Search

The energetic costs of performance constitute a non-trivial component of animals' daily energetic budgets. However, we currently lack an understanding of how those costs are partitioned among the various stages of performance development, maintenance and production. We manipulated individual investment in performance by training

Ongoing research into the application of nanotechnology for cancer treatment and diagnosis has demonstrated its advantages within contemporary oncology as well as its intrinsic limitations. The National Cancer Institute publishes the Cancer Nanotechnology Plan every 5 years since 2005. The most recent iteration helped codify the ongoing basic and translational efforts of the field and displayed its breadth with several evolving areas. From merely a technological perspective, this field has seen tremendous growth and success. However, an incomplete understanding of human cancer biology persists relative to the application of nanoscale materials within contemporary oncology. As such, this review presents several evolving areas in cancer nanotechnology in order to identify key clinical and biological challenges that need to be addressed to improve patient outcomes. From this clinical perspective, a sampling of the nano-enabled solutions attempting to overcome barriers faced by traditional therapeutics and diagnostics in the clinical setting, are discussed. Finally, a strategic outlook of the future is discussed to highlight the need for next-generation cancer nanotechnology tools designed to address critical gaps in clinical cancer care.

Purpose: Grid therapy has promising applications in the radiation treatment of large tumors. However, research and applications of grid therapy are limited by the accessibility of the specialized blocks that produce the grid of pencil-like radiation beams. In this study, a Cerrobend grid block was fabricated using the 3D printing technique. Methods: A grid block mold was designed with flared tubes which follow the divergence of the beam. The mold was 3D printed using a resin with the working temperature below 230 °C. The melted Cerrobend liquid at 120 °C was cast into the resin mold to yield a block with a thickness of 7.4 cm. At the isocenter plane, the grid had a hexagonal pattern, with each pencil beam diameter of 1.4 cm; the distance between the beam centers was 2.1 cm. Results: The dosimetric properties of the grid block were studied using small field dosimeters: a pinpoint ionization chamber and a stereotactic diode. For a 6 MV photon beam, its valley-to-peak ratio was 20% at d max and 30% at 10 cm depth; the output factor was 84.9% at d max and 65.1% at 10 cm depth. Conclusions: This study demonstrates that it is feasible to implement 3D printing technique in applying grid therapy in clinic.

Hepatitis B virus infection is one of the major causes of hepatitis, liver cirrhosis and liver cancer. In this study, we used highly luminescent quantum dot-beads (QBs) as signal amplification probes in the sandwich immunochromatographic assay (ICA) for ultrasensitive and quantitative detection of hepatitis B virus surface antigen (HBsAg) in human serum. Various parameters that influenced the sensitivity and stability of the QB-based ICA (QB-ICA) sensor were investigated. Two linear independent regression equations for detection of serum HBsAg were expressed with Y=0.3361X-0.0059 (R(2)=0.9983) for low HBsAg concentrations between 75 pg mL(-1) and 4.8 ng mL(-1), and Y=0.8404 X-2.9364 (R(2)=0.9939) for high HBsAg concentrations in the range from 4.8 ng mL(-1) to 75 ng mL(-1). The detection limit of the proposed ICA sensor achieved was 75 pg mL(-1), which is much higher than that of the routinely-used gold nanoparticle based ICA. The intra- and inter-assays recovery rates for spiked serum samples at HBsAg concentrations of 75 pg mL(-1), 3.75 ng mL(-1) and 18.75 ng mL(-1) ranged from 90.14% to 97.6%, and coefficients of variation were all below 7%, indicating that the QB-ICA sensor has an acceptable accuracy for HBsAg detection. Additionally, the quantitative method developed showed no false positive results in an analysis of 49 real HBsAg-negative serum samples, and exhibited excellent agreement (R(2)=0.9209) with a commercial chemiluminescence immunoassay kit in identifying 47 HBsAg-positive serum samples. In summary, due to its high fluorescence intensity, the sandwich QB-ICA sensor is a very promising point-of-care test for rapid, simple and ultrasensitive detection of HBsAg, as well as other disease-related protein biomarkers.

Mycotoxin pollutants are commonly related to cereal products and cause fatal threats in food safety, and therefore require simple and sensitive detection. In this work, quantum-dot (QD) submicrobeads (QBs) were synthesized by encapsulating CdSe/ZnS QDs using the microemulsion technique. The resultant QBs, with approximately 2800 times brighter luminescence than the corresponding QDs, were explored as novel fluorescent probes in the immunochromatographic assay (ICA) for sensitive and quantitative detection of zearalenone (ZEN) in corns. Various parameters that influenced the sensitivity and stability of QB-based ICA (QB-ICA) were investigated and optimized. The optimal QB-ICA exhibits good dynamic linear detection for ZEN over the range of 0.125 ng/mL to 10 ng/mL with a median inhibitory concentration of 1.01±0.09 ng/mL (n=3). The detection limits for ZEN in a standard solution and real corn sample (dilution ratio of 1:30) are 0.0625 ng/mL and 3.6 µg/kg, respectively, which is much better than that of a previously reported gold nanoparticle-based ICA method. Forty-six natural corn samples are assayed using both QB-ICA and enzyme-linked immunosorbent assay. The two methods show a highly significant correlation (R(2)=0.92). Nine ZEN-contaminated samples were further confirmed with liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the QB-ICA results also exhibited good agreement with LC-MS/MS method. In brief, this work demonstrates that QB-ICA is capable of rapid, sensitive screening of toxins in food analysis, and shows great promise for point-of-care testing of other analytes.

Background and purpose To evaluate the safety and efficacy of liver stereotactic body radiotherapy (SBRT), and examine potential factors impacting outcomes including prior liver-directed therapy. Materials and methods Patients with ECOG 0–1, Child-Pugh Class A or B, and primary hepatocellular carcinoma (HCC) or liver metastases unsuitable for surgical resection or ablation were eligible for a prospective single arm trial. SBRT was delivered with a CyberKnife system to 45 Gy in 3 fractions with a predetermined dose de-escalation scheme. Adverse events, local control, and survival were assessed. Results A total of 30 patients were enrolled. Eleven patients (37%) had HCC and 19 (63%) patients had liver metastases. Fourteen patients (47%) had prior liver-directed therapies including nine with liver resection, seven with trans-arterial chemoembolization, and six with radiofrequency ablation. Cumulative grade 2 and 3 acute toxicity occurred in 47% and 7% of patients, respectively. Similar rates of ≥grade 2 acute toxicity were observed between patients who had prior liver-directed treatments and those who did not. At a median follow-up of 12.7 months, 1-year local control and overall survival were 81% and 62%, respectively. Prior liver-directed therapy did not affect local control or survival. Conclusions Liver SBRT is a safe and effective treatment even in the setting of prior liver-directed surgical and ablative therapies.

