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Di Si,1 Guochao Nie,2– 4 Tamiika K Hurst,1 Carol A Fierke,1 Raoul Kopelman1 1Department of Chemistry, University of Michigan, Ann Arbor, MI, USA; 2School of Physics and Telecommunication Engineering, Yulin Normal University, Yulin, People’s Republic of China; 3China-Ukraine Joint Research Center for Nano Carbon Black, Yulin, People’s Republic of China; 4Guangxi Key Laboratory of Agricultural Resources Chemistry and Biotechnology, Yulin, People’s Republic of ChinaCorrespondence: Guochao NieSchool of Physics and Telecommunication Engineering, Yulin Normal University, Yulin, People’s Republic of ChinaEmail bccu518@ylu.edu.cnRaoul KopelmanDepartment of Chemistry, University of Michigan, 930 N University Avenue, Ann Arbor, MI, USAEmail kopelman@umich.eduBackground: Due to its excellent biocompatibility, the polyacrylamide (PAAm) hydrogel has shown great potential for the immobilization of enzymes used in biomedical applications. The major challenge involved is to preserve, during the immobilization process, both the biological activity and the structural integrity of the enzymes. Here we report, for the first time, a proof-of-concept study for embedding active carbonic anhydrase (CA) into polyacrylamide (PAAm) nanogels. By immobilizing CA in these nanogels, we hope to provide important advantages, such as matrix protection of the CA as well as its targeted delivery, and also for potentially using these nanogels as zinc nano-biosensors, both in-vitro and in-vivo.Methods and Results: Two methods are reported here for CA immobilization: encapsulation and surface conjugation. In the encapsulation method, the common process was improved, so as to best preserve the CA, by 1) using a novel biofriendly nonionic surfactant system (Span 80/Tween 80/Brij 30) and 2) using an Al2O3 adsorptive filtration purification procedure. In the surface conjugation method, blank PAAm nanogels were activated by N-hydroxysuccinimide and the CA was cross-linked to the nanogels. The amount of active CA immobilized in the nanoparticles was quantified for both methods. Per 1 g nanogels, the CA encapsulated nanogels contain 11.3 mg active CA, while the CA conjugated nanogels contain 22.5 mg active CA. Also, the CA conjugated nanoparticles successfully measured free Zn2+ levels in solution, with the Zn2+ dissociation constant determined to be 9 pM.Conclusion: This work demonstrates universal methods for immobilizing highly fragile bio-macromolecules inside nanoparticle carriers, while preserving their structural integrity and biological activity. The advantages and limitations are discussed, as well as the potential biomedical applications.Keywords: PAAm hydrogel, nanogels, nanoparticles, carbonic anhydrase, encapsulation, conjugation, Zn2+

8-arm PEG (polyethylene-glycol) is a highly promising nanoplatform due to its small size (<10 nm), ease-of-conjugation (many functionalized variants are readily available with "click-like" properties), biocompatibility, and optical inactivity. This study evaluates 8-arm PEG uptake into cells ( in vitro ) and localization and clearance in vasculature ( in vivo ) for targeting of choroidal neovascularization in mice, an animal model of macular degeneration. 8-arm PEG nanoparticles were labeled with fluorescein isothiocyanate (FITC) and functionalized in the absence or presence of pentameric Ar-Gly-Asp (RGD; 4 RGD motifs and a PGC linker), one of the most common peptide motifs used for active targeting. In vitro studies show that RGD-conjugated 8-arm PEG nanoparticles exhibit enhanced cellular uptake relative to non-RGD-conjugated control NPs at 34% ± 9%. Laser-induced choroidal neovascularization (CNV) was performed in a mouse model to measure 8-arm PEG localization and clearance to model macular degeneration lesions in vivo . It was determined that both RGD-conjugated and non-RGD-conjugated (nRGD) 8-arm PEG particles localized to CNV lesions, with a half-life around 24 h. In vivo experiments showed that RGD-conjugated nanoparticles exhibited enhanced localization by 15-20% relative to without RGD controls. Exhibiting a high rate of localization and fast clearance relative to larger nanoparticles, targeted 8-arm PEG nanoparticles with a conjugated RGD-peptide could be a promising modality for macular degeneration diagnosis and therapy.

