Showing papers in "Theranostics in 2015"

MicroRNAs: New Biomarkers for Diagnosis, Prognosis, Therapy Prediction and Therapeutic Tools for Breast Cancer.

Abstract: Dysregulation of microRNAs (miRNAs) is involved in the initiation and progression of several human cancers, including breast cancer (BC), as strong evidence has been found that miRNAs can act as oncogenes or tumor suppressor genes. This review presents the state of the art on the role of miRNAs in the diagnosis, prognosis, and therapy of BC. Based on the results obtained in the last decade, some miRNAs are emerging as biomarkers of BC for diagnosis (i.e., miR-9, miR-10b, and miR-17-5p), prognosis (i.e., miR-148a and miR-335), and prediction of therapeutic outcomes (i.e., miR-30c, miR-187, and miR-339-5p) and have important roles in the control of BC hallmark functions such as invasion, metastasis, proliferation, resting death, apoptosis, and genomic instability. Other miRNAs are of interest as new, easily accessible, affordable, non-invasive tools for the personalized management of patients with BC because they are circulating in body fluids (e.g., miR-155 and miR-210). In particular, circulating multiple miRNA profiles are showing better diagnostic and prognostic performance as well as better sensitivity than individual miRNAs in BC. New miRNA-based drugs are also promising therapy for BC (e.g., miR-9, miR-21, miR34a, miR145, and miR150), and other miRNAs are showing a fundamental role in modulation of the response to other non-miRNA treatments, being able to increase their efficacy (e.g., miR-21, miR34a, miR195, miR200c, and miR203 in combination with chemotherapy).

Magnetic Nanoparticles in Cancer Theranostics.

Abstract: In a report from 2008, The International Agency for Research on Cancer predicted a tripled cancer incidence from 1975, projecting a possible 13-17 million cancer deaths worldwide by 2030. While new treatments are evolving and reaching approval for different cancer types, the main prevention of cancer mortality is through early diagnosis, detection and treatment of malignant cell growth. The last decades have seen a development of new imaging techniques now in widespread clinical use. The development of nano-imaging through fluorescent imaging and magnetic resonance imaging (MRI) has the potential to detect and diagnose cancer at an earlier stage than with current imaging methods. The characteristic properties of nanoparticles result in their theranostic potential allowing for simultaneous detection of and treatment of the disease. This review provides state of the art of the nanotechnological applications for cancer therapy. Furthermore, it advances a novel concept of personalized nanomedical theranostic therapy using iron oxide magnetic nanoparticles in conjunction with MRI imaging. Regulatory and industrial perspectives are also included to outline future perspectives in nanotechnological cancer research.

Cell or Cell Membrane-Based Drug Delivery Systems

Abstract: Natural cells have been explored as drug carriers for a long period. They have received growing interest as a promising drug delivery system (DDS) until recently along with the development of biology and medical science. The synthetic materials, either organic or inorganic, are found to be with more or less immunogenicity and/or toxicity. The cells and extracellular vesicles (EVs), are endogenous and thought to be much safer and friendlier. Furthermore, in view of their host attributes, they may achieve different biological effects and/or targeting specificity, which can meet the needs of personalized medicine as the next generation of DDS. In this review, we summarized the recent progress in cell or cell membrane-based DDS and their fabrication processes, unique properties and applications, including the whole cells, EVs and cell membrane coated nanoparticles. We expect the continuing development of this cell or cell membrane-based DDS will promote their clinic applications.

Nanoparticles for Radiation Therapy Enhancement: the Key Parameters.

Abstract: This review focuses on the radiosensitization strategies that use high-Z nanoparticles. It does not establish an exhaustive list of the works in this field but rather propose constructive criticisms pointing out critical factors that could improve the nano-radiation therapy. Whereas most reviews show the chemists and/or biologists points of view, the present analysis is also seen through the prism of the medical physicist. In particular, we described and evaluated the influence of X-rays energy spectra using a numerical analysis. We observed a lack of standardization in preclinical studies that could partially explain the low number of translation to clinical applications for this innovative therapeutic strategy. Pointing out the critical parameters of high-Z nanoparticles radiosensitization, this review is expected to contribute to a larger preclinical and clinical development.

