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We have synthesized and characterized a library of near-infrared (NIR) heptamethine cyanine dyes for biomedical application as photoacoustic imaging and photothermal agents. These hydrophobic dyes were incorporated into a polymer-based nanoparticle system to provide aqueous solubility and protection of the photophysical properties of each dye scaffold. Among those heptamethine cyanine dyes analyzed, 13 compounds within the nontoxic polymeric nanoparticles have been selected to exemplify structural relationships in terms of photostability, photoacoustic imaging, and photothermal behavior within the NIR (∼650-850 nm) spectral region. The most contributing structural features observed in our dye design include hydrophobicity, rotatable bonds, heavy atom effects, and stability of the central cyclohexene ring within the dye core. The NIR agents developed within this project serve to elicit a structure-function relationship with emphasis on their photoacoustic and photothermal characteristics aiming at producing customizable NIR photoacoustic and photothermal tools for clinical use.

Peri-necrotic tumor regions have been found to be a source of cancer stem cells (CSC), important in tumor recurrence. Necrotic and peri-necrotic tumor zones have poor vascular supply, limiting effective exposure to systemically administered therapeutics. Therefore, there is a critical need to develop agents that can effectively target these relatively protected tumor areas. We have developed a multi-property nanoplatform with necrosis avidity, fluorescence imaging and X-ray tracking capabilities to evaluate its feasibility for therapeutic drug delivery. The developed nanoparticle consists of three elements: poly(ethylene glycol)-block-poly(e-caprolactone) as the biodegradable carrier; hypericin as a natural compound with fluorescence and necrosis avidity; and gold nanoparticles for X-ray tracking. This reproducible nanoparticle has a hydrodynamic size of 103.9 ± 1.7 nm with a uniform spherical morphology (polydispersity index = 0.12). The nanoparticle shows safety with systemic administration and a stable 30 day profile. Intravenous nanoparticle injection into a subcutaneous tumor-bearing mouse and intra-arterial nanoparticle injection into rabbits bearing VX2 orthotopic liver tumors resulted in fluorescence and X-ray attenuation within the tumors. In addition, ex vivo and histological analysis confirmed the accumulation of hypericin and gold in areas of necrosis and peri-necrosis. This nanoplatform, therefore, has the potential to enhance putative therapeutic drug delivery to necrotic and peri-necrotic areas, and may also have an application for monitoring early response to anti-tumor therapies.

Despite its promising therapeutic potential, nanoparticle-mediated magnetic hyperthermia is currently limited to the treatment of localized and relatively accessible cancer tumors because the required therapeutic temperatures above 40 °C can only be achieved by direct intratumoral injection of conventional iron oxide nanoparticles. To realize the true potential of magnetic hyperthermia for cancer treatment, there is an unmet need for nanoparticles with high heating capacity that can efficiently accumulate at tumor sites following systemic administration and generate desirable intratumoral temperatures upon exposure to an alternating magnetic field (AMF). Although there have been many attempts to develop the desired nanoparticles, reported animal studies reveal the challenges associated with reaching therapeutically relevant intratumoral temperatures following systemic administration at clinically relevant doses. Therefore, we developed efficient magnetic nanoclusters with enhanced heating efficiency for systemically delivered magnetic hyperthermia that are composed of cobalt- and manganese-doped, hexagon-shaped iron oxide nanoparticles (CoMn-IONP) encapsulated in biocompatible PEG-PCL (poly(ethylene glycol)- b-poly(ε-caprolactone))-based nanocarriers. Animal studies validated that the developed nanoclusters are nontoxic, efficiently accumulate in ovarian cancer tumors following a single intravenous injection, and elevate intratumoral temperature up to 44 °C upon exposure to safe and tolerable AMF. Moreover, the obtained results confirmed the efficiency of the nanoclusters to generate the required intratumoral temperature after repeated injections and demonstrated that nanocluster-mediated magnetic hyperthermia significantly inhibits cancer growth. In summary, this nanoplatform is a milestone in the development of systemically delivered magnetic hyperthermia for the treatment of cancer tumors that are difficult to access for intratumoral injection.