Purpose: Early detection and diagnosis of cancer is critical for achieving positive therapeutic outcomes. Biomarkers that can provide clinicians with clues to the outcome of a given therapeutic course are highly desired. Oxygen is a small molecule that is nearly universally present in biological tissues and plays a critical role in the effectiveness of radiotherapies by reacting with DNA radicals and subsequently impairing cellular repair of double strand breaks.Techniques for measuring oxygen in biological tissues often use blood oxygen saturation to approximate the oxygen partial pressure in surrounding tissues despite the complex, nonlinear, and dynamic relationship between these two separate oxygen populations., Methods and Materials: We combined a directly oxygen-sensitive, tumor-targeted, chemical contrast nanoelement with the photoacoustic lifetime-based (PALT) oxygen imaging technique to obtain image maps of oxygen in breast cancer tumors in vivo. The oxygen levels of patient-derived xenografts in a mouse model were characterized before and after a course of radiotherapy., Results: We show that, independent of tumor size, radiotherapy induced an increase in the overall oxygenation levels of the tumor. Further, this increase in the oxygenation of the tumor significantly correlated with a positive response to radiotherapy, as demonstrated by a reduction in tumor volume over the twenty-day monitoring period following therapy and histological staining., Conclusion: Our PALT imaging presented here is simple, fast, and non-invasive. Facilized by the PALT approach, imaging of tumor reoxygenation may be utilized as a simple, early indicator for evaluating cancer response to radiotherapy. Further characterization of the reoxygenation degree, temporal onset, and possible theragnostic implications are warranted.

Sodium has many vital and diverse roles in the human body, including maintaining the cellular pH, generating action potential, and regulating osmotic pressure. In cancer, sodium dysregulation has been correlated with tumor growth, metastasis, and immune cell inhibition. However, most in vivo sodium measurements are performed via Na 23 NMR, which is handicapped by slow acquisition times, a low spatial resolution (in mm), and low signal-to-noise ratios. We present here a plasticizer-free, ionophore-based sodium-sensing nanoparticle that utilizes a solvatochromic dye transducer to circumvent the pH cross-sensitivity of most previously reported sodium nano-sensors. We demonstrate that this nano-sensor is non-toxic, boasts a 200 μM detection limit, and is over 1000 times more selective for sodium than potassium. Further, the in vitro photoacoustic calibration curve presented demonstrates the potential of this nano-sensor for performing the in vivo chemical imaging of sodium over the entire physiologically relevant concentration range.

Evaluating the aggressiveness of prostate cancer (PCa) is crucial for PCa diagnosis and prognosis. Previously, studies have shown that photoacoustic spectral analysis (PASA) can assess prostate tissue microarchitecture for evaluating the aggressiveness of PCa. In this study, in a transgenic mouse (TRAMP) model of PCa, we utilized methylene blue polyacrylamide nanoparticles (MB PAA NPs) to label the cancer cells in prostate in vivo. MB PAA NPs can specifically target proliferating cancer cells as a contrast agent, allowing photoacoustic (PA) imaging to better detect PCa tumors, and also assessing prostate glandular architecture. With the PA signals from the prostates measured simultaneously by a needle hydrophone and a PA and ultrasound (US) dual-imaging system, we conducted PASA and correlated the quantified spectral parameter slopes with the cancer grading from histopathology. The PASA results from 18 mice showed significant differences between normal and cancer, and also between low-score cancer and high-score cancer. This study in the clinically relevant TRAMP model of PCa demonstrated that PA imaging and PASA, powered by MB PAA NPs that can label the PCa microarchitectures in vivo after systemic administration, can detect PCa and, more importantly, evaluate cancer aggressiveness.