A Plasmonic Gold Nanostar Theranostic Probe for In Vivo Tumor Imaging and Photothermal Therapy

Abstract: Nanomedicine has attracted increasing attention in recent years, because it offers great promise to provide personalized diagnostics and therapy with improved treatment efficacy and specificity. In this study, we developed a gold nanostar (GNS) probe for multi-modality theranostics including surface-enhanced Raman scattering (SERS) detection, x-ray computed tomography (CT), two-photon luminescence (TPL) imaging, and photothermal therapy (PTT). We performed radiolabeling, as well as CT and optical imaging, to investigate the GNS probe's biodistribution and intratumoral uptake at both macroscopic and microscopic scales. We also characterized the performance of the GNS nanoprobe for in vitro photothermal heating and in vivo photothermal ablation of primary sarcomas in mice. The results showed that 30-nm GNS have higher tumor uptake, as well as deeper penetration into tumor interstitial space compared to 60-nm GNS. In addition, we found that a higher injection dose of GNS can increase the percentage of tumor uptake. We also demonstrated the GNS probe's superior photothermal conversion efficiency with a highly concentrated heating effect due to a tip-enhanced plasmonic effect. In vivo photothermal therapy with a near-infrared (NIR) laser under the maximum permissible exposure (MPE) led to ablation of aggressive tumors containing GNS, but had no effect in the absence of GNS. This multifunctional GNS probe has the potential to be used for in vivo biosensing, preoperative CT imaging, intraoperative detection with optical methods (SERS and TPL), as well as image-guided photothermal therapy.

Graphene as Cancer Theranostic Tool: Progress and Future Challenges

Abstract: Nowadays cancer remains one of the main causes of death in the world. Current diagnostic techniques need to be improved to provide earlier diagnosis and treatment. Traditional therapy approaches to cancer are limited by lack of specificity and systemic toxicity. In this scenario nanomaterials could be good allies to give more specific cancer treatment effectively reducing undesired side effects and giving at the same time accurate diagnosis and successful therapy. In this context, thanks to its unique physical and chemical properties, graphene, graphene oxide (GO) and reduced graphene (rGO) have recently attracted tremendous interest in biomedicine including cancer therapy. Herein we analyzed all studies presented in literature related to cancer fight using graphene and graphene-based conjugates. In this context, we aimed at the full picture of the state of the art providing new inputs for future strategies in the cancer theranostic by using of graphene. We found an impressive increasing interest in the material for cancer therapy and/or diagnosis. The majority of the works (73%) have been carried out on drug and gene delivery applications, following by photothermal therapy (32%), imaging (31%) and photodynamic therapy (10%). A 27% of the studies focused on theranostic applications. Part of the works here discussed contribute to the growth of the theranostic field covering the use of imaging (i.e. ultrasonography, positron electron tomography, and fluorescent imaging) combined to one or more therapeutic modalities. We found that the use of graphene in cancer theranostics is still in an early but rapidly growing stage of investigation. Any technology based on nanomaterials can significantly enhance their possibility to became the real revolution in medicine if combines diagnosis and therapy at the same time. We performed a comprehensive summary of the latest progress of graphene cancer fight and highlighted the future challenges and the innovative possible theranostic applications.

Aptamers: active targeting ligands for cancer diagnosis and therapy.

Abstract: Aptamers, including DNA, RNA and peptide aptamers, are a group of promising recognition units that can specifically bind to target molecules and cells. Due to their excellent specificity and high affinity to targets, aptamers have attracted great attention in various fields in which selective recognition units are required. They have been used in biosensing, drug delivery, disease diagnosis and therapy (especially for cancer treatment). In this review, we summarized recent applications of DNA and RNA aptamers in cancer theranostics. The specific binding ability of aptamers to cancer-related markers and cancer cells ensured their high performance for early diagnosis of cancer. Meanwhile, the efficient targeting ability of aptamers to cancer cells and tissues provided a promising way to deliver imaging agents and drugs for cancer imaging and therapy. Furthermore, with the development of nanoscience and nanotechnology, the conjugation of aptamers with functional nanomaterials paved an exciting way for the fabrication of theranostic agents for different types of cancers, which might be a powerful tool for cancer treatment.

Smart MoS2/Fe3O4 Nanotheranostic for Magnetically Targeted Photothermal Therapy Guided by Magnetic Resonance/Photoacoustic Imaging.

Abstract: The ability to selectively destroy cancer cells while sparing normal tissue is highly desirable during the cancer therapy. Here, magnetic targeted photothermal therapy was demonstrated by the integration of MoS2 (MS) flakes and Fe3O4 (IO) nanoparticles (NPs), where MoS2 converted near-infrared (NIR) light into heat and Fe3O4 NPs served as target moiety directed by external magnetic field to tumor site. The MoS2/Fe3O4 composite (MSIOs) functionalized by biocompatible polyethylene glycol (PEG) were prepared by a simple two-step hydrothermal method. And the as-obtained MSIOs exhibit high stability in bio-fluids and low toxicity in vitro and in vivo. Specifically, the MSIOs can be applied as a dual-modal probe for T2-weighted magnetic resonance (MR) and photoacoustic tomography (PAT) imaging due to their superparamagnetic property and strong NIR absorption. Furthermore, we demonstrate an effective result for magnetically targeted photothermal ablation of cancer. All these results show a great potential for localized photothermal ablation of cancer spatially/timely guided by the magnetic field and indicated the promise of the multifunctional MSIOs for applications in cancer theranostics.

