. This may provide a new insight into the design of precise PDT., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Oxidative stress is one of the important mechanisms in cerebral ischemia/reperfusion (I/R) injury. Antioxidants with high brain accumulation are highly desired to help prevent cerebral I/R injury. Herein, intrathecal injection of polyoxometalate (POM) nanoclusters as nano-antioxidants with preferential brain uptake were applied for neuronal protection in cerebral I/R injury. Using powerful positron emission tomography imaging, the uptake of nano-antioxidants in the brain was non-invasively and real-timely monitored. Our results demonstrated that POM nanoclusters rapidly reached the ischemic penumbra after intrathecal injection and effectively scavenged reactive oxygen species (ROS) for inhibiting oxidative stress. The infarct size was reduced, and neurological function was restored in cerebral I/R injury rat models. As a proof-of-concept, the intrathecal injection of nano-antioxidants is an excellent therapeutic strategy to ameliorate cerebral I/R injury.

Rapid sequestration and prolonged retention of intravenously injected nanoparticles by the liver and spleen (reticuloendothelial system (RES)) presents a major barrier to effective delivery to the target site and hampers clinical translation of nanomedicine. Inspired by biological macromolecular drugs, synthesis of ultrasmall (diameter ≈12-15 nm) porous silica nanoparticles (UPSNs), capable of prolonged plasma half-life, attenuated RES sequestration, and accelerated hepatobiliary clearance, is reported. The study further investigates the effect of tumor vascularization on uptake and retention of UPSNs in two mouse models of triple negative breast cancer with distinctly different microenvironments. A semimechanistic mathematical model is developed to gain mechanistic insights into the interactions between the UPSNs and the biological entities of interest, specifically the RES. Despite similar systemic pharmacokinetic profiles, UPSNs demonstrate strikingly different tumor responses in the two models. Histopathology confirms the differences in vasculature and stromal status of the two models, and corresponding differences in the microscopic distribution of UPSNs within the tumors. The studies demonstrate the successful application of multidisciplinary and complementary approaches, based on laboratory experimentation and mathematical modeling, to concurrently design optimized nanomaterials, and investigate their complex biological interactions, in order to drive innovation and translation., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

It is essential for nanoparticles to delivery drugs accurately and penetrate deeply to tumor. However, complicated tumor microenvironment such as elevated tumor interstitial fluid pressure (IFP) and solid stress reduces the transport efficiency of nanomedicines in tumor. Methods: We herein report a drug delivery system of phenylboronic acid-decorated soy protein nanoparticles with the size of 30 nm, 50 nm and 150 nm. In vitro examinations including cytotoxicity, cellular uptake and penetration in multicellular tumor spheroids and in vivo observations including IFP and tumor solid stress measurements and antitumor activity were performed. Results: It was found that phenylboronic acid moiety could endow the nanoparticles actively targeting affinity to sialic acid (SA) which overexpressed in tumor cells. Simultaneously soy protein could improve tumor microenvironment such as reduction of IFP and tumor stress. Among the soy protein nanoparticles with different sizes, 30 nm-sized nanoparticles showed the best cellular uptake and highest cytotoxicity in vitro after loading doxorubicin (DOX). In vivo , 30 nm-sized nanoparticles showed the best tumor microenvironment improvement efficiency, leading to the enhanced drug accumulation and antitumor efficiency when combination with DOX. Conclusion: Our study introduces a bioactive nanoparticulate design strategy to actively target and significantly improve tumor microenvironment for enhanced cancer therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The mononuclear phagocyte system (MPS, e.g., liver, spleen) is often treated as a "blackbox" by nanoresearchers in translating nanomedicines. Often, most of the injected nanomaterials are sequestered by the MPS, preventing their delivery to the desired disease areas. Here, this imperfection is exploited by applying nano-antioxidants with preferential liver uptake to directly prevent hepatic ischemia-reperfusion injury (IRI), which is a reactive oxygen species (ROS)-related disease. Ceria nanoparticles (NPs) are selected as a representative nano-antioxidant and the detailed mechanism of preventing IRI is investigated. It is found that ceria NPs effectively alleviate the clinical symptoms of hepatic IRI by scavenging ROS, inhibiting activation of Kupffer cells and monocyte/macrophage cells. The released pro-inflammatory cytokines are then significantly reduced and the recruitment and infiltration of neutrophils are minimized, which suppress subsequent inflammatory reaction involved in the liver. The protective effect of nano-antioxidants against hepatic IRI in living animals and the revealed mechanism herein suggests their future use for the treatment of hepatic IRI in the clinic., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Positron emission tomography (PET) provides quantitative information in vivo with ultra-high sensitivity but is limited by its relatively low spatial resolution. Therefore, PET has been combined with other imaging modalities, and commercial systems such as PET/computed tomography (CT) and PET/magnetic resonance (MR) have become available. Inspired by the emerging field of nanomedicine, many PET-based multimodality nanoparticle imaging agents have been developed in recent years. This Minireview highlights recent progress in the design of PET-based multimodality imaging nanoprobes with an aim to overview the major advances and key challenges in this field and substantially improve our knowledge of this fertile research area., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Manganese-based nanoparticles (NPs) have recently attracted much attention in the field of biomedical imaging due to their impressive enhanced T1 contrast ability. Although the reported manganese-based NPs have exhibited good imaging capabilities as contrast agents, it is still urgent to develop novel multifunctional manganese-based imaging probes for future biomedical imaging, especially PET/MRI probes. Herein, we present chelator-free zirconium-89 (89Zr, t1/2: 78.4 h) labeling of manganese oxide NPs (Mn3O4@PEG) with ∼78% labeling yield and good stability. Serial positron emission tomography (PET) and magnetic resonance imaging (MRI) studies non-invasively assessed the biodistribution patterns of the NPs and the feasibility of in vivo dual-modality imaging and lymph-node mapping. Since Mn3O4 NPs exhibited desirable properties for enhanced T1 imaging and the simplicity of chelator-free radiolabeling, [89Zr]Mn3O4@PEG NPs offer a novel, simple, safe and accurate nanoplatforms for future precise cancer imaging and diagnosis.