We hereby apply the approach of photoacoustic chemical imaging, performing an in vivo chemical analysis that is spatially resolved (200 μm) and in real time, to predict a given tumor's response to therapy. Using triple negative breast cancer as a model, we took photoacoustic images of tumors' oxygen distributions in patient-derived xenografts (PDXs) in mice using biocompatible, oxygen-sensitive tumor-targeted chemical contrast nanoelements (nanosonophores), which function as contrast agents for photoacoustic imaging. Following radiation therapy, we established a quantitatively significant correlation between the spatial distribution of the initial oxygen levels in the tumor and its spatial distribution of the therapy's efficacy: the lower the local oxygen, the lower the local radiation therapy efficacy. We thus provide a simple, noninvasive, and inexpensive method to both predict the efficacy of radiation therapy for a given tumor and identify treatment-resistant regions within the tumor's microenvironment.

Breakdowns of two-zone random networks of the Erdős-Rényi type are investigated. They are used as mathematical models for understanding the incompleteness of the tumor network breakdown under radiochemotherapy, an incompleteness that may result from a tumor's physical and/or chemical heterogeneity. Mathematically, having a reduced node removal probability in the network's inner zone hampers the network's breakdown. The latter is described quantitatively as a function of reduction in the inner zone's removal probability, where the network breakdown is described in terms of the largest remaining clusters and their size distributions. The effects on the efficacy of radiochemotherapy due to the tumor micro-environment (TME)'s chemical make-up, and its heterogeneity, are discussed, with the goal of using such TME chemical heterogeneity imaging to inform precision oncology.

Tumor hypoxia was discovered a century ago, and the interference of hypoxia with all radiotherapies is well known. Here, we demonstrate the potentially extreme effects of hypoxia heterogeneity on radiotherapy and combination radiochemotherapy. We observe that there is a decrease in hypoxia from tumor periphery to tumor center, due to oxygen diffusion, resulting in a gradient of radiative cell-kill probability, mathematically expressed as a probability gradient of occupied space removal. The radiotherapy-induced break-up of the tumor/TME network is modeled by the physics model of inverse percolation in a shell-like medium, using Monte Carlo simulations. The different shells now have different probabilities of space removal, spanning from higher probability in the periphery to lower probability in the center of the tumor. Mathematical results regarding the variability of the critical percolation concentration show an increase in the critical threshold with the applied increase in the probability of space removal. Such an observation will have an important medical implication: a much larger than expected radiation dose is needed for a tumor breakup enabling successful follow-up chemotherapy. Information on the TME's hypoxia heterogeneity, as shown here with the numerical percolation model, may enable personalized precision radiation oncology therapy.

We define cell morphodynamics as the cell's time dependent morphology. It could be called the cell's shape shifting ability. To measure it we use a biomarker free, dynamic histology method, which is based on multiplexed Cell Magneto-Rotation and Machine Learning. We note that standard studies looking at cells immobilized on microscope slides cannot reveal their shape shifting, no more than pinned butterfly collections can reveal their flight patterns. Using cell magnetorotation, with the aid of cell embedded magnetic nanoparticles, our method allows each cell to move freely in 3 dimensions, with a rapid following of cell deformations in all 3-dimensions, so as to identify and classify a cell by its dynamic morphology. Using object recognition and machine learning algorithms, we continuously measure the real-time shape dynamics of each cell, where from we successfully resolve the inherent broad heterogeneity of the morphological phenotypes found in a given cancer cell population. In three illustrative experiments we have achieved clustering, differentiation, and identification of cells from (A) two distinct cell lines, (B) cells having gone through the epithelial-to-mesenchymal transition, and (C) cells differing only by their motility. This microfluidic method may enable a fast screening and identification of invasive cells, e.g., metastatic cancer cells, even in the absence of biomarkers, thus providing a rapid diagnostics and assessment protocol for effective personalized cancer therapy., Competing Interests: The authors have declared that no competing interests exist.

Detection of singlet oxygen is of great importance for a range of therapeutic applications, particularly photodynamic therapy, plasma therapy and also during photo-endosomolytic activity. Here we present a novel method of intracellular detection of singlet oxygen using biocompatible polymeric nanosensors, encapsulating the organic fluorescent dye, Singlet Oxygen Sensor Green (SOSG) within its hydrophobic core. The singlet oxygen detection efficiency of the nanosensors was quantified experimentally by treating them with a plasma source and these results were further validated by using Monte Carlo simulations. The change in fluorescence intensity of the nanosensors serves as a metric to detect singlet oxygen in the local micro-environment inside mammalian cancer cells. We used these nanosensors for monitoring singlet oxygen inside endosomes and lysosomes of cancer cells, during cold plasma therapy, using a room-temperature Helium plasma jet.