Nucleic Acid Aptamer-Guided Cancer Therapeutics and Diagnostics: the Next Generation of Cancer Medicine

Abstract: Conventional anticancer therapies, such as chemo- and/or radio-therapy are often unable to completely eradicate cancers due to abnormal tumor microenvironment, as well as increased drug/radiation resistance. More effective therapeutic strategies for overcoming these obstacles are urgently in demand. Aptamers, as chemical antibodies that bind to targets with high affinity and specificity, are a promising new and novel agent for both cancer diagnostic and therapeutic applications. Aptamer-based cancer cell targeting facilitates the development of active targeting in which aptamer-mediated drug delivery could provide promising anticancer outcomes. This review is to update the current progress of aptamer-based cancer diagnosis and aptamer-mediated active targeting for cancer therapy in vivo, exploring the potential of this novel form of targeted cancer therapy.

PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status

Abstract: Prostate cancer (PCa) is the most common malignancy in men worldwide, leading to substantial morbidity and mortality. At present, imaging of PCa has become increasingly important for staging, restaging, and treatment selection. Until recently, choline-based positron emission tomography/computed tomography (PET/CT) represented the state-of-the-art radionuclide imaging technique for these purposes. However, its application is limited to patients with high PSA levels and Gleason scores. Prostate-specific membrane antigen (PSMA) is a promising new target for specific imaging of PCa, because it is upregulated in the majority of PCa. Moreover, PSMA can serve as a target for therapeutic applications. Currently, several small-molecule PSMA ligands with excellent in vivo tumor targeting characteristics are being investigated for their potential in theranostic applications in PCa. Here, a review of the recent developments in PSMA-based diagnostic imaging and therapy in patients with PCa with radiolabeled PSMA ligands is provided.

Theranostic mesoporous silica nanoparticles biodegrade after pro-survival drug delivery and ultrasound/magnetic resonance imaging of stem cells.

Abstract: Increasing cell survival in stem cell therapy is an important challenge for the field of regenerative medicine Here, we report theranostic mesoporous silica nanoparticles that can increase cell survival through both diagnostic and therapeutic approaches First, the nanoparticle offers ultrasound and MRI signal to guide implantation into the peri-infarct zone and away from the most necrotic tissue Second, the nanoparticle serves as a slow release reservoir of insulin-like growth factor (IGF)-a protein shown to increase cell survival Mesenchymal stem cells labeled with these nanoparticles had detection limits near 9000 cells with no cytotoxicity at the 250 µg/mL concentration required for labeling We also studied the degradation of the nanoparticles and showed that they clear from cells in approximately 3 weeks The presence of IGF increased cell survival up to 40% (p<005) versus unlabeled cells under in vitro serum-free culture conditions

Combined cancer photothermal-chemotherapy based on doxorubicin/gold nanorod-loaded polymersomes

Abstract: Gold nanorods (GNRs) are well known in photothermal therapy based on near-infrared (NIR) laser absorption of the longitudinal plasmon band. Herein, we developed an effective stimulus system -- GNRs and doxorubicin co-loaded polymersomes (P-GNRs-DOX) -- to facilitate co-therapy of photothermal and chemotherapy. DOX can be triggered to release once the polymersomes are corrupted under local hyperthermic condition of GNRs induced by NIR laser irradiation. Also, the cytotoxicity of GNRs caused by the residual cetyltrimethylacmmonium bromide (CTAB) was reduced by shielding the polymersomes. The GNRs-loaded polymersomes (P-GNRs) can be efficiently taken up by the tumor cells. The distribution of the nanomaterial was imaged by IR-820 and quantitatively analyzed by ICP-AES. We studied the ablation of tumor cells in vitro and in vivo, and found that co-therapy offers significantly improved therapeutic efficacy (tumors were eliminated without regrowth.) compared with chemotherapy or photothermal therapy alone. By TUNEL immunofluorescent staining of tumors after NIR laser irradiation, we found that the co-therapy showed more apoptotic tumor cells than the other groups. Furthermore, the toxicity study by pathologic examination of the heart tissues demonstrated a lower systematic toxicity of P-GNRs-DOX than free DOX. Thus, the chemo-photothermal treatment based on polymersomes loaded with DOX and GNRs is a useful strategy for maximizing the therapeutic efficacy and minimizing the dosage-related side effects in the treatment of solid tumors.

Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging.

Abstract: Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [(68)Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [(68)Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [(68)Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [(68)Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/CXCL12 ligand interaction in the pathogenesis and treatment of cancer, cardiovascular diseases and autoimmune and inflammatory disorders.

Current Approaches for Improving Intratumoral Accumulation and Distribution of Nanomedicines.