Mass customization along with the ability to generate designs using medical imaging data makes 3D printing an attractive method for the fabrication of patient-tailored drug and medical devices. Herein we describe the application of Continuous Liquid Interface Production (CLIP) as a method to fabricate biocompatible and drug-loaded devices with controlled release properties, using liquid resins containing active pharmaceutical ingredients (API). In this work, we characterize how the release kinetics of a model small molecule, rhodamine B-base (RhB), are affected by device geometry, network crosslink density, and the polymer composition of polycaprolactone- and poly (ethylene glycol)-based networks. To demonstrate the applicability of using API-loaded liquid resins with CLIP, the UV stability was evaluated for a panel of clinically-relevant small molecule drugs. Finally, select formulations were tested for biocompatibility, degradation and encapsulation of docetaxel (DTXL) and dexamethasone-acetate (DexAc). Formulations were shown to be biocompatible over the course of 175 days of in vitro degradation and the clinically-relevant drugs could be encapsulated and released in a controlled fashion. This study reveals the potential of the CLIP manufacturing platform to serve as a method for the fabrication of patient-specific medical and drug-delivery devices for personalized medicine.

Circulating tumor cells (CTCs) are cells that have detached from the primary tumor and entered circulation with potential to initiate a site of metastasis. Currently, CTC detection using CellSearch is cleared by the Food and Drug Administration for monitoring metastatic breast, prostate, and colorectal cancers as a prognostic biomarker for progression-free and overall survival. Accumulating evidence suggests CTCs have similar prognostic value in other metastatic and non-metastatic settings. Current research efforts are focused on extending the utility of CTCs beyond a prognostic biomarker to help guide clinical decision-making. These include using CTCs as a screening tool for diagnosis, liquid biopsy for molecular profiling, predictive biomarker to specific therapies, and monitoring tool to assess response and guide changes to treatment. CTCs have unique advantages vs circulating tumor DNA in this endeavor. Indications for CTCs in daily practice will expand as isolation techniques improve and clinical studies validating their utility continue to grow.

Purpose: To describe a case report of lungradiosurgery in which defining a target using a maximal intensity projection CT omitted a portion of the target due to an overlapping projection of the diaphragm. Methods: A Lung 4DCT was obtained, and all ten breathing phases from 0% to 90% were reconstructed. The gating window was set to treat phases 30% to 70%, and the corresponding Maximum Intensity Projection (MIP) was generated. An ITV was contoured on the MIP. Tumor GTVs were contoured on all phases. Another ITV was generated by using the overlapped projection of all GTVs in the gating window when suspicion arose that part of the target was omitted. The volumes of the ITVs and GTVs were calculated. DVHs were analyzed on the plan generated to cover the MIP ITV. Results: The initial ITV based on the MIP omitted 15% of the target Since the ITVs of the diaphragm and the tumor overlap in the MIP, and the imaging technique cannot differentiate them, contouring tumor only on MIP has risk of missing part of the tumor. We have also found that the volumes of all 10 phases fluctuate with a standard deviation of 5.6%. This indicates the imperfection of 4DCT generation. If the treatment plan was generated based on MIP ITV, DVH shows the lack of coverage for the true ITV. Conclusions: We propose two methods to accurately delineate tumor ITV from 4DCT for cases in which the target is located adjacent to diaphragm. If it is desired to start with contouring ITV on MIP, thorough QA needs to be done by going through all gating phases to adjust the ITV accordingly. A more straightforward method is to contour the GTV on all gating phases and use the overlapped projections as the ITV.

Cytotoxic chemotherapies have a narrow therapeutic window, with high peaks and troughs of plasma concentration. Novel nanoparticle formulations of cytotoxic chemotherapy drugs can enhance pharmacokinetic characteristics and facilitate passive targeting of drugs to tumors via the enhanced permeability and retention effect, thus mitigating toxicity. Nanoparticle vehicles currently in clinical use or undergoing clinical investigation for anticancer therapies include liposomes, polymeric micelles, protein-drug nanoparticles, and dendrimers. Multiple nanoparticle formulations of existing cytotoxic chemotherapies are approved for use in several indications, with clinical data indeed showing optimization of pharmacokinetics and different toxicity profiles compared with their parent drugs. There are also many new nanoparticle drug formulations in development and undergoing early- and late-phase clinical trials, including several that utilize active targeting or triggered release based on environmental stimuli. Here, we review the rationale for nanoparticle formulations of existing or previously investigated cytotoxic drugs, describe currently approved nanoparticle formulations of drugs, and discuss some of the most promising clinical trials currently underway.

Significant advances have been made in the field of cancer immunotherapy by orchestrating the body's immune system to eradicate cancer cells. However, safety and efficacy concerns stemming from the systemic delivery of immunomodulatory compounds limits cancer immunotherapies expansion and application. In this context, nanotechnology presents a number of advantages, such as targeted delivery to immune cells, enhanced clinical outcomes, and reduced adverse events, which may aid in the delivery of cancer vaccines and immunomodulatory agents. With this in mind, a diverse range of nanomaterials with different physicochemical characteristics have been developed to stimulate the immune system and battle cancer. In this review, we will focus on some recent developments and the potential advantages of utilizing nanotechnology within the field of cancer immunotherapy. WIREs Nanomed Nanobiotechnol 2017, 9:e1456. doi: 10.1002/wnan.1456 For further resources related to this article, please visit the WIREs website.

Prostate brachytherapy is an important treatment technique for patients with localized prostate cancer. An inflatable rectal ultrasound probe cover is frequently utilized during the procedure to adjust for unfavorable prostate position relative to the implant grid. However, the inflated cover causes prostate deformation, which is not accounted for during dosimetric planning. Most of the therapeutic dose is delivered after the procedure when the prostate and surrounding organs-at-risk are less deformed. The aim of this study is to quantify the potential dosimetry changes between the initial plan (prostate deformed) and the more realistic dosimetry when the prostate is less deformed without the cover.The authors prospectively collected the ultrasound images of the prostate immediately preceding and just after inflation of the rectal probe cover from thirty-four consecutive patients undergoing real-time planning of I-125 permanent seed implant. Manual segmentations of the deformed and undeformed images from each case were used as the input for model training to generate the initial transformation of a testing patient. During registration, the pixel-to-pixel transformation was further optimized to maximize the mutual information between the transferred deformed image and the undeformed images. The accuracy of image registration was evaluated by comparing the displacement of the urethra and calcification landmarks and by determining the Dice index between the registered and manual prostate contours. After registration, using the optimized transformation, the implanted seeds were mapped from the deformed prostate onto the undeformed prostate. The dose distribution of the undeformed anatomy, calculated using the VariSeed treatment planning system, was then analyzed and compared with that of the deformed prostate.The accuracy of image registration was 1.5 ± 1.0 mm when evaluated by the displacement of calcification landmarks, 1.9 ± 1.1 mm when characterized by the displacement of the centroid of the urethra, and 0.86 ± 0.05 from the determination of the Dice index of prostate contours. The magnitude of dosimetric changes was associated with the degree of prostate deformation. The prostate coverage V100% dropped from 96.6 ± 1.7% on prostate-deformed plans to 92.6 ± 3.8% (p0.01) on undeformed plans, and the rectum V100% decreased from 0.48 ± 0.39 to 0.06 ± 0.14 cmProstate deformation from the inflation of an ultrasound rectal probe cover can significantly alter brachytherapy dosimetry. The authors have developed a deformable image registration method that allows for the characterization of dose with the undeformed anatomy. This may be used to more accurately reflect the dosimetry when the prostate is not deformed by the probe cover.

