Imaging-Guided Metabolic Radiosensitization of Pediatric Rhabdoid Tumors.

Tumor hypoxia leads to increased resistance to radiation therapy (RT), resulting in markedly worse clinical outcomes in the treatment and management of pediatric malignant rhabdoid tumors (MRT). To alleviate hypoxia in MRT, we repurposed an FDA approved, mitochondrial oxidative phosphorylation (OXPHOS) inhibitor, Atovaquone (AVO), to inhibit oxygen consumption and thereby enhance the sensitivity of tumor cells to low dose RT in MRT by hypoxia alleviation. Additionally, to better understand the tumor response induced by AVO and optimize the combination with RT, we employed an emerging, noninvasive imaging modality, known as multispectral optoacoustic tomography (MSOT), to monitor and evaluate real-time dynamic changes in tumor hypoxia and vascular perfusion. Oxygen-Enhanced (OE)-MSOT could measure the change of tumor oxygenation in the MRT xenograft models after AVO and RT treatments, indicating its potential as a response biomarker. OE-MSOT showed that treating MRT mouse models with AVO resulted in a transient increase in oxygen saturation (ΔsO 2 ) in tumors when the mice were subjected to oxygen challenge, while RT or saline treated groups produced no change. In AVO+RT combination groups, the tumors showed an increase in ΔsO 2 after AVO administration followed by a significant decrease after RT, that correlated with a strong anti-tumor response, demarcated by complete regression of tumors, with no relapse on long-term monitoring. These observations were histologically validated. In MRT models of acquired AVO resistance, combination therapy failed to alleviate tumoral hypoxia and elicit any therapeutic benefit. Together, our data highlights the utility of repurposing anti-malarial AVO as an anticancer adjuvant for enabling low dose RT for pediatric patients.

Molecular imaging of innate immunity and immunotherapy.

The innate immune system plays a key role as the first line of defense in various human diseases including cancer, cardiovascular and inflammatory diseases. In contrast to tissue biopsies and blood biopsies, in vivo imaging of the innate immune system can provide whole body measurements of immune cell location and function and changes in response to disease progression and therapy. Rationally developed molecular imaging strategies can be used in evaluating the status and spatio-temporal distributions of the innate immune cells in near real-time, mapping the biodistribution of novel innate immunotherapies, monitoring their efficacy and potential toxicities, and eventually for stratifying patients that are likely to benefit from these immunotherapies. In this review, we will highlight the current state-of-the-art in noninvasive imaging techniques for preclinical imaging of the innate immune system particularly focusing on cell trafficking, biodistribution, as well as pharmacokinetics and dynamics of promising immunotherapies in cancer and other diseases; discuss the unmet needs and current challenges in integrating imaging modalities and immunology and suggest potential solutions to overcome these barriers.

Ultrasmall silica nanoparticles in translational biomedical research: Overview and outlook.

The exemplary progress of silica nanotechnology has attracted extensive attention across a range of biomedical applications such as diagnostics and imaging, drug delivery, and therapy of cancer and other diseases. Ultrasmall silica nanoparticles (USNs) have emerged as a particularly promising class demonstrating unique properties that are especially suitable for and have shown great promise in translational and clinical biomedical research. In this review, we discuss synthetic strategies that allow precise engineering of USNs with excellent control over size and surface chemistry, functionalization, and pharmacokinetic and toxicological profiles. We summarize the current state-of-the-art in the biomedical applications of USNs with a particular focus on select clinical studies. Finally, we illustrate long-standing challenges in the translation of inorganic nanotechnology, particularly in the context of ultrasmall nanomedicines, and provide our perspectives on potential solutions and future opportunities in accelerating the translation and widespread adoption of USN technology in biomedical research.

Accuracy of Bronchial Cytological Diagnosis in Lung Lesions in Comparison with Histopathology.

The incidence of lung cancer has been increasing in the recent years. Bronchial cytology using Papanicolaou society of cytopathology (PSC) system is an effective method for triaging patients. The present study attempts to evaluate the bronchial cytological diagnosis with histopathological correlation of lung lesions. Aims: i. To study the cytological features of lung lesions. ii. To assess the sensitivity, specificity, and diagnostic accuracy of bronchial cytology of lung lesions in comparison with histopathology. Settings and Design: Prospective study at the tertiary care hospital. Methods and Material: It included 63 cases of lung lesions, evaluated using the PSC system for reporting respiratory cytology. The cytological diagnosis was correlated with the final histopathological diagnosis. The study was conducted between January 2019 and June 2020. Statistical Analysis Used: SPSS 20.0 software. Results: The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of bronchial cytology was 60%, 89%, 90%, 58.62%, and 71.42%, respectively. Conclusions: Bronchial cytology including bronchial wash, bronchial brush, endobronchial ultrasound/transbronchial needle aspiration, and computerized tomography-guided fine needle aspiration cytology can be used to increase the sensitivity and specificity for definitive diagnosis and better management.