Abstract: The ability of nanoparticles and macromolecules to passively accumulate in solid tumors and enhance therapeutic effects in comparison with conventional anticancer agents has resulted in the development of various multifunctional nanomedicines including liposomes, polymeric micelles, and magnetic nanoparticles. Further modifications of these nanoparticles have improved their characteristics in terms of tumor selectivity, circulation time in blood, enhanced uptake by cancer cells, and sensitivity to tumor microenvironment. These "smart" systems have enabled highly effective delivery of drugs, genes, shRNA, radioisotopes, and other therapeutic molecules. However, the resulting therapeutically relevant local concentrations of anticancer agents are often insufficient to cause tumor regression and complete elimination. Poor perfusion of inner regions of solid tumors as well as vascular barrier, high interstitial fluid pressure, and dense intercellular matrix are the main intratumoral barriers that impair drug delivery and impede uniform distribution of nanomedicines throughout a tumor. Here we review existing methods and approaches for improving tumoral uptake and distribution of nano-scaled therapeutic particles and macromolecules (i.e. nanomedicines). Briefly, these strategies include tuning physicochemical characteristics of nanomedicines, modulating physiological state of tumors with physical impacts or physiologically active agents, and active delivery of nanomedicines using cellular hitchhiking.

Prediction of tumor recurrence and therapy monitoring using ultrasound-guided photoacoustic imaging

Abstract: Selection and design of individualized treatments remains a key goal in cancer therapeutics; prediction of response and tumor recurrence following a given therapy provides a basis for subsequent personalized treatment design. We demonstrate an approach towards this goal with the example of photodynamic therapy (PDT) as the treatment modality and photoacoustic imaging (PAI) as a non-invasive, response and disease recurrence monitor in a murine model of glioblastoma (GBM). PDT is a photochemistry-based, clinically-used technique that consumes oxygen to generate cytotoxic species, thus causing changes in blood oxygen saturation (StO2). We hypothesize that this change in StO2 can be a surrogate marker for predicting treatment efficacy and tumor recurrence. PAI is a technique that can provide a 3D atlas of tumor StO2 by measuring oxygenated and deoxygenated hemoglobin. We demonstrate that tumors responding to PDT undergo approximately 85% change in StO2 by 24-hrs post-therapy while there is no significant change in StO2 values in the non-responding group. Furthermore, the 3D tumor StO2 maps predicted whether a tumor was likely to regrow at a later time point post-therapy. Information on the likelihood of tumor regrowth that normally would have been available only upon actual regrowth (10-30 days post treatment) in a xenograft tumor model, was available within 24-hrs of treatment using PAI, thus making early intervention a possibility. Given the advances and push towards availability of PAI in the clinical settings, the results of this study encourage applicability of PAI as an important step to guide and monitor therapies (e.g. PDT, radiation, anti-angiogenic) involving a change in StO2.

Off to the organelles - killing cancer cells with targeted gold nanoparticles.

Abstract: Gold nanoparticles (AuNPs) are excellent tools for cancer cell imaging and basic research. However, they have yet to reach their full potential in the clinic. At present, we are only beginning to understand the molecular mechanisms that underlie the biological effects of AuNPs, including the structural and functional changes of cancer cells. This knowledge is critical for two aspects of nanomedicine. First, it will define the AuNP-induced events at the subcellular and molecular level, thereby possibly identifying new targets for cancer treatment. Second, it could provide new strategies to improve AuNP-dependent cancer diagnosis and treatment. Our review summarizes the impact of AuNPs on selected subcellular organelles that are relevant to cancer therapy. We focus on the nucleus, its subcompartments, and mitochondria, because they are intimately linked to cancer cell survival, growth, proliferation and death. While non-targeted AuNPs can damage tumor cells, concentrating AuNPs in particular subcellular locations will likely improve tumor cell killing. Thus, it will increase cancer cell damage by photothermal ablation, mechanical injury or localized drug delivery. This concept is promising, but AuNPs have to overcome multiple hurdles to perform these tasks. AuNP size, morphology and surface modification are critical parameters for their delivery to organelles. Recent strategies explored all of these variables, and surface functionalization has become crucial to concentrate AuNPs in subcellular compartments. Here, we highlight the use of AuNPs to damage cancer cells and their organelles. We discuss current limitations of AuNP-based cancer research and conclude with future directions for AuNP-dependent cancer treatment.