The importance of medical imaging in the diagnosis and monitoring of cancer cannot be overstated. As personalized cancer treatments are gaining popularity, a need for more advanced imaging techniques has grown significantly. Nanoparticles are uniquely suited to fill this void, not only as imaging contrast agents but also as companion diagnostics. This review provides an overview of many ways nanoparticle imaging agents have contributed to cancer imaging, both preclinically and in the clinic, as well as charting future directions in companion diagnostics. We conclude that, while nanoparticle-based imaging agents are not without considerable scientific and developmental challenges, they enable enhanced imaging in nearly every modality, hold potential as in vivo companion diagnostics, and offer precise cancer treatment and maximize intervention efficacy.

As one of the most biocompatible and well-tolerated inorganic nanomaterials, silica-based nanoparticles (SiNPs) have received extensive attention over the last several decades. Recently, positron emission tomography (PET) imaging of radiolabeled SiNPs has provided a highly sensitive, noninvasive, and quantitative readout of the organ/tissue distribution, pharmacokinetics, and tumor targeting efficiency in vivo, which can greatly expedite the clinical translation of these promising NPs. Encouraged by the successful PET imaging of patients with metastatic melanoma using 124 I-labeled ultrasmall SiNPs (known as Cornell dots or C dots) and their approval as an Investigational New Drug (IND) by the United States Food and Drug Administration, different radioisotopes ( 64 Cu, 89 Zr, 18 F, 68 Ga, 124 I, etc.) have been reported to radiolabel a wide variety of SiNPs-based nanostructures, including dense silica (dSiO 2 ), mesoporous silica (MSN), biodegradable mesoporous silica (bMSN), and hollow mesoporous silica nanoparticles (HMSN). With in-depth knowledge of coordination chemistry, abundant silanol groups (-Si-O-) on the silica surface or inside mesoporous channels not only can be directly used for chelator-free radiolabeling but also can be readily modified with the right chelators for chelator-based labeling. However, integrating these labeling strategies for constructing stably radiolabeled SiNPs with high efficiency has proven difficult because of the complexity of the involved key parameters, such as the choice of radioisotopes and chelators, nanostructures, and radiolabeling strategy. In this Account, we present an overview of recent progress in the development of radiolabeled SiNPs for cancer theranostics in the hope of speeding up their biomedical applications and potential translation into the clinic. We first introduce the basic principles and mechanisms for radiolabeling SiNPs via coordination chemistry, including general rules of selecting proper radioisotopes, engineering silica nanoplatforms (e.g., dSiO 2 , MSN, HMSN) accordingly, and chelation strategies for enhanced labeling efficiency and stability, on which our group has focused over the past decade. Generally, the medical applications guide the choice of specific SiNPs for radiolabeling by considering the inherent functionality of SiNPs. The radioisotopes can then be determined according to the amenability of the particular SiNPs for chelator-based or chelator-free radiolabeling to obtain high labeling stability in vivo, which is a prerequisite for PET to truly reflect the behavior of SiNPs since PET imaging detects the isotopes rather than nanoparticles. Next, we highlight several recent representative biomedical applications of radiolabeled SiNPs including molecular imaging to detect specific lesions, PET-guided drug delivery, SiNP-based theranostic cancer agents, and clinical studies. Finally, the challenges and prospects of radiolabeled SiNPs are briefly discussed toward clinical cancer research. We hope that this Account will clarify the recent progress on the radiolabeling of SiNPs for specific medical applications and generate broad interest in integrating nanotechnology and PET imaging. With several ongoing clinical trials, radiolabeled SiNPs offer great potential for future patient stratification and cancer management in clinical settings.

