Adam J. Cole

Gold nanorods for ovarian cancer detection with photoacoustic imaging and resection guidance via Raman imaging in living mice.

Improved imaging approaches are needed for ovarian cancer screening, diagnosis, staging, and resection guidance. Here, we propose a combined photoacoustic (PA)/Raman approach using gold nanorods (GNRs) as a passively targeted molecular imaging agent. GNRs with three different aspect ratios were studied. Those with an aspect ratio of 3.5 were selected for their highest ex vivo and in vivo PA signal and used to image subcutaneous xenografts of the 2008, HEY, and SKOV3 ovarian cancer cell lines in living mice. Maximum PA signal was observed within 3 h for all three lines tested and increased signal persisted for at least two days postadministration. There was a linear relationship (R(2) = 0.95) between the PA signal and the concentration of injected molecular imaging agent with a calculated limit of detection of 0.40 nM GNRs in the 2008 cell line. The same molecular imaging agent could be used for clear visualization of the margin between tumor and normal tissue and tumor debulking via surface-enhanced Raman spectroscopy (SERS) imaging. Finally, we validated the imaging findings with biodistribution data and elemental analysis. To the best of our knowledge, this is the first report of in vivo imaging of ovarian cancer tumors with a photoacoustic and Raman imaging agent.

Polyethylene glycol modified, cross-linked starch-coated iron oxide nanoparticles for enhanced magnetic tumor targeting.

While successful magnetic tumor targeting of iron oxide nanoparticles has been achieved in a number of models, the rapid blood clearance of magnetically suitable particles by the reticuloendothelial system (RES) limits their availability for targeting. This work aimed to develop a long-circulating magnetic iron oxide nanoparticle (MNP) platform capable of sustained tumor exposure via the circulation and, thus, potentially enhanced magnetic tumor targeting. Aminated, cross-linked starch (DN) and aminosilane (A) coated MNPs were successfully modified with 5 kDa (A5, D5) or 20 kDa (A20, D20) polyethylene glycol (PEG) chains using simple N-Hydroxysuccinimide (NHS) chemistry and characterized. Identical PEG-weight analogues between platforms (A5 & D5, A20 & D20) were similar in size (140-190 nm) and relative PEG labeling (1.5% of surface amines - A5/D5, 0.4% - A20/D20), with all PEG-MNPs possessing magnetization properties suitable for magnetic targeting. Candidate PEG-MNPs were studied in RES simulations in vitro to predict long-circulating character. D5 and D20 performed best showing sustained size stability in cell culture medium at 37 °C and 7 (D20) to 10 (D5) fold less uptake in RAW264.7 macrophages when compared to previously targeted, unmodified starch MNPs (D). Observations in vitro were validated in vivo, with D5 (7.29 h) and D20 (11.75 h) showing much longer half-lives than D (0.12 h). Improved plasma stability enhanced tumor MNP exposure 100 (D5) to 150 (D20) fold as measured by plasma AUC(0-∞). Sustained tumor exposure over 24 h was visually confirmed in a 9L-glioma rat model (12 mg Fe/kg) using magnetic resonance imaging (MRI). Findings indicate that a polyethylene glycol modified, cross-linked starch-coated MNP is a promising platform for enhanced magnetic tumor targeting, warranting further study in tumor models.

The artificial peroxidase activity of magnetic iron oxide nanoparticles and its application to glucose detection

Aside from their superparamagnetic properties exploited in clinical magnetic resonance imaging (MRI), it was recently discovered that magnetic, iron oxide nanoparticles could function as an artificial, inorganic peroxidase. In this paper, we studied the impact of coating on the peroxidase activity of these nanoparticles. Nanoparticles with six different coating structures were synthesized and characterized by FTIR, TGA, TEM, size, zeta potential, and SQUID; and evaluated for peroxidase activity. Catalysis was found to follow Michaelis-Menten kinetics and peroxidase activity varied with respect to electrostatic affinity between nanoparticles and substrates, evidenced by differences in determined kinetic parameters. Glucose detection was selected as a model system because glucose could be indirectly measured from the release of hydrogen peroxide after its oxidation. Nanoparticles with high peroxidase activity exhibited higher sensitivity toward glucose, showing a larger linear slope when compared with those of low activity. A significantly improved linear correlation and detection limit of measured glucose could be readily obtained by manipulating the nanoparticle coating. Our findings suggest that iron oxide nanoparticles can be tailor-made to possess improved peroxidase-like activity. Such enhancements could further widen nanoparticle scope in glucose detection and extend its peroxidase functionality to other biomedical applications.