Endoxifen is the primary active metabolite of tamoxifen, a nonsteroidal-selective estrogen receptor modulator (SERM) and widely used medication to treat estrogen receptor-positive (ER+) breast cancer. In this study, endoxifen was conjugated to the surface of polymeric nanoparticles (polymersomes) for targeted delivery of doxorubicin (DOX) to estrogen receptor-positive breast cancer cells (MCF7). Rapid cell growth and insufficient blood supply result in low oxygen concentration (hypoxia) within the solid breast tumors. The polymersomes developed here are prepared from amphiphilic copolymers of polylactic acid (PLA) and poly(ethylene glycol) (PEG) containing diazobenzene as the hypoxia-responsive linker. We prepared two nanoparticle formulations: DOX-encapsulated hypoxia-responsive polymersomes (DOX-HRPs) and endoxifen-conjugated, DOX-encapsulated hypoxia-responsive polymersomes (END-DOX-HRPs). Cellular internalization studies demonstrated eight times higher cytosolic and nuclear localization after incubating breast cancer cells with END-DOX-HRPs (targeted polymersomes) in contrast to DOX-HRPs (nontargeted polymersomes). Cytotoxicity studies on monolayer cell cultures exhibited that END-DOX-HRPs were three times more toxic to ER+ MCF7 cells than DOX-HRPs and free DOX in hypoxia. The cell viability studies on three-dimensional hypoxic cultures also demonstrated twice as much toxicity when the spheroids were treated with targeted polymersomes instead of nontargeted counterparts. This is the first report of surface-decorated polymeric nanoparticles with endoxifen ligands for targeted drug delivery to ER+ breast cancer microtumors. The newly designed endoxifen-conjugated, hypoxia-responsive polymersomes might have translational potential for ER+ breast cancer treatment.

Ewing's sarcoma (EwS) is the second most common bone cancer in children and adolescents. Current chemotherapy regimens are mainly ineffective in patients with relapsed disease and cause long-term effects in survivors. Therefore, we have developed a combinatorial therapy based on a novel drug candidate named ML111 that exhibits selective activity against EwS cells and synergizes with vincristine. To increase the aqueous solubility of hydrophobic ML111, polymeric nanoparticles (ML111-NP) were developed. In vitro data revealed that ML111-NP compromise viability of EwS cells without affecting non-malignant cells. Furthermore, ML111-NP exhibit strong synergistic effects in a combination with vincristine on EwS cells, while this drug pair exhibits antagonistic effects towards normal cells. Finally, animal studies validated that ML111-NP efficiently accumulate in orthotopic EwS xenografts after intravenous injection and provide superior therapeutic outcomes in a combination with vincristine without evident toxicity. These results support the potential of the ML111-based combinatorial therapy for EwS.

Endometriosis is an incurable gynecological disease characterized by the abnormal growth of endometrium-like tissue, characteristic of the uterine lining, outside of the uterine cavity. Millions of people with endometriosis suffer from pelvic pain and infertility. This review aims to discuss whether nanomedicines that are promising therapeutic approaches for various diseases have the potential to create a paradigm shift in endometriosis management. For the first time, the available reports and achievements in the field of endometriosis nanomedicine are critically evaluated, and a summary of how nanoparticle-based systems can improve endometriosis treatment and diagnosis is provided. Parallels between cancer and endometriosis are also drawn to understand whether some fundamental principles of the well-established cancer nanomedicine field can be adopted for the development of novel nanoparticle-based strategies for endometriosis. This review provides the state of the art of endometriosis nanomedicine and perspective for researchers aiming to realize and exploit the full potential of nanoparticles for treatment and imaging of the disorder.

Herein, we report a novel therapy for prostate cancer based on systemically delivered magnetic hyperthermia. Conventional magnetic hyperthermia is a form of thermal therapy where magnetic nanoparticles delivered to cancer sites via intratumoral administration produce heat in the presence of an alternating magnetic field (AMF). To employ this therapy for prostate cancer tumors that are challenging to inject intratumorally, we designed novel nanoclusters with enhanced heating efficiency that reach prostate cancer tumors after systemic administration and generate desirable intratumoral temperatures upon exposure to an AMF. Our nanoclusters are based on hydrophobic iron oxide nanoparticles doped with zinc and manganese. To overcome the challenges associated with the poor water solubility of the synthesized nanoparticles, the solvent evaporation approach was employed to encapsulate and cluster them within the hydrophobic core of PEG-PCL (methoxy poly(ethylene glycol)-b-poly(&epsilon, caprolactone))-based polymeric nanoparticles. Animal studies demonstrated that, following intravenous injection into mice bearing prostate cancer grafts, the nanoclusters efficiently accumulated in cancer tumors within several hours and increased the intratumoral temperature above 42 &deg, C upon exposure to an AMF. Finally, the systemically delivered magnetic hyperthermia significantly inhibited prostate cancer growth and did not exhibit any signs of toxicity.