Radiotherapy has been an integral treatment modality for cancer. The field arose from and progressed through innovations in physics, engineering, and biology. The evolution of radiation oncology will rely on the continued adoption of advances from other fields. A new area of science that possesses the ability to impact radiation oncology is nanomedicine. Materials on the nanoscale provide many unique properties such as enhanced permeability and retention effect and superparamagnetism that are well suited for applications in radiation oncology. In this review, we will provide a comprehensive summary on how nanotechnology can improve cancer radiotherapy in aspects of treatment delivery and monitoring as well as diagnosis.

Peritoneal adhesion occurs in a majority of patients following abdominal surgery and can result in significant side effects and complications. Current strategies to minimize adhesions involve the use of nontargeted anatomical barriers that are either inefficient in protecting injured areas or lacking the adequate residence time to prevent adhesions. Herein, the development of a biologically targeted photo‐crosslinkable nanopatch (pCNP) is reported that can prevent postsurgical adhesion. It is demonstrated that pCNP can form a compact protective barrier over surfaces with exposed collagen IV. Using a rat parietal peritoneal excision adhesion model, it is showed that pCNP is highly effective and safe in preventing postsurgical adhesions. This work presents a novel approach to preventing peritoneal adhesion with nanomaterials.

Background: Circulating tumor cells (CTCs) have great potential as biomarkers for the diagnosis and prognosis of many cancers. The CapioCyteTM chip isolates live CTCs through a unique combination of biomimetic cell rolling and nanoparticle-mediated multivalent immunorecognition. Recently-published work reported the highly sensitive and specific CTC capture from 24 patients in a pilot study [Myung et al., Clinical Cancer Research 2018, 24(11):2439-2547]. Here, we report results from additional cohorts of patients and demonstrate downstream analysis of captured CTCs. Methods: Peripheral blood samples were collected from patients undergoing radiotherapy (RT) (n=12; oligometastic n = 5, head and neck cancer n = 1, non small cell lung cancer n = 2, prostate cancer n = 3, cervical cancer n = 1) or immunotherapy (n=4). Samples were processed the next day by CapioCyteTM chips designed for the immunoisolation cells expressing epithelial cell adhesion molecule (EpCAM), human epidermal growth factor-2 (HER-2), and epidermal growth factor receptor (EGFR). Captured CTCs were identified by immunocytochemistry as containing round nuclei, positive expression of cytokeratin, and negative expression of CD45. Select samples were recovered from the capture surface and submitted for single cell gene expression assays (RNASeq) using 10X Genomics Chromium barcoding and Illumina next-generation sequencing. Results: Immunocytochemical staining identified CTCs in all pre-treatment blood samples from patients undergoing RT (mean 95 CTC/ml whole blood, SE 54, range 4-680) and immunotherapy (mean 70 CTC/ml whole blood, SE 16, range 39-104). CTC counts decreased with time points collected during and post-treatment, consistent with other measures of treatment progress. Single cell RNASeq confirmed the presence of tumor-derived cells in select samples and, importantly, demonstrated the ability to conduct downstream analysis of CTCs isolated on the CapioCyteTM chip. Conclusions: The CapioCyteTM chip effectively captures CTCs for quantification and downstream analysis requiring viable cells such as RNASeq. The liquid biopsy technology has great potential to contribute to diagnosis and personalized treatment of cancer. Citation Format: Michael J. Poellmann, Jiyoon Bu, Dominic Moon, Kyle Wagner, Andrew Z. Wang, Seungpyo Hong. Quantification and downstream analysis of circulating tumor cells isolated using CapioCyteTM liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 410.

Background: One of the major concerns in cancer treatment and clinical translation of many anti-cancer compounds has been their potential toxicities, especially hepatotoxicity. Nanoparticle (NP) holds great potential to solve the problem, as many clinical studies have not shown increased hepatotoxicity for nanotherapeutics with higher accumulation in the liver. However, there are few studies investigating how nanoparticle assists in reducing hepatotoxicity. Herein, we demonstrated that nanoformulation of known hepatotoxic anti-cancer compounds showed lower hepatotoxicity than their small molecule counterparts. Importantly, we demonstrated that slower drug release is associated with reduced hepatotoxicity. We also showed that that Kupffer cell uptake in the liver reduce nanotherapeutics’ hepatotoxicity. Methods: Two different antineoplastic drugs with high hepatotoxicity, SN-38 and wortmannin (Wtmn), were encapsulated into lipid shell-PLGA core nanoparticles separately. NP release kinetics were controlled by adjusting lipids/polymer ratio for fast (Fast-NPs), medium (Medium-NPs) and slow drug release profile (Slow-NPs), respectively. Hepatotoxicity of NPs or free drugs was analyzed by assessing serum ALT and AST levels post intravenous injection at ½ MTD in CD-1 mice. IHC staining of HO-1 and Mn-SOD was also used to show liver damage. In vitro hepatotoxicity of primary hepatocytes after Kupffer cell uptake was assessed by MTS assay and LDH assay. In vivo macrophage depletion was achieved using clodrosome. Results: Nanoformulations of SN-38 and Wtmn showed lower ALT and AST levels than their small molecule counterparts 12 h and 24 h post treatment. The liver damage was further confirmed with IHC staining of Mn-SOD and HO-1. To address the effect of drug release kinetics on hepatotoxicity, we showed that over 90% of drugs were released within 24 h in Fast-NP. While the release rate of Slow-NPs was 66.8% for SN-38 and 67.5% for Wtmn. We showed that Slow-NPs of Wtmn resulted in minimal increase of ALT and AST levels. Compared to the baseline in untreated mice, the ALT level was 2.3-fold for Slow-NPs, 4.4-fold for Medium-NPs and 6-fold for fast-NPs; meanwhile, the AST level was 1.6-fold, 2.5-fold and 3.6-fold, respectively. To assess the effect of Kupffer cell uptake in hepatotoxicity, we found that the toxicity of the nanotherapeutics for primary hepatocytes significantly reduced after Kupffer cell uptake in vitro. We further confirmed it in vivo by depleting Kupffer cells in CD-1 mice. We demonstrated that ALT and AST levels of nanotherapeutics significantly increased to the levels comparable to free drugs after Kupffer cell depletion. Conclusions: We demonstrate that nanoparticle reduces hepatotoxicity of cancer treatment by controlled release and Kupffer cell uptake. Our work bridges an important knowledge in nanoparticle drug delivery and clinical translation of nanomedicine. Citation Format: Yu Mi, Feifei Yang, Andrew Z. Wang. Nanoparticle reduces hepatotoxicity of cancer treatment by controlled release and Kupffer cell uptake [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3899.