The benefits to intracellular drug delivery from nanomedicine have been limited by biological barriers and to some extent by targeting capability. We investigated a size-controlled, dual tumor-mitochondria-targeted theranostic nanoplatform (Porphyrin-PEG Nanocomplexes, PPNs). The maximum tumor accumulation (15.6 %ID g -1 , 72 h p.i.) and ideal tumor-to-muscle ratio (16.6, 72 h p.i.) was achieved using an optimized PPN particle size of approximately 10 nm, as measured by using PET imaging tracing. The stable coordination of PPNs with 177 Lu enables the integration of fluorescence imaging (FL) and photodynamic therapy (PDT) with positron emission tomography (PET) imaging and internal radiotherapy (RT). Furthermore, the efficient tumor and mitochondrial uptake of 177 Lu-PPNs greatly enhanced the efficacies of RT and/or PDT. This work developed a facile approach for the fabrication of tumor-targeted multi-modal nanotheranostic agents, which enables precision and radionuclide-based combination tumor therapy., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Magnetic resonance imaging (MRI) is a highly valuable non-invasive imaging tool owing to its exquisite soft tissue contrast, high spatial resolution, lack of ionizing radiation, and wide clinical applicability. Contrast agents (CAs) can be used to further enhance the sensitivity of MRI to obtain information-rich images. Recently, extensive research efforts have been focused on the design and synthesis of high-performance inorganic nanoparticle-based CAs to improve the quality and specificity of MRI. Herein, the basic rules, including the choice of metal ions, effect of electron motion on water relaxation, and involved mechanisms, of CAs for MRI have been elucidated in detail. In particular, various design principles, including size control, surface modification (e.g. organic ligand, silica shell, and inorganic nanolayers), and shape regulation, to impact relaxation of water molecules have been discussed in detail. Comprehensive understanding of how these factors work can guide the engineering of future inorganic nanoparticles with high relaxivity. Finally, we have summarized the currently available strategies and their mechanism for obtaining high-performance CAs and discussed the challenges and future developments of nanoparticulate CAs for clinical translation in MRI.

Manganese oxide nanoparticles (Mn 3 O 4 NPs) have attracted a great deal of attention in the field of biomedical imaging because of their ability to create an enhanced imaging signal in MRI as novel potent T 1 contrast agents. In this study, we present tumor vasculature-targeted imaging in mice using Mn 3 O 4 NPs through conjugation to the anti-CD105 antibody TRC105 and radionuclide copper-64 ( 64 Cu, t 1/2 : 12.7 h). The Mn 3 O 4 conjugated NPs, 64 Cu-NOTA-Mn 3 O 4 @PEG-TRC105, exhibited sufficient stability in vitro and in vivo. Serial positron emission tomography (PET) and magnetic resonance imaging (MRI) studies evaluated the pharmacokinetics and demonstrated targeting of 64 Cu-NOTA-Mn 3 O 4 @PEG-TRC105 to 4T1 murine breast tumors in vivo, compared to 64 Cu-NOTA-Mn 3 O 4 @PEG. The specificity of 64 Cu-NOTA-Mn 3 O 4 @PEG-TRC105 for the vascular marker CD105 was confirmed through in vivo, in vitro, and ex vivo experiments. Since Mn 3 O 4 conjugated NPs exhibited desirable properties for T 1 enhanced imaging and low toxicity, the tumor-specific Mn 3 O 4 conjugated NPs reported in this study may serve as promising multifunctional nanoplatforms for precise cancer imaging and diagnosis.

Developing tumor-homing nanoparticles with integrated diagnostic and therapeutic functions, and meanwhile could be rapidly excreted from the body, would be of great interest to realize imaging-guided precision treatment of cancer. In this study, an ultrasmall coordination polymer nanodot (CPN) based on the coordination between tungsten ions (W VI ) and gallic acid (W-GA) was developed via a simple method. After polyethylene glycol (PEG) modification, PEGylated W-GA (W-GA-PEG) CPNs with an ultrasmall hydrodynamic diameter of 5 nm were rather stable in various physiological solutions. Without the need of chelator molecules, W-GA-PEG CPNs could be efficiently labeled with radioisotope 64 Cu 2+ , enabling positron emission tomography (PET) imaging, which reveals efficient tumor accumulation and rapid renal clearance of W-GA-PEG CPNs upon intravenous injection. Utilizing the radio-sensitizing function of tungsten with strong X-ray absorption, such W-GA-PEG CPNs were able to greatly enhance the efficacy of cancer radiotherapy in inhibiting the tumor growth. With fast clearance and little long-term body retention, those W-GA-PEG CPNs exhibited no appreciable in vivo toxicity. This study presents a type of CPNs with excellent imaging and therapeutic abilities as well as rapid renal clearance behavior, promising for further clinic translation.