Necrosis targeting and imaging has significant implications for evaluating tumor growth, therapeutic response, and delivery of therapeutics to peri-necrotic tumor zones. Hypericin is a hydrophobic molecule with high necrosis affinity and fluorescence imaging properties. To date, the safe and effective delivery of hypericin to areas of necrosis in vivo remains a challenge due to its incompatible biophysical properties. To address this issue, we have developed a biodegradable nanoparticle (Hyp-NP) for delivery of hypericin to tumors for necrosis targeting and fluorescence imaging. The nanoparticle was developed using methoxy poly(ethylene glycol)- b -poly(ε-caprolactone) (PEG-PCL) and hypericin by a modified solvent evaporation technique. The size of Hyp-NP was 19.0±1.8 nm from cryo-TEM and 37.3±0.7 nm from dynamic light scattering analysis with a polydispersity index of 0.15±0.01. The encapsulation efficiency of hypericin was 95.05% w/w by UV-vis absorption. After storage for 30 days, 91.4% hypericin was retained in Hyp-NP with nearly no change in hydrodynamic size, representing nanoparticle stability. In an ovarian cancer cell line, Hyp-NP demonstrated cellular internalization with intracellular cytoplasmic localization and preserved fluorescence and necrosis affinity. In a mouse subcutaneous tumor model, tumor accumulation was noted at 8 h post-injection, with near-complete clearance at 96 h post-injection. Hyp-NP was shown to be tightly localized within necrotic tumor zones. Histologic analysis of harvested organs demonstrated no gross abnormalities, and in vitro, no hemolysis was observed. This proof-of-concept study demonstrates the potential clinical applications of Hyp-NP for necrosis targeting.

Muscle atrophy occurs during chronic diseases, resulting in diminished quality of life and compromised treatment outcomes. There is a high demand for therapeutics that increase muscle mass while abrogating the need for special dietary and exercise requirements. Therefore, we developed an efficient nanomedicine approach capable of increasing muscle mass. Methods: The therapy is based on nanoparticle-mediated delivery of follistatin messenger RNA (mRNA) to the liver after subcutaneous administration. The delivered mRNA directs hepatic cellular machinery to produce follistatin, a glycoprotein that increases lean mass through inhibition of negative regulators of muscle mass (myostatin and activin A). These factors are elevated in numerous disease states, thereby providing a target for therapeutic intervention. Results: Animal studies validated that mRNA-loaded nanoparticles enter systemic circulation following subcutaneous injection, accumulate and internalize in the liver, where the mRNA is translated into follistatin. Follistatin serum levels were elevated for 72 h post injection and efficiently reduced activin A and myostatin serum concentrations. After eight weeks of repeated injections, the lean mass of mice in the treatment group was ~10% higher when compared to that of the controls. Conclusion: Based on the obtained results demonstrating an increased muscle mass as well as restricted fat accumulation, this nanoplatform might be a milestone in the development of mRNA technologies and the treatment of muscle wasting disorders.

Fluorescence image-guided surgery combined with intraoperative therapeutic modalities has great potential for intraoperative detection of oncologic targets and eradication of unresectable cancer residues. Therefore, we have developed an activatable theranostic nanoplatform that can be used concurrently for two purposes: (1) tumor delineation with real-time near infrared (NIR) fluorescence signal during surgery, and (2) intraoperative targeted treatment to further eliminate unresected disease sites by non-toxic phototherapy. Methods: The developed nanoplatform is based on a single agent, silicon naphthalocyanine (SiNc), encapsulated in biodegradable PEG-PCL (poly (ethylene glycol)-b-poly(ɛ-caprolactone)) nanoparticles. It is engineered to be non-fluorescent initially via dense SiNc packing within the nanoparticle's hydrophobic core, with NIR fluorescence activation after accumulation at the tumor site. The activatable nanoplatform was evaluated in vitro and in two different murine cancer models, including an ovarian intraperitoneal metastasis-mimicking model. Furthermore, fluorescence image-guided surgery mediated by this nanoplatform was performed on the employed animal models using a Fluobeam® 800 imaging system. Finally, the phototherapeutic efficacy of the developed nanoplatform was demonstrated in vivo. Results: Our in vitro data suggest that the intracellular environment of cancer cells is capable of compromising the integrity of self-assembled nanoparticles and thus causes disruption of the tight dye packing inside the hydrophobic cores and activation of the NIR fluorescence. Animal studies demonstrated accumulation of activatable nanoparticles at the tumor site following systemic administration, as well as release and fluorescence recovery of SiNc from the polymeric carrier. It was also validated that the developed nanoparticles are compatible with the intraoperative imaging system Fluobeam® 800, and nanoparticle-mediated image-guided surgery provides successful resection of cancer tumors. Finally, in vivo studies revealed that combinatorial phototherapy mediated by the nanoparticles could efficiently eradicate chemoresistant ovarian cancer tumors. Conclusion: The revealed properties of the activatable nanoplatform make it highly promising for further application in clinical image-guided surgery and combined phototherapy, facilitating a potential translation to clinical studies.