Magnetic brain tumor targeting and biodistribution of long-circulating PEG-modified, cross-linked starch coated iron oxide nanoparticles

Magnetic iron oxide nanoparticles (MNPs) have been studied to circumvent the limitations of status-quo brain tumor therapy and can be targeted by applying an external magnetic field to lesions. To address the pharmacokinetic shortcomings of MNPs that can limit targeting efficiency, we recently reported a long-circulating polyethylene glycol modified, cross-linked starch MNP (PEG-MNP) suitable for magnetic targeting. Using a rat model, this work explores the biodistribution patterns of PEG-MNPs in organs of elimination (liver, spleen, lung, and kidney) and shows proof-of-concept that enhanced magnetic brain tumor targeting can be achieved due to the relatively long circulation lifetime of the nanoparticles. Reductions in liver (∼12-fold) and spleen (∼2.5-fold) PEG-MNP concentrations at 1h compared to parent starch-coated MNPs (D) confirm plasma pharmacokinetics observed previously. While liver concentrations of PEG-MNPs remained considerably lower than those observed for D at 1h through 60 h, spleen values continue to increase and are markedly higher at later time points--a trend also observed with histology. Limited to no distribution of PEG-MNPs was visualized in lung or kidney throughout the 60 h course evaluated. Enhanced, selective magnetic brain tumor targeting (t = 1 h) of PEG-MNPs (12 mg Fe/kg) was confirmed in 9L-glioma tumors, with up to 1.0% injected dose/g tissue nanoparticle delivery achieved--a 15-fold improvement over targeted D (0.07% injected dose/g tissue). MRI and histological analyses visually confirmed enhanced targeting and also suggest a limited contribution of passive mechanisms to tissue retention of nanoparticles. Our results are exciting and justify both further development of PEG-MNP as a drug delivery platform and concurrent optimization of the magnetic brain tumor targeting strategy utilized.

Comparison of Electron Spin Resonance Spectroscopy and Inductively-Coupled Plasma Optical Emission Spectroscopy for Biodistribution Analysis of Iron-Oxide Nanoparticles

Magnetic nanoparticles (MNP) have been widely studied for use in targeted drug delivery. Analysis of MNP biodistribution is essential to evaluating the success of targeting strategies and the potential for off-target toxicity. This work compared the applicability of inductively coupled plasma optical emission spectroscopy (ICP-OES) and electron spin resonance (ESR) spectroscopy in assessing MNP biodistribution. Biodistribution was evaluated in 9L-glioma bearing rats administered with MNP (12-25 mg Fe/kg) under magnetic targeting. Ex vivo analysis of MNP in animal tissues was performed with both ICP-OES and ESR. A cryogenic method was developed to overcome the technical hurdle of loading tissue samples into ESR tubes. Comparison of results from the ICP-OES and ESR measurements revealed two distinct relationships for organs accumulating high or low levels of MNP. In organs with high MNP accumulation such as the liver and spleen, data were strongly correlated (r = 0.97, 0.94 for the liver and spleen, respectively), thus validating the equivalency of the two methods in this high concentration range (>1000 nmol Fe/g tissue). The two sets of measurements, however, differed significantly in organs with lower levels of MNP accumulation such as the brain, kidney, and the tumor. Whereas ESR resolved MNP to 10-55 nmol Fe/g tissue, ICP-OES failed to detect MNP because of masking by endogenous iron. These findings suggest that ESR coupled to cryogenic sample handling is more robust than ICP-OES, attaining better sensitivity in analyses. Such advantages render ESR the method of choice for accurate profiling of MNP biodistribution across tissues with high variability in nanoparticle accumulation.

Magnetic Nanoparticles for Tumor Imaging and Therapy: A So-Called Theranostic System

ABSTRACTIn this review, we discussed the establishment of a so-called “theranostic” system by instituting the basic principles including the use of: [1] magnetic iron oxide nanoparticles (MION)-based drug carrier; [2] intra-arterial (I.A.) magnetic targeting; [3] macromolecular drugs with unmatched therapeutic potency and a repetitive reaction mechanism; [4] cell-penetrating peptide-mediated cellular drug uptake; and [5] heparin/protamine-regulated prodrug protection and tumor-specific drug re-activation into one single drug delivery system to overcome all possible obstacles, thereby achieving a potentially non-invasive, magnetic resonance imaging-guided, clinically enabled yet minimally toxic brain tumor drug therapy. By applying a topography-optimized I.A. magnetic targeting to dodge rapid organ clearance of the carrier during its first passage into the circulation, tumor capture of MION was enriched by >350 folds over that by conventional passive enhanced permeability and retention targeting. By adopting the prodrug strategy, we observed by far the first experimental success in a rat model of delivering micro-gram quantity of the large β-galactosidase model protein selectively into a brain tumor but not to the ipsi- or contra-lateral normal brain regions. With the therapeutic regimens of most toxin/siRNA drugs to fully (>99.9%) eradicate a tumor being in the nano-molar range, the prospects of reaching this threshold become practically accomplishable.