Superior Performance of Aptamer in Tumor Penetration over Antibody: Implication of Aptamer-Based Theranostics in Solid Tumors

Abstract: Insufficient penetration of therapeutic agents into tumor tissues results in inadequate drug distribution and lower intracellular concentration of drugs, leading to the increase of drug resistance and resultant failure of cancer treatment. Targeted drug delivery to solid tumors followed by complete drug penetration and durable retention will significantly improve clinical outcomes of cancer therapy. Monoclonal antibodies have been commonly used in clinic for cancer treatment, but their limitation of penetrating into tumor tissues still remains because of their large size. Aptamers, as "chemical antibodies", are 15-20 times smaller than antibodies. To explore whether aptamers are superior to antibodies in terms of tumor penetration, we carried out the first comprehensive study to compare the performance of an EpCAM aptamer with an EpCAM antibody in theranostic applications. Penetration and retention were studied in in vitro three-dimensional tumorspheres, in vivo live animal imaging and mouse colorectal cancer xenograft model. We found that the EpCAM aptamer can not only effectively penetrate into the tumorsphere cores but can also be retained by tumor sphere cells for at least 24 h, while limited tumor penetration by EpCAM antibody was observed after 4 h incubation. As observed from in vivo live animal imaging, EpCAM aptamers displayed a maximum tumor uptake at around 10 min followed by a rapid clearance after 80 min, while the signal of peak uptake and disappearance of antibody appeared at 3 h and 6 h after intravenous injection, respectively. The signal of PEGylated EpCAM aptamers in xenograft tumors was sustained for 26 h, which was 4.3-fold longer than that of the EpCAM antibody. Consistently, there were 1.67-fold and 6.6-fold higher accumulation of PEGylated aptamer in xenograft tumors than that of antibody, at 3 h and 24 h after intravenous administration, respectively. In addition, the aptamer achieved at least a 4-time better tumor penetration in xenograft tumors than that of the antibody at a 200 μm distances from the blood vessels 3 h after intravenous injection. Taken together, these data indicate that aptmers are superior to antibodies in cancer theranostics due to their better tumor penetration, more homogeneous distribution and longer retention in tumor sites. Thus, aptamers are promising agents for targeted tumor therapeutics and molecular imaging.

Circulating MiR-16-5p and MiR-19b-3p as Two Novel Potential Biomarkers to Indicate Progression of Gastric Cancer.

Abstract: Gastric cancer (GC) is the second most common cancer in China and the second leading cause of cancer-related death in the world. Identifying circulating biomarkers is helpful to improve theranostics of gastric cancer. Herein, we are for the first time to report miR-16-5p and miR-19b-3p were identified to be the novel potential plasma biomarkers to detect gastric cancer. Differentially expressed miRNAs were initially screened out by genome-wide miRNA profiling microarrays between 16 plasma samples of gastric cancer and 18 matched normal controls, and then were quantified and validated by quantitative reverse transcription-PCR method between 155 gastric cancer cases and 111 normal controls. Additionally, 30 plasma samples from precancerous lesions and 18 paired samples from gastric cancer patients with gastrectomy were further detected. Results showed that based on two normalization methods, miR-16-5p and miR-19b-3p in plasma were found to be capable of distinguishing normal population from GC cases with different TNM stages and differentiation grades, particularly including the early cancer cases (P<0.05). And the two miRNAs were down-regulated in GC cases (FC<0.5). Especially, the down-regulation degree was correlated with the progression of the GC cases from the early stage to the advanced stage (0.2< rs<0.3, P<0.01). And the same weak down-regulation of the two biomarkers as the early GC occurred initially in the precancerous diseases (P<0.05). The corresponding performance of the two miRNAs to detect GC in ROC analysis gradually performed better with the disease progression from the earlier stages or lower grades to the advanced stages (TNM Ⅳ stage: AUC=0.832 for miR-16-5p; TNM Ⅲ stage: AUC=0.822 for miR-19b-3p) or high grade (Poorly differentiated: AUC=0.801, 0.791 respectively for miR-16-5p and miR-19b-3p). Additionally, miR-19b-3p remained down-regulated in patient plasma within 9 days after gastrectomy. In conclusion, miR-19b-3p and miR-16-5p maybe prospective biomarkers to detect gastric cancer and indicate its progression, and thus may own great potential in applications such as early screening and progression evaluation of gastric cancer in the near future.

CD44v6 Monoclonal Antibody-Conjugated Gold Nanostars for Targeted Photoacoustic Imaging and Plasmonic Photothermal Therapy of Gastric Cancer Stem-like Cells.

Abstract: Developing safe and effective nanoprobes for targeted imaging and selective therapy of gastric cancer stem cells (GCSCs) has become one of the most promising anticancer strategies. Herein, gold nanostars-based PEGylated multifunctional nanoprobes were prepared with conjugated CD44v6 monoclonal antibodies (CD44v6-GNS) as the targeting ligands. It was observed that the prepared nanoprobes had high affinity towards GCSC spheroid colonies and destroyed them completely with a low power density upon near-infrared (NIR) laser treatment (790 nm, 1.5 W/cm(2), 5 min) in vitro experiment. Orthotopic and subcutaneous xenografted nude mice models of human gastric cancer were established. Subsequently, biodistribution and photothermal therapeutic effects after being intravenously injected with the prepared nanoprobes were assessed. Photoacoustic imaging revealed that CD44v6-GNS nanoprobes could target the gastric cancer vascular system actively at 4 h post-injection, while the probes inhibited tumor growth remarkably upon NIR laser irradiation, and even extended survivability of the gastric cancer-bearing mice. The CD44v6-GNS nanoprobes exhibited great potential for applications of gastric cancer targeted imaging and photothermal therapy in the near future.