Surface Engineering and Multimodal Imaging of Multistage Delivery Vectorsin Metastatic Breast Cancer.

The design of effective nanoformulations that target metastatic breast cancers is challenging due to a lack of competent imaging and image analysis protocols that can capture the interactions between the injected nanoparticles and metastatic lesions. Here, we describe the integration of in vivo whole-body PET-CT with high temporal resolution, ex vivo whole-organ optical imaging and high spatial resolution confocal microscopy to deconstruct the trafficking of injectable nanoparticle generators encapsulated with polymeric doxorubicin (iNPG-pDox) in pulmonary metastases of triple-negative breast cancer. We describe the details of image acquisition and analysis in a step-wise manner along with the development of a mouse model for metastatic breast cancer. The methods described herein can be easily adapted to any nanoparticle or disease model, allowing a standardized pipeline for in vivo preclinical studies that focus on delineating nanoparticle kinetics and interactions within metastases.

Massive lateral neck mass: aberrant ectopic thyroid malignancy.

Lateral aberrant ectopic thyroid is very rare, comprising only 1%-3% of all the ectopic thyroid tissue. Clinically, these lesions are mistaken for lymph node swelling or metastatic tumour. Primary carcinoma in lateral aberrant ectopic thyroid with normal active native thyroid is very uncommon. We report a case of papillary carcinoma in lateral aberrant ectopic thyroid tissue, with a completely normal native thyroid gland in a 53-year-old man, who presented with a massive swelling in the lateral aspect of the neck clinically and radiologically diagnosed as a malignant soft tissue tumour with differential diagnosis of malignant lymphoma. Fine needle aspiration cytology revealed metastatic papillary carcinoma. In toto excision of the soft tissue mass along with subtotal thyroidectomy was performed. Histology of the mass revealed papillary carcinoma of lateral aberrant ectopic thyroid, while the thyroid gland did not show evidence of malignancy. The postsurgical period was uneventful, and the patient underwent radioiodine ablation.

Ultrasmall Porous Silica Nanoparticles with Enhanced Pharmacokinetics for Cancer Theranostics.

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 90/86Y, enabling both noninvasive imaging as well as internal radiotherapy. In vivo PET imaging demonstrates prolonged blood circulation and excellent tumor contrast with 86Y-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. 90Y-DOTA-UPSN significantly inhibits tumor growth and increases overall survival, indicating the promise of UPSN for future clinical translation as a cancer theranostic agent.

Seed- and Soil-Dependent Differences in Murine Breast Tumor Microenvironments Dictate Anti-PD-L1 IgG Delivery and Therapeutic Efficacy.

We sought to determine if Stephen Paget's "seed and soil" hypothesis of organ-preference patterns of cancer metastasis can explain the development of heterogeneity in a tumor microenvironment (TME) as well as immunotherapeutic delivery and efficacy. We established single-cell-derived clones (clones 1 and 16) from parental 4T1 murine breast cancer cells to create orthotopic primary and liver metastasis models to deconvolute polyclonal complexity cancer cells and the difference in TME-derived heterogeneities. Tumor-bearing mice were treated with anti-PD-L1 IgG or a control antibody, and immunofluorescent imaging and quantification were then performed to evaluate the therapeutic efficacy on tumor growth, the delivery of therapy to tumors, the development of blood vessels, the expression of PD-L1, the accumulation of immune cells, and the amount of coagulation inside tumors. The quantification showed an inverse correlation between the amount of delivered therapy and therapeutic efficacy in parental-cell-derived tumors. In contrast, tumors originating from clone 16 cells accumulated a significantly greater amount of therapy and responded better than clone-1-derived tumors. This difference was greater when tumors grew in the liver than the primary site. A similar trend was found in PD-L1 expression and immune cell accumulation. However, the change in the number of blood vessels was not significant. In addition, the amount of coagulation was more abundant in clone-1-derived tumors when compared to others. Thus, our findings reconfirmed the seed- and soil-dependent differences in PD-L1 expression, therapeutic delivery, immune cell accumulation, and tumor coagulation, which can constitute a heterogeneous delivery and response of immunotherapy in polyclonal tumors growing in different organs.

Moving Beyond the Pillars of Cancer Treatment: Perspectives From Nanotechnology.