Cancer immunotherapy has achieved remarkable clinical efficacy through recent advances such as chimeric antigen receptor‐T cell (CAR‐T) therapy, immune checkpoint blockade (ICB) therapy, and neoantigen vaccines. However, application of immunotherapy in a clinical setting has been limited by low durable response rates and immune‐related adverse events. The rapid development of nano‐/microtechnologies in the past decade provides potential strategies to improve cancer immunotherapy. Advances of nano‐/microparticles such as virus‐like size, high surface to volume ratio, and modifiable surfaces for precise targeting of specific cell types can be exploited in the design of cancer vaccines and delivery of immunomodulators. Here, the emerging nano‐/microapproaches in the field of cancer vaccines, immune checkpoint blockade, and adoptive or indirect immunotherapies are summarized. How nano‐/microparticles improve the efficacy of these therapies, relevant immunological mechanisms, and how nano‐/microparticle methods are able to accelerate the clinical translation of cancer immunotherapy are explored.

MAGNETIC IRON OXIDE NANOPARTICLES (IONPs) have been used as contrast agents of magnetic resonance imaging (MRI) for diagnostic imaging (1-3) and more recently for developing MRI-based molecular imaging probes in various biomedical applications, including cell tracking (4,5), biomarker targeted cancer imaging (6-8), and image guided drug delivery (9-11). IONPs, as a superparamagnetic agent, primarily shorten transverse relaxation times, ie, T2 and T2*, which leads to prominent signal decrease or "negative contrast" of targeted tissue on T2- and T2*-weighted images (12-14). The typical drawback of the T2- and T2*-weighted negative contrast is its poor sensitivity when used to study areas with low background signal. In addition, T2- and T2*-weighted imaging methods are also vulnerable to blooming artifacts and the partial volume errors from the effect of local magnetic inhomogeneity and high susceptibility of paramagnetic IONPs (15,16), making accurate localization and quantitative imaging of magnetic nanoparticles more difficult. It should also be mentioned that further improvement of negative contrast is limited by the threshold of the negative contrast which is the difference between the signal level of IONP affected area and signal intensity of zero (17). Therefore, conventional T2- and T2*-weighted imaging methods may not be able to take advantage of those magnetic nanoparticle probes with very high r2 relaxivity or increase of the dosage of administered IONPs because of the threshold of the negative contrast, as the maximal contrast that the negative contrast can reach is the signal intensity of zero. Therefore, a method of generating positive contrast from magnetic nanoparticles, ie, signal brightening, to improve the detection, and even quantification, of magnetic nanoparticles is desirable and has attracted increasing effort in translating magnetic nanoparticle imaging probes to broader applications (18-20). A number of approaches have been investigated to obtain positive contrast from IONPs, including ultrashort echo time (UTE) imaging (18,21,22), off-resonance saturation (ORS) techniques (23), sweep imaging with Fourier transformation (SWIFT) (24-27), phase contrast (28-30) and, most recently, adiabatic imaging (31,32). Among them, UTE imaging offers a relatively simple strategy by taking advantage of high longitudinal relaxivity r1 of IONPs while reducing the contribution of predominant T2 and T2* and spin dephase effects of IONPs that are also sources of imaging artifacts. With a very short echo time, typically below 0.1 msec, UTE imaging enables capturing signal enhancement from T1 effect with little influence of signal decay from the T2 and T2* effect, allowing for obtaining positive contrast on T1-weighted UTE images. Furthermore, the signal enhancement obtained from the UTE imaging is a function of T1 relaxation times of IONPs at different core sizes and concentrations in a certain range (18). A recent study by Girard et al (22) discussed the general strategy to optimize IONP detection sensitivity using UTE imaging. Through detailed computer simulation, imaging experiments on IONP phantoms in vitro and a proof-of-concept mouse model bearing human prostate tumors in vivo, it was shown that UTE imaging and subtraction of a longer echo signal from that of the UTE (SubUTE) were good approaches for imaging of IONP. In the present study, we report further investigation and application of UTE and SubUTE imaging for the detection and visualization of the receptor targeted IONP imaging probes in cancer xenograft mouse models using positive contrast enhancement. The main purpose was to demonstrate the capability of UTE imaging to obtain positive contrast from biomarker targeted magnetic nanoparticle probes selectively accumulated in the human pancreatic and breast cancer xenograft models in the mice in vivo.

Nanoparticle (NP) drug loading is one of the key defining characteristics of an NP formulation. However, the effect of NP drug loading on therapeutic efficacy and pharmacokinetics has not been thoroughly evaluated. Herein, we characterized the efficacy, toxicity and pharmacokinetic properties of NP docetaxel formulations that have differential drug loading but are otherwise identical. Particle Replication in Non-wetting Templates (PRINT(®)), a soft-lithography fabrication technique, was used to formulate NPs with identical size, shape and surface chemistry, but with variable docetaxel loading. The lower weight loading (9%-NP) of docetaxel was found to have a superior pharmacokinetic profile and enhanced efficacy in a murine cancer model when compared to that of a higher docetaxel loading (20%-NP). The 9%-NP docetaxel increased plasma and tumor docetaxel exposure and reduced liver, spleen and lung exposure when compared to that of 20%-NP docetaxel.

Recent advances in molecular imaging and nanotechnology are providing new opportunities for biomedical imaging with great promise for the development of novel imaging agents. The unique optical, magnetic, and chemical properties of materials at the scale of nanometers allow the creation of imaging probes with better contrast enhancement, increased sensitivity, controlled biodistribution, better spatial and temporal information, multi-functionality and multi-modal imaging across MRI, PET, SPECT, and ultrasound. These features could ultimately translate to clinical advantages such as earlier detection, real time assessment of disease progression and personalized medicine. However, several years of investigation into the application of these materials to cancer research has revealed challenges that have delayed the successful application of these agents to the field of biomedical imaging. Understanding these challenges is critical to take full advantage of the benefits offered by nano-sized imaging agents. Therefore, this article presents the lessons learned and challenges encountered by a group of leading researchers in this field, and suggests ways forward to develop nanoparticle probes for cancer imaging. Published by Elsevier Ltd.