Macrophage targeted theranostics as personalized nanomedicine strategies for inflammatory diseases.

Abstract: Inflammatory disease management poses challenges due to the complexity of inflammation and inherent patient variability, thereby necessitating patient-specific therapeutic interventions. Theranostics, which integrate therapeutic and imaging functionalities, can be used for simultaneous imaging and treatment of inflammatory diseases. Theranostics could facilitate assessment of safety, toxicity and real-time therapeutic efficacy leading to personalized treatment strategies. Macrophages are an important cellular component of inflammatory diseases, participating in varied roles of disease exacerbation and resolution. The inherent phagocytic nature, abundance and disease homing properties of macrophages can be targeted for imaging and therapeutic purposes. This review discusses the utility of theranostics in macrophage ablation, phenotype modulation and inhibition of their inflammatory activity leading to resolution of inflammation in several diseases.

Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1β.

Abstract: Although strains of attenuated Salmonella typhimurium and wild-type Escherichia coli show similar tumor-targeting capacities, only S. typhimurium significantly suppresses tumor growth in mice. The aim of the present study was to examine bacteria-mediated immune responses by conducting comparative analyses of the cytokine profiles and immune cell populations within tumor tissues colonized by E. coli or attenuated Salmonellae. CT26 tumor-bearing mice were treated with two different bacterial strains: S. typhimurium defective in ppGpp synthesis (ΔppGpp Salmonellae) or wild-type E. coli MG1655. Cytokine profiles and immune cell populations in tumor tissue colonized by these two bacterial strains were examined at two time points based on the pattern of tumor growth after ΔppGpp Salmonellae treatment: 1) when tumor growth was suppressed ('suppression stage') and 2) when they began to re-grow ('re-growing stage'). The levels of IL-1β and TNF-α were markedly increased in tumors colonized by ΔppGpp Salmonellae. This increase was associated with tumor regression; the levels of both IL-1β and TNF-α returned to normal level when the tumors started to re-grow. To identify the immune cells primarily responsible for Salmonellae-mediated tumor suppression, we examined the major cell types that produce IL-1β and TNF-α. We found that macrophages and dendritic cells were the main producers of TNF-α and IL-1β. Inhibiting IL-1β production in Salmonellae-treated mice restored tumor growth, whereas tumor growth was suppressed for longer by local administration of recombinant IL-1β or TNF-α in conjunction with Salmonella therapy. These findings suggested that IL-1β and TNF-α play important roles in Salmonella-mediated cancer therapy. A better understanding of host immune responses in Salmonella therapy may increase the success of a given drug, particularly when various strategies are combined with bacteriotherapy.

Coating Solid Lipid Nanoparticles with Hyaluronic Acid Enhances Antitumor Activity against Melanoma Stem-like Cells

Abstract: Successful anticancer chemotherapy requires targeting tumors efficiently and further potential to eliminate cancer stem cell (CSC) subpopulations. Since CD44 is present on many types of CSCs, and it binds specially to hyaluronic acid (HA), we tested whether coating solid lipid nanoparticles with hyaluronan (HA-SLNs)would allow targeted delivery of paclitaxel (PTX) to CD44-overexpressing B16F10 melanoma cells. First, we developed a model system based on melanoma stem-like cells for experiments in vitro and in mouse xenografts, and we showed that cells expressing high levels of CD44 (CD44(+)) displayed a strong CSC phenotype while cells expressing low levels of CD44 (CD44(-)) did not. This phenotype included sphere and colony formation, higher proportion of side population cells, expression of CSC-related markers (ALDH, CD133, Oct-4) and tumorigenicity in vivo. Next we showed that administering PTX-loaded HA-SLNs led to efficient intracellular delivery of PTX and induced substantial apoptosis in CD44(+) cells in vitro. In the B16F10-CD44(+) lung metastasis model, PTX-loaded HA-SLNs targeted the tumor-bearing lung tissues well and subsequently exhibited significant antitumor effects with a relative low dose of PTX, which provided significant survival benefit without evidence of adverse events. These findings suggest that the HA-SLNs targeting system shows promise for enhancing cancer therapy.