Over the last few years, a plethora of radiolabeled inorganic nanoparticles have been developed and evaluated for their potential use as probes in positron emission tomography (PET) imaging of a wide variety of cancers. Inorganic nanoparticles represent an emerging paradigm in molecular imaging probe design, allowing the incorporation of various imaging modalities, targeting ligands, and therapeutic payloads into a single vector. A major challenge in this endeavor is to develop disease-specific nanoparticles with facile and robust radiolabeling strategies. Also, the radiolabeled nanoparticles should demonstrate adequate in vitro and in vivo stability, enhanced sensitivity for detection of disease at an early stage, optimized in vivo pharmacokinetics for reduced non-specific organ uptake, and improved targeting for achieving high efficacy. Owing to these challenges and other technological and regulatory issues, only a single radiolabeled nanoparticle formulation, namely "C-dots" (Cornell dots), has found its way into clinical trials thus far. This review describes the available options for radiolabeling of nanoparticles and summarizes the recent developments in PET imaging of cancer in preclinical and clinical settings using radiolabeled nanoparticles as probes. The key considerations toward clinical translation of these novel PET imaging probes are discussed, which will be beneficial for advancement of the field.

Titanium-45 ( 45 Ti) with a three-hour half-life (t 1/2 =3.08 h), low maximum positron energy and high positron emission branching ratio, is a suitable positron emission tomography (PET) isotope whose potential has not yet been fully explored. Complicated radiochemistry and rapid hydrolysis continue to be major challenges to the development of 45 Ti compounds based on a traditional chelator-based radiolabeling strategy. In this study we introduced an intrinsic (or chelator-free) radiolabeling technique for the successful labeling of 45 Ti using mesoporous silica nanoparticle (MSN). We synthesized uniform MSN with an average particle size of ∼150 nm in diameter. The intrinsic 45 Ti-labeling was accomplished through strong interactions between 45 Ti (hard Lewis acid) and hard oxygen donors (hard Lewis bases), the deprotonated silanol groups (-Si-O-) from the outer surface and inner meso-channels of MSN. In vivo tumor-targeted PET imaging of as-developed PEGylated [ 45 Ti]MSN was further demonstrated in the 4T1 murine breast tumor-bearing mice. This MSN-based intrinsic radiolabeling strategy could open up new possibilities and speed up the biomedical applications of 45 Ti in the future.

Although various types of imaging agents have been developed for photoacoustic (PA) imaging, relatively few imaging agents exhibit high selectivity/sensitivity to the tumor microenvironment for on-demand PA imaging and therapy. Herein, molybdenum-based polyoxometalate (POM) clusters with the highest oxidation state of Mo(VI) (denoted as Ox-POM) were designed as novel agents for redox-activated PA imaging-guided photothermal therapy. Capable of escaping from recognition and capture by the liver and spleen, these renal clearable clusters with ultrasmall size (hydrodynamic size: 1.9 nm) can accumulate in the tumor, self-assemble into larger nanoclusters at low pH, and are reduced to NIR absorptive agents in the tumor microenvironment. Studies in 4T1 tumor-bearing mice indicated that these clusters could be employed for bioresponsive PA imaging-guided tumor ablation in vivo. Our finding is expected to establish a new physicochemical paradigm for the design of PA imaging agents based on clusters, bridging the conventional concepts of "molecule" and "nano" in the bioimaging field.