Objective: Measure effect of late-afternoon communication and patient planning (CAPP) rounds to increase early electronic discharge orders (EDO)., Methods: We enrolled 4485 patients discharged from six subspecialty medical services. We implemented late-afternoon CAPP rounds to identify patients who could have morning discharge the subsequent day. After an initial successful implementation of the intervention, we identified lack of sustainability. We made changes with sustained implementation of the intervention. This is a before-after study of a quality improvement intervention., Program Evaluation: Primary measures of intervention effectiveness were percentage of patients who received EDO by 11 am and patients discharged by noon. Additional measure of effectiveness were percent of patients admitted to the correct ward, emergency department (ED)-to-ward transfer time compared between intervention and nonintervention periods. We compared the overall expected LOS and the average weekly discharges to assess for comparability across the control and intervention time periods. We used the readmission rate as balancing measure to ensure that the intervention was not have unintended negative patients consequences., Results: Expected length of stay based upon discharge diagnosis/comorbidities and readmission rates were similar across the intervention and control time periods. The average weekly discharges were not statistically significant. Percentage of EDO by 11 am was higher in the first intervention period, second intervention period and combined intervention periods (28.9% vs. 21.8%, P < 0.001) compared with the respective control periods. Percent discharged before noon increased in the first intervention period, second intervention period and for the combined intervention periods (17 vs. 11.8%, P < 0.001). There was no difference in the percent admitted to the correct ward and ED-to-ward transfer time., Conclusion: Afternoon CAPP rounds to identify early patient discharges the following day led to increase in EDO entered by 11 am and discharges by noon without an adverse change in readmission rates and LOS.

The accumulation of potassium (K + ) in the tumor microenvironment (TME) has been recently shown to inhibit immune cell efficacy, and thus immunotherapy. Despite the abundance of K + in the body, few ways exist to measure it in vivo . To address this technology gap, we combine an optical K + nanosensor with photoacoustic (PA) imaging. Using multi-wavelength deconvolution, we are able to quantitatively evaluate the TME K + concentration in vivo , and its distribution. Significantly elevated K + levels were found in the TME, with an average concentration of approximately 29 mM, compared to 19 mM found in muscle. These PA measurements were confirmed by extraction of the tumor interstitial fluid and subsequent measurement via inductively coupled plasma mass spectrometry., Competing Interests: The authors declare no conflicts of interest., (© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Lifetime imaging methods using phosphorescence quenching by oxygen for molecular oxygen concentration measurement have been developed and used for noninvasive oxygen monitoring. This study reports photoacoustic (PA) oxygen imaging powered by polyacrylamide (PAAm) hydrogel nanoparticles (NP) which offer advantages including improved biocompatibility, reduced toxicity, and active tumor targeting. A known oxygen indicator, oxyphor G2, was conjugated with the matrix of the NPs, giving G2-PAA NPs, followed by PEGylation for biocompatibility and F3 surface modification for tumor targeting. Using two lasers providing pump and probe pulses, respectively, PA imaging was performed so as to quantitatively map the oxygen concentration in biological tissues in vivo , including cancer tumors and normal thigh muscles. Furthermore, via the imaging at the pump wavelength and two additional wavelengths, the accumulation of the G2-PAA NPs in the tumors were also determined. The successful imaging experiment accomplished on animal models renders a method for in vivo noninvasive imaging and assessment of hypoxic tumor microenvironments, which is critical for assessing cancer progression, metastasis, and treatment.

We describe how 4-dimensional in vivo biochemical analysis can be performed using photoacoustic contrast nanoagents that have been designed to probe both structural and chemical information in vivo, enabling noninvasive, real time, spatially resolved chemical imaging. Early chemical imaging of a patient's tumor can inform the decision of effective treatment, regarding choices of chemotherapy, radiation, or immunotherapy.