DNA Aptamer Selected against Pancreatic Ductal Adenocarcinoma for in vivo Imaging and Clinical Tissue Recognition

Abstract: In this work, we have developed a truncated DNA aptamer, termed XQ-2d, with high affinity and specificity for pancreatic ductal adenocarcinoma (PDAC). Aptamer XQ-2d selectively binds to PL45 cells with a dissociation constant in the nanomolar range, as determined by its recognition of PL45 tumor cells in mice. Moreover, XQ-2d shows better recognition ratio for 40 tissue sections of clinical PDAC samples (82.5%) compared to the initial cell-SELEX selection library (5%). Therefore, XQ-2d can be considered a promising candidate as a tool for PDAC diagnosis and treatment.

A Light-Driven Therapy of Pancreatic Adenocarcinoma Using Gold Nanorods-Based Nanocarriers for Co-Delivery of Doxorubicin and siRNA

Abstract: In this work, we report the engineering of polyelectrolyte polymers coated Gold nanorods (AuNRs)-based nanocarriers that are capable of co-delivering small interfering RNA (siRNA) and an anticancer drug doxorubicin (DOX) to Panc-1 cancer cells for combination of both chemo- and siRNA-mediated mutant K-Ras gene silencing therapy. Superior anticancer efficacy was observed through synergistic combination of promoted siRNA and DOX release upon irradiating the nanoplex formulation with 665 nm light. Our antitumor study shows that the synergistic effect of AuNRs nanoplex formulation with 665 nm light treatment is able to inhibit the in vivo tumor volume growth rate by 90%. The antitumor effect is contributed from the inactivation of K-Ras gene and thereby causing a profound synthesis (S) phase arrest in treated Panc-1 cells. Our study shows that the percentage of Panc-1 cells treated by nanoplex formulation with S phase is determined to be 35% and it is 17% much higher than that of Panc-1 cells without any treatments. The developed nanotherapy formulation here, that combines chemotherapy, RNA silencing and NIR window light-mediated therapy, will be seen to be the next natural step to be taken in the clinical research for improving the therapeutic outcomes of the pancreatic adenocarcinoma treatment.

Direct Imaging of Cerebral Thromboemboli Using Computed Tomography and Fibrin-targeted Gold Nanoparticles

Abstract: Computed tomography (CT) is the current standard for time-critical decision-making in stroke patients, informing decisions on thrombolytic therapy with tissue plasminogen activator (tPA), which has a narrow therapeutic index. We aimed to develop a CT-based method to directly visualize cerebrovascular thrombi and guide thrombolytic therapy. Glycol-chitosan-coated gold nanoparticles (GC-AuNPs) were synthesized and conjugated to fibrin-targeting peptides, forming fib-GC-AuNP. This targeted imaging agent and non-targeted control agent were characterized in vitro and in vivo in C57Bl/6 mice (n = 107) with FeCl3-induced carotid thrombosis and/or embolic ischemic stroke. Fibrin-binding capacity was superior with fib-GC-AuNPs compared to GC-AuNPs, with thrombi visualized as high density on microCT (mCT). mCT imaging using fib-GC-AuNP allowed the prompt detection and quantification of cerebral thrombi, and monitoring of tPA-mediated thrombolytic effect, which reflected histological stroke outcome. Furthermore, recurrent thrombosis could be diagnosed by mCT without further nanoparticle administration for up to 3 weeks. fib-GC-AuNP-based direct cerebral thrombus imaging greatly enhance the value and information obtainable by regular CT, has multiple uses in basic / translational vascular research, and will likely allow personalized thrombolytic therapy in clinic by a) optimizing tPA-dosing to match thrombus burden, b) enabling the rational triage of patients to more radical therapies such as endovascular clot-retrieval, and c) potentially serving as a theranostic platform for targeted delivery of concurrent thrombolysis.

CO2 bubbling-based 'Nanobomb' System for Targetedly Suppressing Panc-1 Pancreatic Tumor via Low Intensity Ultrasound-activated Inertial Cavitation.

Abstract: Noninvasive and targeted physical treatment is still desirable especially for those cancerous patients. Herein, we develop a new physical treatment protocol by employing CO2 bubbling-based 'nanobomb' system consisting of low-intensity ultrasound (1.0 W/cm(2)) and a well-constructed pH/temperature dual-responsive CO2 release system. Depending on the temperature elevation caused by exogenous low-intensity therapeutic ultrasound irradiation and the low pH caused by the endogenous acidic-environment around/within tumor, dual-responsive CO2 release system can quickly release CO2 bubbles, and afterwards, the generated CO2 bubbles waves will timely explode before dissolution due to triggering by therapeutic ultrasound waves. Related bio-effects (e.g., cavitation, mechanical, shock waves, etc) caused by CO2 bubbles' explosion effectively induce instant necrosis of panc-1 cells and blood vessel destruction within panc-1 tumor, and consequently inhibit the growth of panc-1 solid tumor, simultaneously minimizing the side effects to normal organs. This new physiotherapy employing CO2 bubbling-based 'nanobomb' system promises significant potentials in targetedly suppressing tumors, especially for those highly deadly cancers.