Development of novel imaging probes for cancer diagnosis is critical for early disease detection and management. The past two decades have witnessed a surge in the development and evolution of radiolabeled nanoparticles as a new frontier in personalized cancer nanomedicine. The dynamic synergism of positron emission tomography (PET) and nanotechnology combines the sensitivity and quantitative nature of PET with the multifunctionality and tunability of nanomaterials, which can help overcome certain key challenges in the field. In this review, we discuss the recent advances in radionanomedicine, exemplifying the ability to tailor the physicochemical properties of nanomaterials to achieve optimal in vivo pharmacokinetics and targeted molecular imaging in living subjects. Innovations in development of facile and robust radiolabeling strategies and biomedical applications of such radionanoprobes in cancer theranostics are highlighted. Imminent issues in clinical translation of radiolabeled nanomaterials are also discussed, with emphasis on multidisciplinary efforts needed to quickly move these promising agents from bench to bedside., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Macrocyclic chelators have been widely employed in the realm of nanoparticle-based positron emission tomography (PET) imaging, whereas its accuracy remains questionable. Here, we found that 64 Cu can be intrinsically labeled onto nanographene based on interactions between Cu and the π electrons of graphene without the need of chelator conjugation, providing a promising alternative radiolabeling approach that maintains the native in vivo pharmacokinetics of the nanoparticles. Due to abundant π bonds, reduced graphene oxide (RGO) exhibited significantly higher labeling efficiency in comparison with graphene oxide (GO) and exhibited excellent radiostability in vivo. More importantly, nonspecific attachment of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) on nanographene was observed, which revealed that chelator-mediated nanoparticle-based PET imaging has its inherent drawbacks and can possibly lead to erroneous imaging results in vivo., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The development of new image-guided drug delivery tools to improve the therapeutic efficacy of chemotherapeutics remains an important goal in nanomedicine. Using labeling strategies that involve radioelements that have theranostic pairs of diagnostic positron-emitting isotopes and therapeutic electron-emitting isotopes has promise in achieving this goal and further enhancing drug performance through radiotherapeutic effects. The isotopes of radioarsenic offer such theranostic potential and would allow for the use of positron emission tomography (PET) for image-guided drug delivery studies of the arsenic-based chemotherapeutic arsenic trioxide (ATO). Thiolated mesoporous silica nanoparticles (MSN) are shown to effectively and stably bind cyclotron-produced radioarsenic. Labeling studies elucidate that this affinity is a result of specific binding between trivalent arsenic and nanoparticle thiol surface modification. Serial PET imaging of the in vivo murine biodistribution of radiolabeled silica nanoparticles shows very good stability toward dearsenylation that is directly proportional to silica porosity. Thiolated MSNs are found to have a macroscopic arsenic loading capacity of 20 mg of ATO per gram of MSN, sufficient for delivery of chemotherapeutic quantities of the drug. These results show the great potential of radioarsenic-labeled thiolated MSN for the preparation of theranostic radiopharmaceuticals and image-guided drug delivery of ATO-based chemotherapeutics.

While position emission tomography (PET) is an important molecular imaging technique for both preclinical research and clinical disease diagnosis/prognosis, chelator-free radiolabeling has emerged as a promising alternative approach to label biomolecules or nanoprobes in a facile way. Herein, starting from bottom-up synthesized WS 2 nanoflakes, this study fabricates a unique type of WS 2 /WO x nanodots, which can function as inherent hard oxygen donor for stable radiolabeling with Zirconium-89 isotope ( 89 Zr). Upon simply mixing, 89 Zr can be anchored on the surface of polyethylene glycol (PEG) modified WS 2 /WO x (WS 2 /WO x -PEG) nanodots via a chelator-free method with surprisingly high labeling yield and great stability. A higher degree of oxidation in the WS 2 /WO x -PEG sample (WS 2 /WO x (0.4)) produces more electron pairs, which would be beneficial for chelator-free labeling of 89 Zr with higher yields, suggesting the importance of surface chemistry and particle composition to the efficiency of chelator-free radiolabeling. Such 89 Zr-WS 2 /WO x (0.4)-PEG nanodots are found to be an excellent PET contrast agent for in vivo imaging of tumors upon intravenous administration, or mapping of draining lymph nodes after local injection., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Traditional photodynamic therapy (PDT) requires external light to activate photosensitizers for therapeutic purposes. However, the limited tissue penetration of light is still a major challenge for this method. To overcome this limitation, we report an optimized system that uses Cerenkov radiation for PDT by using radionuclides to activate a well-known photosensitizer (chlorin e6, Ce6). By taking advantage of hollow mesoporous silica nanoparticles (HMSNs) that can intrinsically radiolabel an oxophilic zirconium-89 ( 89 Zr, t 1/2 = 78.4 h) radionuclide, as well as possess great drug loading capacity, Ce6 can be activated by Cerenkov radiation from 89 Zr in the same nanoconstruct. In vitro cell viability experiments demonstrated dose-dependent cell deconstruction as a function of the concentration of Ce6 and 89 Zr. In vivo studies show inhibition of tumor growth when mice were subcutaneously injected with [ 89 Zr]HMSN-Ce6, and histological analysis of the tumor section showed damage to tumor tissues, implying that reactive oxygen species mediated the destruction. This study offers a way to use an internal radiation source to achieve deep-seated tumor therapy without using any external light source for future applications.