Platinum-based chemotherapy, such as cisplatin, oxaliplatin, and carboplatin, is one of the most widely utilized classes of cancer therapeutics. While highly effective, the clinical applications of platinum-based drugs are limited by their toxicity profiles as well as suboptimal pharmacokinetic properties. Therefore, one of the key research areas in oncology has been to develop novel platinum analog drugs and engineer new platinum drug formulations to improve the therapeutic ratio further. Such efforts have led to the development of platinum analogs including nedaplatin, heptaplatin, and lobaplatin. Moreover, reformulating platinum drugs using liposomes has resulted in the development of L-NDPP (Aroplatin™), SPI-77, Lipoplatin™, Lipoxal™, and LiPlaCis®. Liposomes possess several attractive biological activities, including biocompatibility, high drug loading, and improved pharmacokinetics, that are well suited for platinum drug delivery. In this review, we discuss the various platinum drugs and their delivery using liposome-based drug delivery vehicles. We compare and contrast the different liposome platforms as well as speculate on the future of platinum drug delivery research.

Chemoradiotherapy, the concurrent administration of chemotherapy and radiotherapy, is a treatment paradigm in oncology. It is part of the standard of care and curative treatment of many cancers. Given its importance, one of the primary goals of cancer research has been to identify agents and/or strategies that can improve the therapeutic index of chemoradiation. Recent advances in nanomedicine have provided a unique and unprecedented opportunity for improving chemoradiotherapy. Nanoparticles possess properties that are ideally suited for delivering chemotherapy in the chemoradiation setting. The goal of this review is to examine the role of incorporating nanomedicine into chemoradiation and the potential impact of nanomedicine to chemoradiotherapy.

Nanomedicine is a relatively new field that is rapidly evolving. Formulation of drugs on the nanoscale imparts many physical and biological advantages. Such advantages can in turn translate into improved therapeutic efficacy and reduced toxicity. While approximately 50 nanotherapeutics have already entered clinical practice, a greater number of drugs are undergoing clinical investigation for a variety of indications. This review aims to examine all the nanoformulations that are currently undergoing clinical investigation and their outlook for ultimate clinical translation. WIREs Nanomed Nanobiotechnol 2017, 9:e1416. doi: 10.1002/wnan.1416 For further resources related to this article, please visit the WIREs website.

Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.

Purpose The importance of patient-reported outcomes is well-recognized. Long-term patient-reported symptoms have been described for individuals who completed radiation therapy (RT) for prostate cancer. However, the trajectory of symptom development during the course of treatment has not been well-described in patients receiving modern, image-guided RT. Methods and materials Quality-of-life data were prospectively collected for 111 prostate cancer patients undergoing RT using the validated Prostate Cancer Symptom Indices, which assessed 5 urinary obstructive/irritative and 6 bowel symptoms. Patients who received definitive RT (N = 73) and postprostatectomy RT (N = 38) were analyzed separately. The frequency and severity of symptoms over multiple time points are reported. Results An increasing number of patients had clinically meaningful urinary and bowel symptoms over the course of RT. A greater proportion of patients undergoing definitive RT reported clinically meaningful urinary symptoms at the end of RT compared with baseline in terms of flow (33% vs 19%) and frequency (39% vs 18%). Individuals receiving postprostatectomy radiation also reported an increase in symptoms including frequency (29% vs 3%) and nocturia (50% vs 21%). Clinically meaningful bowel symptoms were less commonly reported. Patients receiving definitive RT reported an increase in diarrhea (9% vs 4%) and urgency (12% vs 6%) at the completion of RT compared with baseline. Both bowel and urinary symptoms approached their baseline levels by the time of first follow-up after treatment completion. The majority of patients who had clinically meaningful urinary or bowel symptoms during RT did not have them at 2 years or beyond, and development of new symptoms in the long term was uncommon. Conclusions There is a modest increase in urinary and bowel symptoms over the course of treatment for individuals receiving definitive and postprostatectomy image-guided RT. These data can help inform both providers and patients regarding the trajectory of symptoms and allow for reasonable expectations regarding toxicity under treatment.

Tumor vasculature is known to be immature and leaky. Its hyperpermeability is thought to be the cause of high tumor interstitial pressure as well as the enhanced permeability and retention (EPR) effect, in which small particles escape the vasculature and are retained in the tumor. The traditional view of tumor vessel leakiness is that they possess pores and are constantly leaky. However, this view does not completely account for observations of uneven nanoparticle distribution within tumors despite their small size. Matsumoto et al. aimed to characterize and understand the differences in tumor distribution between 30- and 70-nm fluorescent nanoparticles. To visualize their distribution, the investigators used intravital microscopy in mice bearing human pancreatic and glioblastoma tumors. They observed “eruptions”—vascular bursts followed by brief, vigorous outflows of fluid—from the tumors. Both types of nanoparticles were released by these eruptions, but the smaller nanoparticles were dispersed more readily. Based on these observations, the authors proposed a “dynamic vent” model for tumor vasculature. The results from this study have strong implications for designing drug delivery systems for cancer, suggesting that even very large particles can extravasate into the tumor interstitium. In addition, the study provides more support for the EPR effect as well as an explanation for tumor distribution variability between different sizes of nanoparticles. How best to take advantage of this dynamic vent, to design more effective nanotherapeutics for cancer treatment, is yet to be seen. Y. Matsumoto et al. , Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery. Nat. Nanotechnol. 10.1038/nnano.2015.342 (2016). [[Abstract]][1] [1]: http://www.nature.com/nnano/journal/vaop/ncurrent/full/nnano.2015.342.html

Gene therapy promises to correct genomic aberrations and treat many human illnesses, especially owing to the advent of CRISPR/Cas9 technology, a gene editing tool. Another gene therapy technology that involves nanoparticle delivery of nucleic acids, such as mRNA and siRNA, which alter gene

Segmenting male pelvic organs from CT images is a prerequisite for prostate cancer radiotherapy. The efficacy of radiation treatment highly depends on segmentation accuracy. However, accurate segmentation of male pelvic organs is challenging due to low tissue contrast of CT images, as well as large variations of shape and appearance of the pelvic organs. Among existing segmentation methods, deformable models are the most popular, as shape prior can be easily incorporated to regularize the segmentation. Nonetheless, the sensitivity to initialization often limits their performance, especially for segmenting organs with large shape variations. In this paper, we propose a novel approach to guide deformable models, thus making them robust against arbitrary initializations. Specifically, we learn a displacement regressor, which predicts 3D displacement from any image voxel to the target organ boundary based on the local patch appearance. This regressor provides a non-local external force for each vertex of deformable model, thus overcoming the initialization problem suffered by the traditional deformable models. To learn a reliable displacement regressor, two strategies are particularly proposed. 1) A multi-task random forest is proposed to learn the displacement regressor jointly with the organ classifier; 2) an auto-context model is used to iteratively enforce structural information during voxel-wise prediction. Extensive experiments on 313 planning CT scans of 313 patients show that our method achieves better results than alternative classification or regression based methods, and also several other existing methods in CT pelvic organ segmentation.