Prostate cancer is the leading cause of cancer death in American men. The high mortality rate is attributable to current treatments not providing a cure for hormone-refractory prostate cancer. The main goal of this project is to provide a novel therapeutic approach based on nanoparticle-mediated magnetic hyperthermia for efficient treatment of this cancer. Magnetic hyperthermia is a form of thermal therapy where magnetic nanoparticles delivered to cancer sites generate heat after exposure to an external alternating magnetic field (AMF). Many studies suggest that it has significant potential to kill cancer cells directly or enhance their susceptibility to radiation, chemotherapy and immunotherapy. Magnetic hyperthermia, however, is restricted to the treatment of localized and accessible tumors because therapeutic temperatures above 40 Celsius have only been achieved by intratumoral injection of magnetic nanoparticles. This is due to the low heating efficiency of conventional iron oxide nanoparticles combined with low tumor accumulation of these nanoparticles following systemic delivery. To employ this therapy for primary and metastatic prostate cancer tumors that are difficult to access for intratumoral injection, we have designed novel biocompatible nanoclusters with high heating efficiency that efficiently accumulate in prostate cancer tumors after intravenous injection at clinically relevant doses and generate the desirable intratumoral temperatures upon exposure to AMF. Our nanoclusters are built on hydrophobic iron oxide nanoparticles doped with zinc and manganese. To overcome challenges associated with poor water solubility of the synthesized nanoparticles, the solvent evaporation approach was employed to encapsulate and cluster them within the hydrophobic core of PEG-PCL-based polymeric nanoparticles. The amphiphilic PEG-PCL (methoxy poly(ethylene glycol)-b-poly(ϵ-caprolactone)) molecules, composed of hydrophobic 10 kDa PCL and hydrophilic 5 kDa PEG blocks, self-assemble in aqueous solution upon evaporation of the organic solvent to form nanoparticles with a hydrophilic PEG outer shell and hydrophobic PCL core. The transmission electron microscope images reveal that iron oxide nanoparticles form clusters within a single PEG-PCL nanoparticle. It is validated that the clustering of iron oxide nanoparticles enhances their heating efficiency. Animal studies demonstrate that following intravenous injection into mice bearing prostate cancer grafts the nanoclusters efficiently accumulate in cancer tumors and increase the intratumoral temperature up to 42 Celsius upon exposure to AMF. Finally, the systemically delivered magnetic hyperthermia significantly inhibits prostate cancer growth and does not exhibit any sign of toxicity. In summary, this discovery will allow to realize the true therapeutic potential of magnetic hyperthermia alone and in combination with other therapies for inaccessible primary and metastatic prostate cancer tumors. Citation Format: Oleh Taratula, Olena Taratula. Intravascular delivery of nanoclusters for treatment of prostate cancer with magnetic hyperthermia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2875.

An urgent need for early detection and diagnosis of diseases continuously pushes the advancements of imaging modalities and contrast agents. Current challenges remain for fast and detailed imaging of tissue microstructures and lesion characterization that could be achieved via development of nontoxic contrast agents with longer circulation time. Nanoparticle technology offers this possibility. Here, we review nanoparticle-based contrast agents employed in most common biomedical imaging modalities, including fluorescence imaging, MRI, CT, US, PET and SPECT, addressing their structure related features, advantages and limitations. Furthermore, their applications in each imaging modality are also reviewed using commonly studied examples. Future research will investigate multifunctional nanoplatforms to address safety, efficacy and theranostic capabilities. Nanoparticles as imaging contrast agents have promise to greatly benefit clinical practice.

Endometriosis is a painful disorder where endometrium-like tissue forms lesions outside of the uterine cavity. Intraoperative identification and removal of these lesions are difficult. This study presents a nanoplatform that concurrently delineates and ablates endometriosis tissues using real-time near-infrared (NIR) fluorescence and photothermal therapy (PTT). The nanoplatform consists of a dye, silicon naphthalocyanine (SiNc), capable of both NIR fluorescence imaging and PTT, and a polymeric nanoparticle as a SiNc carrier to endometriosis tissue following systemic administration. To achieve high contrast during fluorescence imaging of endometriotic lesions, nanoparticles are constructed to be non-fluorescent prior to internalization by endometriosis cells. In vitro studies confirm that these nanoparticles activate the fluorescence signal following internalization in macaque endometrial stromal cells and ablate them by increasing cellular temperature to 53 ° C upon interaction with NIR light. To demonstrate in vivo efficiency of the nanoparticles, biopsies of endometrium and endometriosis from rhesus macaques are transplanted into immunodeficient mice. Imaging with the intraoperative Fluobeam 800 system reveals that 24 h following intravenous injection, nanoparticles efficiently accumulate in, and demarcate, endometriotic grafts with fluorescence. Finally, the nanoparticles increase the temperature of endometriotic grafts up to 47 °C upon exposure to NIR light, completely eradicating them after a single treatment.