As peripheral arterial disease (PAD) results in muscle ischemia and neovascularization, it has been claimed that nanoparticles can passively accumulate in ischemic tissues through the enhanced permeability and retention (EPR) effect. At this time, a quantitative evaluation of the passive targeting capabilities of nanoparticles has not been reported in PAD. Using a murine model of hindlimb ischemia, we quantitatively assessed the passive targeting capabilities of (64)Cu-labeled PEGylated reduced graphene oxide - iron oxide nanoparticles ((64)Cu-RGO-IONP-PEG) through the EPR effect using positron emission tomography (PET) imaging. Serial laser Doppler imaging was performed to monitor changes in blood perfusion upon surgical induction of ischemia. Nanoparticle accumulation was assessed at 3, 10, and 17 days post-surgery and found to be highest at 3 days post-surgery, with the ischemic hindlimb displaying an accumulation of 14.7 ± 0.5% injected dose per gram (%ID/g). Accumulation of (64)Cu-RGO-IONP-PEG was lowest at 17 days post-surgery, with the ischemic hindlimb displaying only 5.1 ± 0.5%ID/g. Furthermore, nanoparticle accumulation was confirmed by photoacoustic imaging (PA). The combination of PET and serial Doppler imaging showed that nanoparticle accumulation in the ischemic hindlimb negatively correlated with blood perfusion. Thus, we quantitatively confirmed that (64)Cu-RGO-IONP-PEG passively accumulated in ischemic tissue via the EPR effect, which is reduced as the perfusion normalizes. As (64)Cu-RGO-IONP-PEG displayed substantial accumulation in the ischemic tissue, this nanoparticle platform may function as a future theranostic agent, providing both imaging and therapeutic applications., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Multifunctional nanoparticles with combined diagnostic and therapeutic functions show great promise in nanomedicine. Herein, we develop an organic photodynamic therapy (PDT) system based on polyethylene glycol (PEG)-coated nanomicelles conjugated with ∼20% chlorin e6 (PEG-Ce 6 nanomicelles), which functions as an optical imaging agent, as well as a PDT agent. The formed PEG-Ce 6 nanomicelles with the size of ∼20 nm were highly stable in various physiological solutions for a long time. Moreover, Ce 6 can also be a (64)Cu chelating agent for in vivo positron emission tomography (PET). By simply mixing, more than 90% of (64)Cu was chelator-free labeled on PEG-Ce 6 nanomicelles, and they also showed high stability in serum conditions. Both fluorescence imaging and PET imaging revealed that PEG-Ce 6 nanomicelles displayed high tumor uptake (13.7 ± 2.2%ID/g) after intravenous injection into tumor-bearing mice at the 48 h time point. In addition, PEG-Ce 6 nanomicelles exhibited excellent PDT properties upon laser irradiation, confirming the theranostic properties of PEG-Ce 6 nanomicelles for imaging and treatment of cancer. In addition, PDT was not shown to render any appreciable toxicity. This work presents a theranostic platform based on polymer nanomicelles with great potential in multimodality imaging-guided photodynamic cancer therapy.

Peripheral arterial disease (PAD) is a leading global health concern. Due to limited imaging and therapeutic options, PAD and other ischemia-related diseases may benefit from the use of long circulating nanoparticles as imaging probes and/or drug delivery vehicles. Polyethylene glycol (PEG)-conjugated nanoparticles have shown shortened circulation half-lives in vivo when injected multiple times into a single subject. This phenomenon has become known as the accelerated blood clearance (ABC) effect. The phenomenon is of concern for clinical translation of nanomaterials as it limits the passive accumulation of nanoparticles in many diseases, yet it has not been evaluated using inorganic or organic-inorganic hybrid nanoparticles. Herein, we found that the ABC phenomenon was induced by reinjection of PEGylated long circulating organic-inorganic hybrid nanoparticles, which significantly reduced the passive targeting of (64)Cu-labeled PEGylated reduced graphene oxide-iron oxide nanoparticles ((64)Cu-RGO-IONP-PEG) in a murine model of PAD. Positron emission tomography (PET) imaging was performed at 3, 10, and 17 days postsurgical induction of hindlimb ischemia. At day 3 postsurgery, the nanoparticles displayed a long circulation half-life with enhanced accumulation in the ischemic hindlimb. At days 10 and 17 postsurgery, reinjected mice displayed a short circulation half-life and lower accumulation of the nanoparticles in the ischemic hindlimb, in comparison to the naïve group. Also, reinjected mice showed significantly higher liver uptake than the naïve group, indicating that the nanoparticles experienced higher sequestration by the liver in the reinjected group. Furthermore, photoacoustic (PA) imaging and Prussian blue staining confirmed the enhanced accumulation of the nanoparticles in the liver tissue of reinjected mice. These findings validate the ABC phenomenon using long circulating organic-inorganic hybrid nanoparticles upon multiple administrations to the same animal, which may provide valuable insight into the future clinical applications of nanoparticles for imaging and treatment of PAD.