We present a new targetable nanoconstruct (NC) capable of simultaneously serving as a therapeutic platform for photodynamic therapy (PDT) as well as a magnetic resonance (MR) molecular imaging agent, free of heavy metal atoms. PDT has seen much interest with the introduction of NC-assisted cell-specific targeting of the photosensitizer (PS). The previously reported ultrasmall 8-arm polyethylene glycol amine (8PEGA) NC, with an attached chlorin e6 (Ce6) PS, yielded promising results for PDT of heart arrhythmia, in vivo and ex vivo , on live rat and sheep hearts, respectively, when using targeting peptides for cell-specific ablation of cardio-myocytes. Here we explore the extension of this NC-based PDT to cancer. For this purpose, we switched the targeting peptide from CTP-cys to F3-cys. Notably, the 8PEGA-Ce6 NCs have a superior reactive oxygen species (ROS) production compared to traditional Ce6 encapsulated polyacrylamide (PAAm) NCs, which should be advantageous for PDT. This NC is also cyto-compatible and offers chemical flexibility for the attachment of a choice of targeting peptides. Finally, this label-free 8PEGA NC can be directly and selectively imaged by MRI, using standard spin-echo imaging sequences with large diffusion magnetic field gradients to suppress the water signal. Notably, due to its ultrasmall size this NC is also expected to have improved in vivo penetration and bioelimination, as was already shown in previous biodistribution studies.

With the capability of presenting endogenous tissue contrast or exogenous contrast agents in deep biological samples at high spatial resolution, photoacoustic (PA) imaging has shown significant potential for many preclinical and clinical applications. However, due to strong background signals from various intrinsic chromophores in biological tissue, such as hemoglobin, achieving highly sensitive PA imaging of targeting probes labeled by contrast agents has remained a challenge. In this study, we introduce a novel technique called transient triplet differential (TTD) imaging which allows for substantial reduction of tissue background signals. TTD imaging detects directly the triplet state absorption, which is a special characteristic of phosphorescence capable dyes not normally present among intrinsic chromophores of biological tissue. Thus, these triplet state absorption PA images can facilitate "true" background free molecular imaging. We prepared a known phosphorescent dye probe, methylene blue conjugated polyacrylamide nanoparticles, with peak absorption at 660 nm and peak lowest triplet state absorption at 840 nm. We find, through studies on phantoms and on an in vivo tumor model, that TTD imaging can generate a superior contrast-to-noise ratio, compared to other image enhancement techniques, through the removal of noise generated by strongly absorbing intrinsic chromophores, regardless of their identity.

Changes of physiological pH are correlated with several pathologies, therefore the development of more effective medical pH imaging methods is of paramount importance. Here, we report on an in vivo pH mapping nanotechnology. This subsurface chemical imaging is based on tumor-targeted, pH sensing nanoprobes and multi-wavelength photoacoustic imaging (PAI). The nanotechnology consists of an optical pH indicator, SNARF-5F, 5-(and-6)-Carboxylic Acid, encapsulated into polyacrylamide nanoparticles with surface modification for tumor targeting. Facilitated by multi-wavelength PAI plus a spectral unmixing technique, the accuracy of pH measurement inside the biological environment is not susceptible to the background optical absorption of biomolecules, i.e., hemoglobins. As a result, both the pH levels and the hemodynamic properties across the entire tumor can be quantitatively evaluated with high sensitivity and high spatial resolution in in vivo cancer models. The imaging technology reported here holds the potential for both research on and clinical management of a variety of cancers.Background optical absorption of several biomolecules impedes an effective in vivo pH imaging in tumors. Here, the authors developed a visible light-based in vivo pH mapping method by coupling photoacoustic imaging and pH-responsive modified nanoparticles that selectively target tumor cells.