EpCAM Aptamer-mediated Survivin Silencing Sensitized Cancer Stem Cells to Doxorubicin in a Breast Cancer Model

Abstract: Understanding the molecular basis of drug resistance and utilising this information to overcome chemoresistance remains a key challenge in oncology. Here we report that survivin, a key protein implicated in drug resistance, is overexpressed in cancer stem cell pool of doxorubicin-resistant breast cancer cells. Moreover, by utilising an active targeting system consisting of an RNA aptamer targeted against the epithelial cell adhesion molecule and a Dicer substrate survivin siRNA, we could deliver a high dose of the siRNA to cancer stem cells in xenograft tumours. Importantly, silencing of survivin with this aptamer-siRNA chimera in cancer stem cell population led to the reversal of chemoresistance, such that combined treatment with low dose of doxorubicin inhibited stemness, eliminated cancer stem cells via apoptosis, suppressed tumour growth, and prolonged survival in mice bearing chemoresistant tumours. This strategy for in vivo cancer stem cell targeting has wide application for future effective silencing of anti-death genes and in fact any dysregulated genes involved in chemoresistance and tumour relapse.

Molecular imaging of apoptosis: from micro to macro.

Abstract: Apoptosis, or programmed cell death, is involved in numerous human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer, and is often confused with other types of cell death. Therefore strategies that enable visualized detection of apoptosis would be of enormous benefit in the clinic for diagnosis, patient management, and development of new therapies. In recent years, improved understanding of the apoptotic machinery and progress in imaging modalities have provided opportunities for researchers to formulate microscopic and macroscopic imaging strategies based on well-defined molecular markers and/or physiological features. Correspondingly, a large collection of apoptosis imaging probes and approaches have been documented in preclinical and clinical studies. In this review, we mainly discuss microscopic imaging assays and macroscopic imaging probes, ranging in complexity from simple attachments of reporter moieties to proteins that interact with apoptotic biomarkers, to rationally designed probes that target biochemical changes. Their clinical translation will also be our focus.

Analysis of the in vivo and in vitro effects of photodynamic therapy on breast cancer by using a sensitizer, sinoporphyrin sodium.

Abstract: Photodynamic therapy (PDT) is an emerging theranostic modality for various cancers and diseases. Photosensitizers are critical components for PDT. Sinoporphyrin sodium, referred to as DVDMS, is a newly identified photosensitizer that was isolated from Photofrin. Here, we evaluated the effects of DVDMS-mediated PDT (DVDMS-PDT) on tumor cell proliferation and metastasis in the highly metastatic 4T1 cell line and a mouse xenograft model. DVDMS-PDT elicited a potent phototoxic effect in vitro, which was abolished using the reactive oxygen species (ROS) scavenger N-acetylcysteine. In addition, DVDMS-PDT effectively inhibited the migration of 4T1 cells in scratch wound-healing and transwell assays. Using an in vivo mouse model, DVDMS-PDT greatly prolonged the survival time of tumor-bearing mice and inhibited tumor growth and lung metastasis, consistent with in vitro findings. PDT with DVDMS had a greater anti-tumor efficacy than clinically used Photofrin. Moreover, preliminary toxicological results indicate that DVDMS is relatively safe. These results suggest that DVDMS is a promising sensitizer that warrants further development for use in cancer treatment with PDT or other sensitizing agent-based therapies.

3D Porous Calcium-Alginate Scaffolds Cell Culture System Improved Human Osteoblast Cell Clusters for Cell Therapy

Abstract: Age-related orthopedic disorders and bone defects have become a critical public health issue, and cell-based therapy is potentially a novel solution for issues surrounding bone tissue engineering and regenerative medicine. Long-term cultures of primary bone cells exhibit phenotypic and functional degeneration; therefore, culturing cells or tissues suitable for clinical use remain a challenge. A platform consisting of human osteoblasts (hOBs), calcium-alginate (Ca-Alginate) scaffolds, and a self-made bioreactor system was established for autologous transplantation of human osteoblast cell clusters. The Ca-Alginate scaffold facilitated the growth and differentiation of human bone cell clusters, and the functionally-closed process bioreactor system supplied the soluble nutrients and osteogenic signals required to maintain the cell viability. This system preserved the proliferative ability of cells and cell viability and up-regulated bone-related gene expression and biological apatite crystals formation. The bone-like tissue generated could be extracted by removal of calcium ions via ethylenediaminetetraacetic acid (EDTA) chelation, and exhibited a size suitable for injection. The described strategy could be used in therapeutic application and opens new avenues for surgical interventions to correct skeletal defects.