Nanotechnology has made a significant impact on basic and clinical cancer research over the past two decades. Owing to multidisciplinary advances, cancer nanotechnology aims to address the problems in current cancer treatment paradigms, with the ultimate goal to improve treatment efficacy, increase patient survival, and decrease toxic side-effects. The potential for use of nanomedicine in cancer targeting and therapy has grown, and is now used to advance the four traditional pillars of cancer treatment: surgery, chemotherapy, radiation therapy and the newest pillar, immunotherapy. In this review we provide an overview of notable advances of nanomedicine in improving drug delivery, radiation therapy and immunotherapy. Potential barriers in the translation of nanomedicine from bench to bedside as well as strategies to overcome these barriers are also discussed. Promising preclinical findings highlight the translational and clinical potential of integrating nanotechnology approaches into cancer care.

Sequential deconstruction of composite drug transport in metastatic breast cancer.

It is challenging to design effective drug delivery systems (DDS) that target metastatic breast cancers (MBC) because of lack of competent imaging and image analysis protocols that suitably capture the interactions between DDS and metastatic lesions. Here, we integrate high temporal resolution of in vivo whole-body PET-CT, ex vivo whole-organ optical imaging, high spatial resolution of confocal microscopy, and mathematical modeling, to systematically deconstruct the trafficking of injectable nanoparticle generators encapsulated with polymeric doxorubicin (iNPG-pDox) in pulmonary MBC. iNPG-pDox accumulated substantially in metastatic lungs, compared to healthy lungs. Intratumoral distribution and retention of iNPG-pDox varied with lesion size, possibly induced by locally remodeled microenvironment. We further used multiscale imaging and mathematical simulations to provide improved drug delivery strategies for MBC. Our work presents a multidisciplinary translational toolbox to evaluate transport and interactions of DDS within metastases. This knowledge can be recursively applied to rationally design advanced therapies for metastatic cancers.

Image-guided mathematical modeling for pharmacological evaluation of nanomaterials and monoclonal antibodies.

While plasma concentration kinetics has traditionally been the predictor of drug pharmacological effects, it can occasionally fail to represent kinetics at the site of action, particularly for solid tumors. This is especially true in the case of delivery of therapeutic macromolecules (drug-loaded nanomaterials or monoclonal antibodies), which can experience challenges to effective delivery due to particle size-dependent diffusion barriers at the target site. As a result, disparity between therapeutic plasma kinetics and kinetics at the site of action may exist, highlighting the importance of target site concentration kinetics in determining the pharmacodynamic effects of macromolecular therapeutic agents. Assessment of concentration kinetics at the target site has been facilitated by non-invasive in vivo imaging modalities. This allows for visualization and quantification of the whole-body disposition behavior of therapeutics that is essential for a comprehensive understanding of their pharmacokinetics and pharmacodynamics. Quantitative non-invasive imaging can also help guide the development and parameterization of mathematical models for descriptive and predictive purposes. Here, we present a review of the application of state-of-the-art imaging modalities for quantitative pharmacological evaluation of therapeutic nanoparticles and monoclonal antibodies, with a focus on their integration with mathematical models, and identify challenges and opportunities. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > in vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

In vitro study of enhanced photodynamic cancer cell killing effect by nanometer-thick gold nanosheets.

Photodynamic therapy (PDT) by near-infrared (NIR) irradiation is a promising technique for treating various cancers. Here, we reported the development of free-standing wafer-scale Au nanosheets (NSs) that exhibited an impressive PDT effect. The Au NSs were synthesized by ionic layer epitaxy at the air-water interface with a uniform thickness in the range from 2 to 8.5 nm. These Au NSs were found very effective in generating singlet oxygen under NIR irradiation. In vitro cellular study showed that the Au NSs had very low cytotoxicity and high PDT efficiency due to their uniform 2D morphology. Au NSs could kill cancer cells after 5 min NIR irradiation with little heat generation. This performance is comparable to using 10 times mass loading of Au nanoparticles (NPs). This work suggests that two-dimensional (2D) Au NSs could be a new type of biocompatible nanomaterial for PDT of cancer with an extraordinary photon conversion and cancer cell killing efficiency.

Surfactant-Stripped Pheophytin Micelles for Multimodal Tumor Imaging and Photodynamic Therapy.

Porphyrin-based nanomaterials can inherently integrate multiple contrast imaging functionalities with phototherapeutic capabilities. We dispersed pheophytin (Pheo) into Pluronic F127 and carried out low-temperature surfactant-stripping to remove the bulk surfactant. Surfactant-stripped Pheo (ss-Pheo) micelles exhibited a similar size, but higher near-infrared fluorescence, compared to two other nanomaterials also with high porphyrin density (surfactant-stripped chlorophyll micelles and porphysomes). Singlet oxygen generation, which was higher for ss-Pheo, enabled photodynamic therapy (PDT). ss-Pheo provided contrast for photoacoustic and fluorescence imaging, and following seamless labeling with 64Cu, was used for positron emission tomography. ss-Pheo had a long blood circulation and favorable accumulation in an orthotopic murine mammary tumor model. Trimodal tumor imaging was demonstrated, and PDT resulted in delayed tumor growth.