Herein, we report an efficient combinatorial therapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin. DJ-1 protein modulates, either directly or indirectly, different oncogenic pathways that support and promote survival, growth, and invasion of ovarian cancer cells. To evaluate the potential of this novel therapy, we have engineered a cancer-targeted nanoplatform and validated that DJ-1 siRNA delivered by this nanoplatform after intraperitoneal injection efficiently downregulates the DJ-1 protein in metastatic ovarian cancer tumors and ascites. In vivo experiments revealed that DJ-1 siRNA monotherapy outperformed cisplatin alone by inhibiting tumor growth and increasing survival of mice with metastatic ovarian cancer. Finally, three cycles of siRNA-mediated DJ-1 therapy in combination with a low dose of cisplatin completely eradicated ovarian cancer tumors from the mice, and there was no cancer recurrence detected for the duration of the study, which lasted 35 weeks.

Image-guided phototherapy is extensively considered as a promising therapy for cancer treatment. To enhance translational potential of this modality, we developed a single agent-based biocompatible nanoplatform that provides both real time near-infrared (NIR) fluorescence imaging and combinatorial phototherapy with dual photothermal and photodynamic therapeutic mechanisms. The developed theranostic nanoplatform consists of two building blocks: (1) silicon naphthalocyanine (SiNc) as a NIR fluorescence imaging and phototherapeutic agent and (2) a copolymer, poly(ethylene glycol)-block-poly(e-caprolactone) (PEG–PCL) as the biodegradable SiNc carrier. Our simple, highly reproducible, and robust approach results in preparation of spherical, monodisperse SiNc-loaded PEG–PCL polymeric nanoparticles (SiNc-PNP) with a hydrodynamic size of 37.66 ± 0.26 nm (polydispersity index = 0.06) and surface charge of −2.76 ± 1.83 mV. The SiNc-loaded nanoparticles exhibit a strong NIR light absorption with an extinction coeffi...

The (+) and ( − ) enantiomers for a cryptophane-7-bond-linker-benzenesulfonamide biosensor (C7B) were synthesised and their chirality was confirmed by electronic circular dichroism spectroscopy. Biosensor binding to carbonic anhydrase II (CAII) was characterised for both enantiomers by hyperpolarised (HP) 129Xe NMR spectroscopy. Our previous study of the racemic ( ± ) C7B biosensor–CAII complex [Chambers, J.M.; Hill, P.A.; Aaron, J.A.; Han, Z.H.; Christianson, D.W.; Kuzma, N.N.; Dmochowski, I.J. J. Am. Chem. Soc.2009, 131, 563–569] identified two ‘bound’ 129Xe@C7B peaks by HP 129Xe NMR (at 71 and 67 ppm, relative to ‘free’ biosensor at 64 ppm), which led to the initial hypothesis that (+) and ( − ) enantiomers produce diastereomeric peaks when coordinated to Zn2+ at the chiral CAII active site. Unexpectedly, the single enantiomers complexed with CAII also identified two ‘bound’ 129Xe@C7B peaks: (+) 72, 68 ppm and ( − ) 68, 67 ppm. These results are consistent with X-ray crystallographic evidence for benze...

Purpose: The proposed project is aimed at enhancing the efficiency of epithelial ovarian cancer treatment and reducing adverse side effects of chemotherapy using nanotechnology. Overexpression of the CD44 membrane receptor results in tumor initiation, growth, cancer stem cells' specific behavior, development of drug resistance, and metastases. We hypothesize that a developed cancer-targeted delivery system that combines CD44 siRNA with paclitaxel would successfully deliver its payload inside cancer cells, effectively induce cell death, and prevent metastases. Experimental Design: We synthesized, characterized, and tested a nanoscale-based drug delivery system (DDS) containing a modified polypropylenimine (PPI) dendrimer as a carrier; anticancer drug paclitaxel as a cell death inducer; a synthetic analog of luteinizing hormone–releasing hormone (LHRH) peptide as a tumor-targeting moiety; and siRNA targeted to CD44 mRNA. The proposed DDS was tested in vitro and in vivo using metastatic ovarian cancer cells isolated from patients with malignant ascites. Results: We found that in contrast with cells isolated from primary tumors, CD44 was highly overexpressed in metastatic cancer cells. Treatment with the proposed tumor-targeted nanoscale-based nucleic acid and DDS led to the suppression of CD44 mRNA and protein, efficient induction of cell death, effective tumor shrinkage, and prevention of adverse side effects on healthy organs. Conclusion: We show a high therapeutic potential for combinatorial treatment of ovarian carcinoma with a novel DDS that effectively transports siRNA targeting to CD44 mRNA simultaneously with cytotoxic agents. Clin Cancer Res; 19(22); 6193–204. ©2013 AACR.