Purpose: Prostate brachytherapy is an important treatment technique for patients with localized prostate cancer. An inflatable rectal ultrasound probe cover is frequently utilized during the procedure to adjust for unfavorable prostate position relative to the implant grid. However, the inflated cover causes prostate deformation, which is not accounted for during dosimetric planning. Most of the therapeutic dose is delivered after the procedure when the prostate and surrounding organs-at-risk are less deformed. The aim of this study is to quantify the potential dosimetry changes between the initial plan (prostate deformed) and the more realistic dosimetry when the prostate is less deformed without the cover. Methods: The authors prospectively collected the ultrasound images of the prostate immediately preceding and just after inflation of the rectal probe cover from thirty-four consecutive patients undergoing real-time planning of I-125 permanent seed implant. Manual segmentations of the deformed and undeformed images from each case were used as the input for model training to generate the initial transformation of a testing patient. During registration, the pixel-to-pixel transformation was further optimized to maximize the mutual information between the transferred deformed image and the undeformed images. The accuracy of image registration was evaluated by comparing the displacement of the urethra and calcification landmarks and by determining the Dice index between the registered and manual prostate contours. After registration, using the optimized transformation, the implanted seeds were mapped from the deformed prostate onto the undeformed prostate. The dose distribution of the undeformed anatomy, calculated using the VariSeed treatment planning system, was then analyzed and compared with that of the deformed prostate. Results: The accuracy of image registration was 1.5 ± 1.0 mm when evaluated by the displacement of calcification landmarks, 1.9 ± 1.1 mm when characterized by the displacement of the centroid of the urethra, and 0.86 ± 0.05 from the determination of the Dice index of prostate contours. The magnitude of dosimetric changes was associated with the degree of prostate deformation. The prostate coverage V100% dropped from 96.6 ± 1.7% on prostate-deformed plans to 92.6 ± 3.8% (p < 0.01) on undeformed plans, and the rectum V100% decreased from 0.48 ± 0.39 to 0.06 ± 0.14 cm3 (p < 0.01). The dose to the urethra increased, with the V150% increasing from 0.02 ± 0.06 to 0.11 ± 0.10 cm3 (p < 0.01) and D1% changing from 203.5 ± 22.7 to 239.5 ± 25.6 Gy (p < 0.01). Conclusions: Prostate deformation from the inflation of an ultrasound rectal probe cover can significantly alter brachytherapy dosimetry. The authors have developed a deformable image registration method that allows for the characterization of dose with the undeformed anatomy. This may be used to more accurately reflect the dosimetry when the prostate is not deformed by the probe cover.

Inflammation-triggered combination delivery of anti-PD-1 antibody (aPD1) and CpG oligodeoxynucleotides (CpG ODNs) has been demonstrated to prevent cancer relapse utilizing post-surgical inflammatory response. The controlled release of anti-PD1 antibodies and CpG ODN by CpG DNA-based “nano-cocoon” can induce considerable immune response, which in turn significantly prolonged the survival time and complete response (CR) rate. This study provides a new strategy to reduce the risk of cancer relapse and metastasis after resection of the primary tumor.

Study Type – Therapy (phase 1) Level of Evidence 2a What's known on the subject? and What does the study add? High-risk and locally advanced prostate cancers are difficult to cure with the standard regimen of radiation therapy (RT) with concurrent androgen-deprivation therapy (ADT). Multiple studies have explored the addition of docetaxel chemotherapy in attempt to improve patient outcomes. Prior Phase I studies have shown that docetaxel 20 mg/m2 is a safe dose, when given concurrently with 70 Gy of radiation. But current standard RT for prostate cancer uses higher doses, and it is unclear if concurrent chemotherapy is safe with modern RT. This is a Phase I study that explored the addition of concurrent docetaxel chemotherapy to modern RT (intensity-modulated RT to 78 Gy) plus ADT. The study showed that weekly docetaxel at 20 mg/m2 is safe with modern RT. At a median follow-up of 2.2 years, biochemical progression-free survival was 94%. This triple-therapy regimen is safe and promising for further evaluation in prospective trials. OBJECTIVE • To evaluate in a phase I trial, the feasibility of adding concurrent weekly docetaxel chemotherapy to high-dose intensity modulated radiation therapy (IMRT) and androgen-deprivation therapy (ADT) for treatment of high-risk prostate cancer. PATIENTS AND METHODS • Patients with high-risk prostate cancer were treated with a luteinising hormone-releasing hormone agonist (starting 2–3 months before IMRT and lasting 2 years), IMRT of 78 Gy to the prostate and seminal vesicles, and weekly docetaxel during RT. • All patients had computed tomography and bone scans to exclude metastatic disease. • A standard 3 + 3 design was used for docetaxel dose escalation. Successive patients were treated on dose levels of 10, 15, and 20 mg/m2 of weekly docetaxel. RESULTS • In all, 18 patients participated in the study: 15 (83%) had Gleason 8–10 disease; the other three had either clinical T3 disease and/or a prostate-specific antigen (PSA) level of >20 ng/mL. • Grade 3 diarrhoea (a defined dose-limiting toxicity, DLT) occurred in one patient in each of the first two dose levels. However, when the cohorts were expanded, no further DLT was seen. • Weekly docetaxel at 20 mg/m2 (dose level 3) was successfully given without DLT. • No patient had grade 4 or 5 toxicity. • At a median follow-up of 2.2 years, all patients achieved a PSA nadir of

The purpose of this study was to synthesize, characterize and tailor the surface properties of magnetic nanoparticles with biocompatible copolymer coatings and to evaluate the efficiency of the resulting nanoconjugates as magnetic resonance imaging (MRI) contrast agents for liver imaging. Magnetic nanoparticles with core diameters of 10 and 30 nm were synthesized by pyrolysis and were subsequently coated with a copolymer containing either carboxyl (SHP) or methoxy groups as termini. All four formulas, and ferumoxides (Feridex I.V.®), were individually injected intravenously into separate, normal Balb/C mice (at 2.5, 1.0 and 0.56 mg Fe kg−1), and the animals underwent T2-weighted MRI at multiple time points post injection (p.i.) to evaluate the hepatic uptake and clearance. Furthermore, we compared the abilities of the new formulas and Feridex to detect tumors in an orthotropic Huh7 tumor model. Transmission electron microscopy (TEM) revealed a narrow size distribution of both the 10 and 30 nm nanoparticles, in contrast to a wide size distribution of Feridex. MTT, apoptosis and cyclin/DNA flow cytometry assays showed that the polymer coated nanoparticles had no adverse effect on cell growth. Among all the tested formulas, including Feridex, SHP-30 showed the highest macrophage uptake at the in vitro level. In vivo MRI studies on normal mice confirmed the superiority of SHP-30 in inducing hypointensities in the liver tissue, especially at clinical dose (0.56 mg Fe kg−1) and 3 T field. SHP-30 showed better contrast-to-noise ratio than Feridex on the orthotropic Huh7 tumor model. SHP-30 was found to be an efficient contrast agent for liver MR imaging. The success of this study suggests that, by improving the synthetic approach and by tuning the surface properties of IONPs, one can arrive at better formulas than Feridex for clinical practice. Copyright © 2012 John Wiley & Sons, Ltd.