Size-Optimized Ultrasmall Porous Silica Nanoparticles Depict Vasculature-Based Differential Targeting in Triple Negative Breast Cancer.

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.

Mathematical modeling in cancer nanomedicine: a review.

Cancer continues to be among the leading healthcare problems worldwide, and efforts continue not just to find better drugs, but also better drug delivery methods. The need for delivering cytotoxic agents selectively to cancerous cells, for improved safety and efficacy, has triggered the application of nanotechnology in medicine. This effort has provided drug delivery systems that can potentially revolutionize cancer treatment. Nanocarriers, due to their capacity for targeted drug delivery, can shift the balance of cytotoxicity from healthy to cancerous cells. The field of cancer nanomedicine has made significant progress, but challenges remain that impede its clinical translation. Several biophysical barriers to the transport of nanocarriers to the tumor exist, and a much deeper understanding of nano-bio interactions is necessary to change the status quo. Mathematical modeling has been instrumental in improving our understanding of the physicochemical and physiological underpinnings of nanomaterial behavior in biological systems. Here, we present a comprehensive review of literature on mathematical modeling works that have been and are being employed towards a better understanding of nano-bio interactions for improved tumor delivery efficacy.

Recent advancements in mesoporous silica nanoparticles towards therapeutic applications for cancer.

Recently, drug delivery systems based on nanotechnology have received great attention in cancer therapeutics and diagnostics since they can not only improve the treatment efficacy but also reduce the side effects. Among them, mesoporous silica nanoparticles (MSNs) with large surface area, high pore volume, tunable pore size, abundant surface chemistry, and acceptable biocompatibility exhibit unique advantages and are considered as promising candidates for cancer diagnosis and therapy. In this review, we update the recent progress on MSN-based systems for cancer treatment purposes. We also discuss the drug loading mechanism of MSNs, stimuli-responsive drug release, and surface modification strategies for improving biocompatibility, and targeting functionalities. STATEMENT OF SIGNIFICANCE: The development of MSN-based delivery systems that can be used in both diagnosis and treatment of cancer has attracted tremendous interest in the past decade. MSN-based delivery systems can improve therapeutic efficacy and reduce cytotoxicity to normal tissue. To further improve the in vivo properties of MSNs and potential translation to the clinics, it is critical to design MSNs with appropriate surface engineering and desirable cancer targeting. This review is intended to provide the readers a comprehensive background of the vast literature till date on silica-based drug delivery systems, and to inspire further innovations in silica nanomedicine in the future.

In Vivo Tumor-Targeted Dual-Modality PET/Optical Imaging with a Yolk/Shell-Structured Silica Nanosystem.

Silica nanoparticles have been one of the most promising nanosystems for biomedical applications due to their facile surface chemistry and non-toxic nature. However, it is still challenging to effectively deliver them into tumor sites and noninvasively visualize their in vivo biodistribution with excellent sensitivity and accuracy for effective cancer diagnosis. In this study, we design a yolk/shell-structured silica nanosystem 64Cu-NOTA-QD@HMSN-PEG-TRC105, which can be employed for tumor vasculature targeting and dual-modality PET/optical imaging, leading to superior targeting specificity, excellent imaging capability and more reliable diagnostic outcomes. By combining vasculature targeting, pH-sensitive drug delivery, and dual-modality imaging into a single platform, as-designed yolk/shell-structured silica nanosystems may be employed for the future image-guided tumor-targeted drug delivery, to further enable cancer theranostics.

General synthesis of silica-based yolk/shell hybrid nanomaterials and in vivo tumor vasculature targeting.

Multifunctional yolk/shell-structured hybrid nanomaterials have attracted increasing interest as theranostic nanoplatforms for cancer imaging and therapy. However, because of the lack of suitable surface engineering and tumor targeting strategies, previous research has focused mainly on nanostructure design and synthesis with few successful examples showing active tumor targeting after systemic administration. In this study, we report the general synthetic strategy of chelator-free zirconium-89 (89Zr)-radiolabeled, TRC105 antibody-conjugated, silica-based yolk/shell hybrid nanoparticles for in vivo tumor vasculature targeting. Three types of inorganic nanoparticles with varying morphologies and sizes were selected as the internal cores, which were encapsulated into single hollow mesoporous silica nanoshells to form the yolk/shell-structured hybrid nanoparticles. As a proof-of-concept, we demonstrated successful surface functionalization of the nanoparticles with polyethylene glycol, TRC105 antibody (specific forCD105/endoglin), and 89Zr (a positron-emitting radioisotope), and enhanced in vivo tumor vasculature-targeted positron emission tomography imaging in 4T1murine breast tumor-bearing mice. This strategy could be applied to the synthesis of other types of yolk/shell theranostic nanoparticles for tumor-targeted imaging and drug delivery.