Owing to the outstanding near-infrared (NIR) optical properties, phthalocyanines (Pc) have promising potential as theranostic agents for fluorescence image-guided drug delivery and noninvasive treatment of deep tumors by photodynamic therapy (PDT). Nevertheless, clinical application of phthalocyanines is substantially limited by poor water solubility, aggregation and insufficient selectivity for cancer cells. To address these issues, we have developed a novel dendrimer-based theranostic platform for tumor-targeted delivery of phthalocyanines. The preparation procedure involved the modification of the Pc molecule with a hydrophobic linker, which significantly enhances physical encapsulation of the hydrophobic drug into a generation 4 polypropylenimine (PPI G4) dendrimer. In order to improve biocompatibility and tumor-targeted delivery, the surface of the resulting Pc-PPIG4 complexes was additionally modified with poly(ethylene glycol) (PEG) and luteinizing hormone-releasing hormone (LHRH) peptide, respectively. The developed nanocarriers have an average diameter of 62.3 nm and narrow size distribution with a polydispersity index of 0.100. The drug encapsulation efficiency was 20% w/w, and the synthesized phthalocyanine derivative entrapped in the dendrimer-based nanocarrier exhibits a distinct NIR absorption (700 nm) and fluorescence emission (710 and 815 nm), required for an efficient PDT and fluorescence imaging. It was demonstrated that subcellular localization in vitro and organ distribution in vivo of the developed nanocarrier can be determined based on the intrinsic fluorescence properties of encapsulated phthalocyanine, validating its role as an imaging agent. The imaging experiments revealed that the LHRH targeted nanocarrier is capable of an efficient internalization into cancer cells as well as tumor accumulation when intravenously administered into mice. Finally, the prepared formulation exhibited low dark cytotoxicity (IC50=28 μg/mL) while light irradiation of the cancer cells transfected with the developed theranostic agents resulted in significant PDT effects (IC50=0.9 μg/mL) through excessive generation of toxic reactive oxygen species. Thus, the obtained results demonstrated significant potential of the designed dendrimer-based nanocarrier as an efficient NIR theranostic agent.

Targeted delivery of therapeutic and diagnostic agents to cancer sites has significant potential to improve the therapeutic outcome of treatment while minimizing severe side effects. It is widely accepted that decoration of the drug delivery systems with targeting ligands that bind specifically to the receptors on the cancer cells is a promising strategy that may substantially enhance accumulation of anticancer agents in the tumors. Due to the transformed cellular nature, cancer cells exhibit a variety of overexpressed cell surface receptors for peptides, hormones, and essential nutrients, providing a significant number of target candidates for selective drug delivery. Among others, luteinizing hormone-releasing hormone (LHRH) receptors are overexpressed in the majority of cancers, while their expression in healthy tissues, apart from pituitary cells, is limited. The recent studies indicate that LHRH peptides can be employed to efficiently guide anticancer and imaging agents directly to cancerous cells, thereby increasing the amount of these substances in tumor tissue and preventing normal cells from unnecessary exposure. This manuscript provides an overview of the targeted drug delivery platforms that take advantage of the LHRH receptors overexpression by cancer cells.

We report an efficient therapeutic modality for platinum resistant ovarian cancer based on siRNA-mediated suppression of a multifunctional DJ-1 protein that is responsible for the proliferation, growth, invasion, oxidative stress, and overall survival of various cancers. The developed therapeutic strategy can work alone or in concert with a low dose of the first line chemotherapeutic agent cisplatin, to elicit a maximal therapeutic response. To achieve an efficient DJ-1 knockdown, we constructed the polypropylenimine dendrimer-based nanoplatform targeted to LHRH receptors overexpressed on ovarian cancer cells. The quantitative PCR and Western immunoblotting analysis revealed that the delivered DJ-1 siRNA downregulated the expression of targeted mRNA and corresponding protein by more than 80% in various ovarian cancer cells. It was further demonstrated that siRNA-mediated DJ-1 suppression dramatically impaired proliferation, viability, and migration of the employed ovarian cancer cells. Finally, the combinatorial approach led to the most pronounced therapeutic response in all the studied cell lines, outperforming both siRNA-mediated DJ-1 knockdown and cisplatin treatment alone. It is noteworthy that the platinum-resistant cancer cells (A2780/CDDP) with the highest basal level of DJ-1 protein are most susceptible to the developed therapy and this susceptibility declines with decreasing basal levels of DJ-1. Finally, we interrogate the molecular underpinnings of the DJ-1 knockdown effects in the treatment of the ovarian cancer cells. By using various experimental techniques, it was revealed that DJ-1 depletion (1) decreases the activity of the Akt pathway, thereby reducing cellular proliferation and migration and increasing the antiproliferative effect of cisplatin on ovarian cancer cells; (2) enhances the activity of p53 tumor suppressor protein therefore restoring cell cycle arrest functionality and upregulating the Bax-caspase pathway, triggering cell death; and (3) weakens the cellular defense mechanisms against inherited oxidative stress thereby increasing toxic intracellular radicals and amplifying the reactive oxygen species created by the administration of cisplatin.