Chemoradiotherapy is an important treatment paradigm in oncology and is part of the curative treatment for many solid cancers, such as lung, pancreatic and cervical cancers. One of the main goals in oncology research is to develop approaches that can improve the efficacy of chemoradiotherapy while minimizing treatment toxicity. A new and exciting approach is to incorporate advances in nanomedicine into chemoradiotherapy. Nanoparticles possess unique properties, such as preferential accumulation in tumors and minimal uptake in normal tissues, that make them ideally suited for delivering chemotherapy in chemoradiotherapy. In this review, we plan to discuss the rationale and evidence for applying nanomedicine to chemoradiotherapy.

Nanoparticles containing stable holmium ((165) Ho) are prepared by nanotemplate engineering and subsequently irradiated in a neutron flux to yield (166) Ho, a beta-emitting radiotherapeutic isotope. After intraperitoneal injection to mice bearing SKOV-3 ovarian tumors, significant tumor accumulation of the (166) Ho-nanoparticles is observed by SPECT imaging indicating the potential of these neutron activatable nanoparticles for internal radiation therapy of ovarian cancer metastases.

Peritoneal metastasis is a major cause of morbidity and mortality in ovarian cancer. While intraperitoneal chemotherapy and radiotherapy have shown favorable clinical results, both are limited by their non-targeted nature. We aimed to develop a biologically targeted nanoparticle therapeutic for the treatment of ovarian cancer peritoneal metastasis. Folate-targeted nanoparticles encapsulating chemotherapy and/or radiotherapy were engineered. Paclitaxel (Ptxl) was used as the chemotherapeutic and yittrium-90 ((90)Y) was employed as the therapeutic radioisotope. Folate was utilized as the targeting ligand as most ovarian cancers overexpress the folate receptor. Nanoparticle characterization studies showed monodispersed particles with controlled Ptxl release. Folate targeting ligand mediated the uptake of NPs into tumor cells. In vitro efficacy studies demonstrated folate-targeted NPs containing chemoradiotherapy was the most effective therapeutic compared to folate-targeted NPs containing a single therapeutic or any non-targeted NP therapeutics. In vivo efficacy studies using an ovarian peritoneal metastasis model showed that folate-targeted NP therapeutics were significantly more effective than non-targeted NP therapeutics. Among the folate-targeted therapeutics, the NP containing chemoradiotherapy appeared to be the most effective. Our results suggest that folate-targeted nanoparticles containing chemoradiotherapy have the potential as a treatment for ovarian peritoneal metastasis.

Nanoparticle (NP) chemotherapeutics hold great potential as radiosensitizers. Their unique properties, such as preferential accumulation in tumors and their ability to target tumors through molecular targeting ligands, are ideally suited for radiosensitization. We aimed to develop a molecularly targeted nanoparticle formulation of docetaxel (Dtxl) and evaluate its property as a radiosensitizer. Using a biodegradable and biocompatible lipid-polymer NP platform and folate as a molecular targeting ligand, we engineered a folate-targeted nanoparticle (FT-NP) formulation of Dtxl. These NPs have sizes of 72±4 nm and surface charges of −42±8 mV. Using folate receptor over-expressing KB cells and folate receptor low HTB-43 cells, we showed folate-mediated intracellular uptake of NPs. In vitro radiosensitization studies initially showed FT-NP is less effective than Dtxl as a radiosensitizer. However, the radiosensitization efficacy is dependent on the timing of radiotherapy. In vitro radiosensitization conducted with irradiation given at the optimal time (24 hours) showed FT-NP Dtxl is as effective as Dtxl. When FT-NP Dtxl is compared to Dtxl and non-targeted nanoparticle (NT-NP) Dtxl in vivo, FT-NP was found to be significantly more effective than Dtxl or NT-NP Dtxl as a radiosensitizer. We also confirmed that radiosensitization is dependent on timing of irradiation in vivo. In summary, FT-NP Dtxl is an effective radiosensitizer in folate-receptor over-expressing tumor cells. Time of irradiation is critical in achieving maximal efficacy with this nanoparticle platform. To the best of our knowledge, our report is the first to demonstrate the potential of molecularly targeted NPs as a promising new class of radiosensitizers.

Concurrent administration of chemotherapy and radiotherapy has been increasingly used in cancer treatment, leading to improvements in survival as well as quality of life. Currently, it is a feasible preference, often regarded as the standard therapeutic option, for many locally confined solid tumors, including anal, bladder, cervical, esophageal, gastric, head and neck, lung, pancreatic and rectal cancers. In patients with these tumors, combined modality therapy improves local tumor control and survival while, in some instances, obviating the need for surgical removal of the organ of origin. The scientific rationale for the use of chemoradiation derives from the preclinical and clinical observations of synergistic interactions between radiotherapy and chemotherapy. When chemotherapy and radiotherapy are administered together, the chemotherapeutic agents can sensitize the cancer cells to the effects of ionizing radiation, leading to increased tumor-killing effects within the radiotherapy field. This, in turn, can improve local control of the primary tumor and, in some cancers, render surgical resection unnecessary. In other cases, patients with tumors that were initially considered unresectable are able to undergo curative interventions after completing chemoradiation. The chemotherapy component can address any potential micrometastatic disease that, without therapy, leads to an increased risk of distant recurrence. A large body of evidence exists that supports the use of chemoradiotherapy in gastrointestinal cancers. In fact, one of the first tumor types in which the superior efficacy of chemoradiation was described was anal cancer. Since then, chemoradiotherapy has been explored in other gastrointestinal malignancies with superior outcomes when compared with either radiation or chemotherapy alone. This article aims to recapitulate the clinical evidence supporting the use of chemoradiotherapy in a variety of gastrointestinal tumor types.