Polyethylene glycol (PEG) surface modification is one of the most widely used approaches to improve the solubility of inorganic nanoparticles, prevent their aggregation and prolong their in vivo blood circulation half-life. Herein, we developed double-PEGylated biocompatible reduced graphene oxide nanosheets anchored with iron oxide nanoparticles (RGO-IONP-(1st)PEG-(2nd)PEG). The nanoconjugates exhibited a prolonged blood circulation half-life (∼27.7 h) and remarkable tumor accumulation (>11 %ID g(-1)) via an enhanced permeability and retention (EPR) effect. Due to the strong near-infrared absorbance and superparamagnetism of RGO-IONP-(1st)PEG-(2nd)PEG, multimodality imaging combining positron emission tomography (PET) imaging with magnetic resonance imaging (MRI) and photoacoustic (PA) imaging was successfully achieved. The promising results suggest the great potential of these nanoconjugates for multi-dimensional and more accurate tumor diagnosis and therapy in the future.

Achieving effective treatment of deep-seated tumors is a major challenge for traditional photodynamic therapy (PDT) due to difficulties in delivering light into the subsurface. Thanks to their great tissue penetration, X-rays hold the potential to become an ideal excitation source for activating photosensitizers (PS) that accumulate in deep tumor tissue. Recently, a wide variety of nanoparticles have been developed for this purpose. The nanoparticles are designed as carriers for loading various kinds of PSs and can facilitate the activation process by transferring energy harvested from X-ray irradiation to the loaded PS. In this review, we focus on recent developments of nanoscintillators with high energy transfer efficiency, their rational designs, as well as potential applications in next-generation PDT. Treatment of deep-seated tumors by using radioisotopes as an internal light source will also be discussed.

Layered double hydroxide (LDH) nanomaterial has emerged as a novel delivery agent for biomedical applications due to its unique structure and properties. However, in vivo positron emission tomography (PET) imaging with LDH nanoparticles has not been achieved. The aim of this study is to explore chelator-free labeling of LDH nanoparticles with radioisotopes for in vivo PET imaging. Bivalent cation (64)Cu(2+) and trivalent cation (44)Sc(3+) were found to readily label LDH nanoparticles with excellent labeling efficiency and stability, whereas tetravalent cation (89)Zr(4+) could not label LDH since it does not fit into the LDH crystal structure. PET imaging shows that prominent tumor uptake was achieved in 4T1 breast cancer with (64)Cu-LDH-BSA via passive targeting alone (7.7 ± 0.1%ID/g at 16 h post-injection; n = 3). These results support that LDH is a versatile platform that can be labeled with various bivalent and trivalent radiometals without comprising the native properties, highly desirable for PET image-guided drug delivery.

Traditional chelator-based radio-labeled nanoparticles and positron emission tomography (PET) imaging are playing vital roles in the field of nano-oncology. However, their long-term in vivo integrity and potential mismatch of the biodistribution patterns between nanoparticles and radio-isotopes are two major concerns for this approach. Here, we present a chelator-free zirconium-89 ((89)Zr, t1/2 = 78.4 h) labeling of mesoporous silica nanoparticle (MSN) with significantly enhanced in vivo long-term (>20 days) stability. Successful radio-labeling and in vivo stability are demonstrated to be highly dependent on both the concentration and location of deprotonated silanol groups (-Si-O(-)) from two types of silica nanoparticles investigated. This work reports (89)Zr-labeled MSN with a detailed labeling mechanism investigation and long-term stability study. With its attractive radio-stability and the simplicity of chelator-free radio-labeling, (89)Zr-MSN offers a novel, simple, and accurate way for studying the in vivo long-term fate and PET image-guided drug delivery of MSN in the near future.

Hexamodal imaging using simple nanoparticles is demonstrated. Porphyrin-phospholipids are used to coat upconversion nanoparticles in order to generate a new biocompatible material. The nanoparticles are characterized in vitro and in vivo for imaging via fluorescence, upconversion, positron emission tomography, computed tomography, Cerenkov luminescence, and photoacoustic tomography., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aim: Development of multifunctional and well-dispersed hollow mesoporous silica nanoparticles (HMSNs) for tumor vasculature targeted drug delivery and PET imaging., Materials & Methods: Amine functionalized HMSNs (150-250 nm) were conjugated with a macrocyclic chelator, (S)-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triaceticacid (NOTA), PEGylated and loaded with antiangiogenesis drug, Sunitinib. Cyclo(Arg-Gly-Asp-D-Tyr-Lys) (cRGDyK) peptide was attached to the nanoconjugate and radiolabeled with (64)Cu for PET imaging., Results: (64)Cu-NOTA-HMSN-PEG-cRGDyK exhibited integrin-specific uptake both in vitro and in vivo. PET results indicated approximately 8% ID/g uptake of targeted nanoconjugates in U87MG tumors, which correlated well with ex vivo and histological analyses. Enhanced tumor-targeted delivery of sunitinib was also observed., Conclusion: We successfully developed tumor vasculature targeted HMSNs for PET imaging and image-guided drug delivery.