We report a ZnO-nanostructure-based quartz crystal microbalance (nano-QCM) device for biosensing applications. ZnO nanotips are directly grown on the sensing area of a conventional QCM by metalorganic chemical vapor deposition (MOCVD). Scanning electron microscopy (SEM) shows that the ZnO nanotips are dense and uniformly aligned along the normal to the substrate surface. By using superhydrophilic nano-ZnO surface, more than tenfold increase in mass loading sensitivity of the nano-QCM device is achieved over the conventional QCM. The ZnO nanotip arrays on the nano-QCM are functionalized. The selective immobilization and hybridization of DNA oligonucleotide molecules are confirmed by fluorescence microscopy of the nano-QCM sensing areas.

in Undetermined Ruthenium polypyridyl rigid-rod compounds with phenylene-ethynelene (OPE) spacers and an isophthalic acid (Ipa) binding group were synthesized and characterized for sensitization of nanocrystalline TiO(2) (anatase) thin films. Density functional theory predicted that the most stable structure oriented the isophthalic group about 45 degrees from normal to the TiO(2) surface. Comparative experimental studies of meta- and para-isomers revealed small changes in the ground state absorption spectra and very similar excited state and redox properties. The excited state injection yields (inj = 0.15 +/- 0.03)into nanocrystalline TiO(2) and the subsequent charge recombination rates were found to be insensitive to the isomer utilized. Meta-substitution enabled the synthesis of sensitizers with two Ru(II) sensitizers that displayed enhanced sunlight absorption relative to the monomeric compound. (Less)

Zinc oxide (ZnO) and its ternary alloy magnesium zinc oxide (Mg x Zn1−x O) are piezoelectric materials that can be used for high-quality-factor bulk acoustic wave (BAW) resonators operating at GHz frequencies. Thin-film bulk acoustic resonators (TFBARs) are attractive for applications in advanced communication and in various sensors as they offer the capability of monolithic integration of BAW resonators with radio-frequency integrated circuits (RF ICs). In this paper we report Mg x Zn1−x O-based TFBAR biosensors. The devices are built on Si substrates with an acoustic mirror consisting of alternating quarter-wavelength silicon dioxide (SiO2) and tungsten (W) layers to isolate the TFBAR from the Si substrate. High-quality ZnO and Mg x Zn1−x O thin films are achieved through a radio-frequency (RF) sputtering technique. Tuning of the device operating frequency is realized by varying the Mg composition in the piezoelectric Mg x Zn1−x O layer. Simulation results based on a transmission-line model of the TFBAR show close agreement with the experimental results. ZnO nanostructures are grown on the TFBAR’s top surface using metal- organic chemical vapor deposition (MOCVD) to form the nano-TFBAR sensor, which offers giant sensing area, faster response, and higher sensitivity over the planar sensor configuration. Mass sensitivity higher than 103 Hz cm2/ng is achieved. In order to study the feasibility of the nano-TFBAR for biosensing, the nanostructured ZnO surfaces were functionalized to selectively immobilize␣DNA, as verified by hybridization with its fluorescence-tagged DNA complement.

A surface functionalization methodology for the development of ZnO nanotips biosensors that can be integrated with microelectronics was developed. Two types of long chain carboxylic acids linkers were employed for the functionalization of 0.5 mum thick MOCVD-grown ZnO nanotip films with single-stranded DNA (ssDNA), followed by hybridization with complementary ssDNA tagged with fluorescein. The ZnO functionalization strategy was developed for the fabrication of ZnO nanotips-linker-biomolecule films integrated with bulk acoustic wave (BAW) biosensors, and it involved three main steps. First, 16-(2-pyridyldithiol)hexadecanoic acid or N-(15-carboxypentadecanoyloxy)succinimide, both bifunctional C16 carboxylic acids, were bound to ZnO nanotip films through the COOH group, leaving at the opposite end of the alkyl chain a thiol group protected as a 2-pyridyl disulfide, or a carboxylic group protected as a N-succinimide, respectively. In the second step, ssDNA was covalently linked to each type of ZnO-linker film: the 2-pyridyl disulfide end group was substituted with 16 bases 5'-thiol-modified DNA (SH-ssDNA), and the N-succinimide ester end group was substituted with 16 bases 5'-amino-modified DNA (NH(2)-ssDNA). In the third step, the DNA-functionalized ZnO nanotip films were hybridized with complementary 5'-fluorescein ssDNA. The surface-modified ZnO nanotip films were characterized after each step by FT-IR-ATR, fluorescence emission spectroscopy, and fluorescence microscopy. This functionalization approach allows sequential reactions on the surface and, in principle, can be extended to numerous other molecules and biomolecules.