Roller and centrifugal pumps: A retrospective comparison of bleeding complications in extracorporeal membrane oxygenation

Centrifugal pumps are increasingly used for extracorporeal membrane oxygenation (ECMO) rather than roller pumps. However, shear forces induced by these types of continuousflow pumps are associated with acquired von Willebrand factor deficiency and bleeding complications. This study was undertaken to compare adverse bleeding complications with the use of centrifugal and roller pumps in patients on prolonged ECMO support. The records of all adult ECMO patients from June 2002 to 2013 were retrospectively reviewed using the University of Michigan Health System database and the Extracorporeal Life Support Organization registry, focusing on patients supported for at least 5 days. Ninety-five ECMO patients met criteria for inclusion (48 roller vs. 47 centrifugal pump). Indications included pulmonary (79%), cardiac (15%), and extracorporeal cardiopulmonary resuscitation (6%), without significant difference between the two groups. Despite lower heparin anticoagulation (10.9 vs. 13.7 IU/kg/hr) with centrifugal pumps, there was a higher incidence of nonsurgical bleeding (gastrointestinal, pulmonary, and neurological) in centrifugal pump patients (26.1 vs. 9.0 events/1,000 patient-days, p = 0.024). In conclusion, in our historical comparison, despite reduced anticoagulation, ECMO support using centrifugal pumps was associated with a higher incidence of nonsurgical bleeding. The mechanisms behind this are multifactorial and require further investigation

Co-encapsulation and sustained-release of four components in ginkgo terpenes from injectable PELGE nanoparticles.

It is difficult to develop injectable sustained delivery systems for herbal medicines because of their composition complexity. Encapsulating various compounds with different physiochemical properties and achieving their synchronized and sustained release seem too hard to realize. In this paper, an injectable nanoparticulate system based on an mPEG-PLGA-mPEG (PELGE) platform was prepared for co-encapsulation and sustained release of four active components (ginkgolides A, B, C and bilobalide) in Ginkgo biloba extract. Different carriers were screened by macrophage uptake experiment for their ability to be long-circulation. Drug loaded nanoparticles were prepared with 10% PEG(2000) modified PLGA by a co-precipitation method. The encapsulation efficiency of the total ginkgo terpenes (GT) in the optimal formulation was 78.84±2.06% with a loading dose of 11.90±0.31mg/150mg PELGE. The particles exhibited a spherical shape with a mean diameter of 123.3±44.0nm and zeta potential of -30.86±2.49mV. Sustained and synchronized release of the four components from PELGE nanoparticles was observed both in vitro and in vivo, which was mainly contributed to the long circulation of PEGylated nanoparticles and the slow degradation of PLGA. The half-life time of the four terpenoid compounds were also significantly improved by incorporation into PELGE nanoparticles. The results indicate that a PELGE nanoparticle is a promising carrier system for sustained and synchronized release of herbal medicines containing multiple components.

Development and Validation of a Novel Integrated Clinical-Genomic Risk Group Classification for Localized Prostate Cancer

Purpose It is clinically challenging to integrate genomic-classifier results that report a numeric risk of recurrence into treatment recommendations for localized prostate cancer, which are founded in the framework of risk groups. We aimed to develop a novel clinical-genomic risk grouping system that can readily be incorporated into treatment guidelines for localized prostate cancer. Materials and Methods Two multicenter cohorts (n = 991) were used for training and validation of the clinical-genomic risk groups, and two additional cohorts (n = 5,937) were used for reclassification analyses. Competing risks analysis was used to estimate the risk of distant metastasis. Time-dependent c-indices were constructed to compare clinicopathologic risk models with the clinical-genomic risk groups. Results With a median follow-up of 8 years for patients in the training cohort, 10-year distant metastasis rates for National Comprehensive Cancer Network (NCCN) low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.3%, 9.2%, 38.0%, and 39.5%, respectively. In contrast, the three-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.5%, 29.4%, and 54.6%, for low-, intermediate-, and high-risk, respectively, which were consistent in the validation cohort (0%, 25.9%, and 55.2%, respectively). C-indices for the clinical-genomic risk grouping system (0.84; 95% CI, 0.61 to 0.93) were improved over NCCN (0.73; 95% CI, 0.60 to 0.86) and Cancer of the Prostate Risk Assessment (0.74; 95% CI, 0.65 to 0.84), and 30% of patients using NCCN low/intermediate/high would be reclassified by the new three-tier system and 67% of patients would be reclassified from NCCN six-tier (very-low- to very-high-risk) by the new six-tier system. Conclusion A commercially available genomic classifier in combination with standard clinicopathologic variables can generate a simple-to-use clinical-genomic risk grouping that more accurately identifies patients at low, intermediate, and high risk for metastasis and can be easily incorporated into current guidelines to better risk-stratify patients.

Magnetically targeted nanoparticles for brain tumor therapy: what does the future hold?

CNS cancers account for approximately 142,000 deaths annually – with brain tumor patients typically surviving up to just 12 months after diagnosis [1]. Today’s ‘standard of care’ therapy for brain tumors includes surgical tumor resection coupled with adjuvant radiation and/ or small-molecule chemotherapy treatments. Despite advancements in each of these intervention routes, overall patient survival rates have generally remained unchanged for decades. The limitations of status quo treatments can generally be attributed to the challenge of providing remissive therapy and concurrently avoiding off-target damage to healthy tissues. Clearly, the development of new technologies is required to realize a cure for brain tumors. To that end, many ongoing investigations have been focused toward achieving more selective, more therapeutic tumor drug action.