The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling cascade plays a critical role in tumor angiogenesis and metastasis and has been correlated with several poorly prognostic cancers such as malignant gliomas. Although a number of anti-VEGFR therapies have been conceived, inefficient drug administration still limits their therapeutic efficacy and raises concerns of potential side effects. In the present work, we propose the use of uniform mesoporous silica nanoparticles (MSNs) for VEGFR targeted positron emission tomography imaging and delivery of the anti-VEGFR drug (i.e., sunitinib) in human glioblastoma (U87MG) bearing murine models. MSNs were synthesized, characterized and modified with polyethylene glycol, anti-VEGFR ligand VEGF121 and radioisotope (64)Cu, followed by extensive in vitro, in vivo and ex vivo studies. Our results demonstrated that a significantly higher amount of sunitinib could be delivered to the U87MG tumor by targeting VEGFR when compared with the non-targeted counterparts. The as-developed VEGF121-conjugated MSN could become another attractive nanoplatform for the design of future theranostic nanomedicine.

Theranostic nanoparticles hold the potential to revolutionize disease management. Over the last decade, there has been growing interest in the engineering of various kinds of theranostic nanoparticles for simultaneous cancer imaging and therapy in small animals. Efficient targeting of theranostic nanoparticles to the tumor site is critical for both diagnosis and therapy. However, difficulties still exist in the engineering of biocompatible theranostic nanoparticles with highly specific in vivo tumor-targeting capabilities. Here, we discuss the current and prospective status of theranostic nanoparticles that actively target tumors, as well as the challenges that still exist., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Multifunctional mesoporous silica nanoparticles (MSN) with well-integrated multimodality imaging properties have generated increasing research interest in the past decade. However, limited progress has been made in developing MSN-based multimodality imaging agents to image tumors. We describe the successful conjugation of, copper-64 ((64)Cu, t1/2 = 12.7 h), 800CW (a near-infrared fluorescence [NIRF] dye), and TRC105 (a human/murine chimeric IgG1 monoclonal antibody) to the surface of MSN via well-developed surface engineering procedures, resulting in a dual-labeled MSN for in vivo targeted positron emission tomography (PET) imaging/NIRF imaging of the tumor vasculature. Pharmacokinetics and tumor targeting efficacy/specificity in 4T1 murine breast tumor-bearing mice were thoroughly investigated through various in vitro, in vivo, and ex vivo experiments. Dual-labeled MSN is an attractive candidate for future cancer theranostics.

Although chelator-based radiolabeling techniques have been used for decades, concerns about the complexity of coordination chemistry, possible altering of pharmacokinetics of carriers, and potential detachment of radioisotopes during imaging have driven the need for developing a simple yet better technique for future radiolabeling. Here, the emerging concept of intrinsically radiolabeled nanoparticles, which could be synthesized using methods such as hot-plus-cold precursors, specific trapping, cation exchange, and proton beam activation, is introduced. Representative examples of using these multifunctional nanoparticles for multimodality molecular imaging are highlighted together with current challenges and future research directions. Although still in the early stages, design and synthesis of intrinsically radiolabeled nanoparticles has shown attractive potential to offer easier, faster, and more specific radiolabeling possibilities for the next generation of molecular imaging., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

There is a need for safer and improved methods for non-invasive imaging of the gastrointestinal tract. Modalities based on X-ray radiation, magnetic resonance and ultrasound suffer from limitations with respect to safety, accessibility or lack of adequate contrast. Functional intestinal imaging of dynamic gut processes has not been practical using existing approaches. Here, we report the development of a family of nanoparticles that can withstand the harsh conditions of the stomach and intestine, avoid systemic absorption, and provide good optical contrast for photoacoustic imaging. The hydrophobicity of naphthalocyanine dyes was exploited to generate purified ∼ 20 nm frozen micelles, which we call nanonaps, with tunable and large near-infrared absorption values (>1,000). Unlike conventional chromophores, nanonaps exhibit non-shifting spectra at ultrahigh optical densities and, following oral administration in mice, passed safely through the gastrointestinal tract. Non-invasive, non-ionizing photoacoustic techniques were used to visualize nanonap intestinal distribution with low background and remarkable resolution, and enabled real-time intestinal functional imaging with ultrasound co-registration. Positron emission tomography following seamless nanonap radiolabelling allowed complementary whole-body imaging.