Ion-selective optodes (ISOs), the optical analog of ion-selective electrodes, have played an increasingly important role in chemical and biochemical analysis. Here we extend this technique to ion-selective photoacoustic optodes (ISPAOs) that serve at the same time as fluorescence-based ISOs, and apply it specifically to potassium (K + ). Notably, the potassium ion is one of the most abundant cations in biological systems, involved in numerous physiological and pathological processes. Furthermore, it has been recently reported that the presence of abnormal extracellular potassium concentrations in tumors suppresses the immune responses and thus suppresses immunotherapy. However, unfortunately, sensors capable of providing potassium images in vivo are still a future proposition. Here, we prepared an ion-selective potassium nanosensor (NS) aimed at in vivo photoacoustic (PA) chemical imaging of the extracellular environment, while being also capable of fluorescence based intracellular ion-selective imaging. This potassium nanosensor (K + NS) modulates its optical properties (absorbance and fluorescence) according to the potassium concentration. The K + NS is capable of measuring potassium, in the range of 1 mM to 100 mM, with high sensitivity and selectivity, by ISPAO based measurements. Also, a near infrared dye surface modified K + NS allows fluorescence-based potassium sensing in the range of 20 mM to 1 M. The K + NS serves thus as both PA and fluorescence based nanosensor, with response across the biologically relevant K + concentrations, from the extracellular 5 mM typical values (through PA imaging) to the intracellular 150 mM typical values (through fluorescence imaging).

The use of a nanoparticle (NP)-based antitumor drug carrier has been an emerging strategy for selectively delivering the drugs to the tumor area and, thus, reducing the side effects that are associated with a high systemic dose of antitumor drugs. Precise control of drug loading and release is critical so as to maximize the therapeutic index of the NPs. Here, we propose a simple method of synthesizing NPs with tunable drug release while maintaining their loading ability, by varying the polymer matrix density of amine- or carboxyl-functionalized hydrogel NPs. We find that the NPs with a loose matrix released more cisplatin, with up to a 33 times faster rate. Also, carboxyl-functionalized NPs loaded more cisplatin and released it at a faster rate than amine-functionalized NPs. We performed detailed Monte Carlo computer simulations that elucidate the relation between the matrix density and drug release kinetics. We found good agreement between the simulation model and the experimental results for drug release as a function of time. Also, we compared the cellular uptake between amine-functionalized NPs and carboxyl-functionalized NPs, as a higher cellular uptake of NPs leads to improved cisplatin delivery. The amine-functionalized NPs can deliver 3.5 times more cisplatin into cells than the carboxyl-functionalized NPs. The cytotoxic efficacy of both the amine-functionalized NPs and the carboxyl-functionalized NPs showed a strong correlation with the cisplatin release profile, and the latter showed a strong correlation with the NP matrix density.

A new optical scattering contrast-agent based on polymer-nanoparticle encapsulated silver nanoplates (PESNs) is presented. Silver nanoplates were chosen due to the flexibility of tuning their plasmon frequencies. The polymer coating preserves their physical and optical properties and confers other advantages such as controlled contrast agent delivery. Finite difference time domain (FDTD) simulations model the interaction of light with the nanoplates in different orientations in the cluster. Hyperspectral dark field microscopy (HYDFM) observes the scattering spectra of the PESNs. An unsupervised sequential maximum angle convex cone (SMACC) image analysis resolves spectral endmembers corresponding to different stacking orientations of the nanoplates. The orientation-dependent endmembers qualitatively agree with the FDTD results. For contrast enhancement, the uptake and spatial distribution of PESNs are demonstrated by an HYDFM study of single melanoma cells to result in an enhanced contrast of up to 400%. A supervised spatial mapping of the endmembers obtained by the unsupervised SMACC algorithm reveals spatial distributions of PESNs with various clustering orientations of encapsulated nanoplates. Our study demonstrates tunability in plasmonics properties in clustered metal nanoparticles and its utility for the development of scatter-based imaging contrast agents for a broad range of applications, including studies of single cells and other biomedical systems., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The Methylene Blue loaded Polyacrylamide Nanoparticles (MB-PAA NPs) are used for oxygen sensing and Photodynamic therapy (PDT), a promising therapeutic modality employed for various tumors, with distinct advantages of delivery of biomedical agents and protection from other bio-molecules overcoming inherent limitations of molecular dyes. Lifetime-resolved photoacoustic spectroscopy using quenched-phosphorescence method is applied with MB-PAA NPs so as to sense oxygen, while the same light source is used for PDT. The dye is excited by absorbing 650 nm wavelength light from a pump laser to reach triplet state. The probe laser at 810 nm wavelength is used to excite the first triplet state at certain delayed time to measure the dye lifetime which indicates oxygen concentration. The 9L cells (106 cells/ml) incubated with MB-PAA NP solution are used for monitoring oxygen level change during PDT in situ test. The oxygen level and PDT efficacy are confirmed with a commercial oximeter, and fluorescence microscope imaging and flow cytometry results. This technique with the MB-PAA NPs allowed us to demonstrate a potential non-invasive theragnostic operation, by monitoring oxygen depletion during PDT in situ, without the addition of secondary probes. Here, we demonstrate this theragnostic operation, in vitro, performing PDT while monitoring oxygen depletion. We also show the correlation between O2 depletion and cell death.