Background: Although immune checkpoint inhibitors (ICIs) have shown efficacy in a range of solid tumors, there are no established circulating biomarkers able to identify early responders to treatment. Circulating tumor cells (CTCs) allow a non-invasive peripheral assessment of disease burden over time. We evaluated the prevalence of CTCs before and during treatment with ICIs. Methods: Patients were enrolled prospectively at Duke Cancer Center and UNC Lineberger Cancer Center and selected for metastatic renal cell carcinoma (mRCC) and metastatic malignant melanoma (mMM) receiving standard of care immunotherapy. Using E-selectin for slowing cell rolling and a nanoparticle dendrimer based technology for cell capture with EpCAM, HER2, and EGFR, the CapioCyte platform was used for CTC capture at baseline, during treatment, and upon disease progression. Results: We enrolled 5 subjects with mRCC and 4 subjects with mMM. Prior to treatment, subjects had a median of 293 CTCs/mL (all healthy volunteers (HVs, n=10) had Conclusions: CapioCyte is a sensitive platform to detect CTCs in mRCC and mMM. Based on CTC detection, many patients had early response to ICI treatment, but rapid progression corresponding to clinical progression. This pilot data suggest that CTCs can be a valuable biomarker for monitoring the clinical benefit of cancer immunotherapies. Citation Format: Tian Zhang, SinJung Park, Daniella Runyambo, Michael J. Poellmann, Marco Reyes-Martinez, Zahra Mahbooba, Rebecca Green, Carrie Lee, Daniel J. George, Andrew J. Armstrong, Seungpyo Hong, Andrew Z. Wang. Characterization of circulating tumor cells during immune checkpoint inhibition in metastatic renal cell carcinoma and malignant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5702.

e24106Background: Circulating tumor cells (CTCs) have been demonstrated as a biomarker in certain advanced cancers. Additionally, there has been increasing recognition that definitive treatment, in...

Aim: The development of chemoradiation – the concurrent administration of chemotherapy and radiotherapy – has led to significant improvements in local tumor control and survival. However, it is limited by its high toxicity. In this study, we report the development of a novel NP (nanoparticle) therapeutic, ChemoRad NP, which can deliver biologically targeted chemoradiation. Method: A biodegradable and biocompatible lipid–polymer hybrid NP that is capable of delivering both chemotherapy and radiotherapy was formulated. Results: Using docetaxel, indium111 and yttrium90 as model drugs, we demonstrated that the ChemoRad NP can encapsulate chemotherapeutics (up to 9% of NP weight) and radiotherapeutics (100 mCi of radioisotope per gram of NP) efficiently and deliver both effectively. Using prostate cancer as a disease model, we demonstrated the targeted delivery of ChemoRad NPs and the higher therapeutic efficacy of ChemoRad NPs. Conclusion: We believe that the ChemoRad NP represents a new class of therapeutics that holds great potential to improve cancer treatment.

Nanotechnology, the area of study involving nanoparticles, century; medical fields. The nanotechnology is one of the fastest growing sectors of the high-tech economy in the 21st industry, it is currently undergoing unprecedented development in nowadays especially in areas of biological research for clinical, environmental and life science applications. The most frequently used nanoparticles are superparamagnetic iron oxide (SPIO) nanoparticles and semiconductor quantum dots (QDs). SPIO nanoparticles with nanometer sizes and superparamagnetic properties are widely used for labeling and sorting cells or organelles, magnetic resonance imaging, targeted drug delivery, and hyperthermia. QDs combined the unique size-dependent physical properties, excellent chemical and photochemical stability, controlled and increased endocytosis, enhanced cooperative binding activity, and easy introduction of multi-functionality for targeted delivery and imaging, and became the most promising labeling tool for life science studies. Both types of nanomaterials provide special approaches for complex studies and play very important roles in modern biomedical research. However, non-specific uptake of QDs and SPIO nanoparticles is a major concern because it can lead to false positives or false results. Hence, we report cellular uptake studies on SPIO nanoparticles and QDs conducted on breast cancer cell line SK-BR3. The results show that both QDs and SPIO nanoparticles have very strong non-specific cellular uptake. With specially designed blocking buffer (BBB) the non-specific signals were significantly decreased.

We report the development of early stage detection of breast cancer cells using quantum dots (QDs) as fluorescent signal generator for detection. The QDs based imaging of breast cancer cells involved two kinds of antibodies: the first was for labeling the cells and the second was for imaging the breast cancer cells. Anti-Her2/neu (10Ab) was used for labeling the captured SK-BR3 cells. The second antibody against anti-Her2/neu (20Ab) that was conjugated to QDs (20Ab~QDs) forms the complete assay, SK-BR3 + 10Ab + 20Ab~QDs, to generate the fluorescent cells for imaging. Fluorescent images of the complete assay for SK-BR3 cells were evaluated under a microscope with a UV light source. The preliminary results showed that the breast cancer cell SK-BR3 in the complete assay were successfully observed as fluorescent cells that had brighter signals compared with those labeled with organic dye using similar parameters and the same number of cells.

ThemajorshortcomingofCombidexisitsinabilitytodetectPCadiseaseoutsideofthelymphnodes.Herein, we report the development of a novel, multifunc-tional, thermally cross-linked SPION (TCL-SPION) that can bothdetect PCa cells, and deliver targeted chemotherapeuticagents directly to the PCa cells. We previously reported theuseoftheA10RNAaptamer (Apt), which bindstheextracellu-lar domain of the prostate-specific membrane antigen (PSMA),to engineer targeted nanoparticles for PCa therapy and imag-ing.

Oncogenic tyrosine kinases, such as BCR-ABL, TEL-ABL, TEL-PDGFβR, and FLT3-ITD, play a major role in the development of hematopoietic malignancy. They activate many of the same signal transduction pathways. To identify the critical target genes required for transformation in hematopoietic cells, we used a comparative gene expression strategy in which selective small molecules were applied to 32Dcl3 cells that had been transformed to factor-independent growth by these respective oncogenic alleles. We identified inhibitor of DNA binding 1 (Id1), a gene involved in development, cell cycle, and tumorigenesis, as a common target of these oncogenic kinases. These findings were prospectively confirmed in cell lines and primary bone marrow cells engineered to express the respective tyrosine kinase alleles and were also confirmed in vivo in murine models of disease. Moreover, human AML cell lines Molm-14 and K562, which express the FLT3-ITD and BCR-ABL tyrosine kinases, respectively, showed high levels of Id1 expression. Antisense and siRNA based knockdown of Id1-inhibited growth of these cells associated with increased p27Kip1 expression and increased sensitivity to Trail-induced apoptosis. These findings indicate that Id1 is an important target of constitutively activated tyrosine kinases and may be a therapeutic target for leukemias associated with oncogenic tyrosine kinases.