During the past decades, prostate cancer (PCa), with an annual incident rate much higher than any other cancer, is the most commonly diagnosed cancer in American men. PCa has a relatively low progression rate yet the survival percentage decreases dramatically once the cancer has metastasized. Identifying aggressive from indolent PCa to prevent metastasis and death is critical to improve outcomes for patients with PCa. Standard procedure for assessing the aggressiveness of PCa involves the removal of tumor tissues by transrectal (TR) ultrasound (US) guided needle biopsy. The microscopic architecture of the biopsied tissue is visualized by histological or immunohistochemical staining procedures. The heterogeneity of the microscopic architecture is characterized by a Gleason score, a quantitative description of the aggressiveness of PCa. Due to the inability to identify the cancer cells, most noninvasive imaging modalities can only provide diagnosis of PCa at limited accuracy. This study investigates the feasibility of identifying PCa tumors and characterizing the aggressiveness of PCa by photoacoustic imaging assisted by cancer targeting polyacrylamide (PAA) nanoparticles (NPs). PAA is a biocompatible material used in clinics for the past 20 years. PAA NPs can protect capsulated optical contrast agents from interference by enzymes and enable prolonged systematic circulation in the living biological environment. The cancer targeting mechanism is achieved by conjugating the NPs to F3 peptides, which trace nucleolin overexpressed on the surface of cancer cells. Preliminary studies have shown that the NPs are capable of staining the PCa cells in vivo .

Nanoparticles (NPs) containing the photo-therapeutic dye Chlorin e6 (Ce6) have been explored in multiple studies for photo-dynamic therapy (PDT). However, little work has been carried out regarding their PDT efficacy, relative to other dye containing NPs. Here polyacrylamide nanoparticles (PAAm NPs) containing Ce6 were prepared and their PDT efficacy compared to previously reported methylene blue (MB) containing PAAmNPs. It was found that, for identical NP dosages and photon doses, the Ce6 NPs are an order of magnitude more potent in killing cancer cells.

Heart disease, a leading cause of death in the developed world, is overwhelmingly correlated with arrhythmias, where heart muscle cells, myocytes, beat abnormally. Cardiac arrhythmias are usually managed by electric shock intervention, antiarrhythmic drugs, surgery, and/or catheter ablation. Despite recent improvements in techniques, ablation procedures are still limited by the risk of complications from unwanted cellular damage, caused by the nonspecific delivery of ablative energy to all heart cell types. We describe an engineered nanoparticle containing a cardiac-targeting peptide (CTP) and a photosensitizer, chlorin e6 (Ce6), for specific delivery to myocytes. Specificity was confirmed in vitro using adult rat heart cell and human stem cell-derived cardiomyocyte and fibroblast cocultures. In vivo, the CTP-Ce6 nanoparticles were injected intravenously into rats and, upon laser illumination of the heart, induced localized, myocyte-specific ablation with 85% efficiency, restoring sinus rhythm without collateral damage to other cell types in the heart, such as fibroblasts. In both sheep and rat hearts ex vivo, upon perfusion of CTP-Ce6 particles, laser illumination led to the formation of a complete electrical block at the ablated region and restored the physiological rhythm of the heart. This nano-based, cell-targeted approach could improve ablative technologies for patients with arrhythmias by reducing currently encountered complications., (Copyright © 2015, American Association for the Advancement of Science.)