This study represents a novel approach for intraoperative ovarian cancer treatment based on the combinatorial effect of a targeted photodynamic therapy (PDT) associated with suppression of the DJ-1 protein, one of the key players in the ROS defense of cancer cells. To assess the potential of the developed therapy, dendrimer-based nanoplatforms for cancer-targeted delivery of near-infrared photosensitizer, phthalocyanine, and DJ-1 siRNA have been constructed. In vitro studies revealed that therapeutic efficacy of the combinatorial approach was enhanced when compared to PDT alone and this enhancement was more pronounced in ovarian carcinoma cells, which are characterized by higher basal levels of DJ-1 protein. Moreover, the ovarian cancer tumors exposed to a single dose of combinatorial therapy were completely eradicated from the mice and the treated animals showed no evidence of cancer recurrence. Thus, the developed therapeutic approach can be potentially employed intraoperatively to eradicate unresactable cancer cells.The complete clearance of microscopic residual tumor cells during excision surgery is important to improve survival of the patient. In this interesting paper, the authors developed a novel approach using targeted photodynamic therapy (PDT), combining a photosensitizer, phthalocyanine, and DJ-1 siRNA for the treatment of ovarian cancer. The data showed that this approach increased cancer cell killing and may pave way for future clinical studies.

Phenylenethynylene (PE) rigid linkers (para and meta) were used to anchor pyrene to the surface of TiO2 (anatase) and ZrO2 nanoparticle thin films through the two COOH groups of an isophthalic acid (Ipa) unit. Four chromophore-linker models were studied in solution and bound. Two are novel meta-pyrene-PE linker systems: dimethyl 5-(3-(1-pyrenylethynyl)phenylethynyl)-isophthalate, carrying one pyrene, and dimethyl 5-(bis-3,5-(1-pyrenylethynyl)phenylethynyl)-isophthalate, carrying two. These were compared with para rigid-rods dimethyl 5-(1-pyrenylethynyl)isophthalate and dimethyl 5-(4-(1-pyrenylethynyl)phenylethynyl)-isophthalate, each carrying one pyrene but varying in length. The length of the PE linkers and the para or meta substitution influence the photophysical properties of the compounds. The extinction coefficient increased, and the long wavelength absorbance of the pyrene chromophore was shifted to the red with increasing conjugation. Compared to unsubstituted pyrene, the pyrene-linker systems were characterized by short fluorescence lifetimes (tau approximately 2 ns in tetrahydrofuran solutions), but quantum yields were close to unity. ZINDO/S CI calculations attribute this effect to a switching in the order of the two lowest-lying singlet states of pyrene. High surface coverages, approximately 10(-8) mol/cm2, and carboxylate binding modes on nanostructured TiO2 films were obtained in all cases. The appearance of a pyrene excimer emission on ZrO2, an insulator, indicates that the pyrene-linker system is closely packed (Py-Py4 A) on the surface. The fluorescence emission on TiO2 was completely quenched, consistent with quantitative and rapid electron injection into the semiconductor indicating that the pyrene excimer acts as a sensitizer. Photoelectrochemical studies in regenerative solar cells with I3-/I- as the redox mediator indicated near-quantitative conversion of absorbed photons into an electrical current.

PURPOSE: Surgery plays a decisive role in cancer treatment and patient prognosis is closely linked to the size of residual tumors after cytoreduction. Even with the best surgical techniques, however, palpation and visual inspection do not always permit discrimination between malignant and normal tissue types and can lead to incomplete cancer resection. It is extremely important, therefore, to improve tumor delineation during surgery and provide efficient adjuvant treatment intraoperatively, to further eliminate occult disease sites that may be left behind. Among the explored fluorescent agents, near infrared (NIR, 750 – 900 nm) fluorescent imaging agents possess advantages of deep tissue penetration and minimal tissue autofluorescence and light scattering, making them promising candidates for optical imaging guided cancer debulking surgery. Our study is aimed to develop a nanomedicine capable of maximizing selective tumor detection via fluorescence imaging and immediate phototherapy for tumor tissue eradication. METHODS: To develop an effective theranostic probe, silicon naphthalocyanine (SiNc) with strong light absorption in the NIR region was loaded into a biodegradable polymeric nanoparticle based on the amphiphilic block polymer, poly (ethylene glycol)–poly(ε–caprolactone) (PEG–PCL). Such a design has provided a possibility to control and improve fluorescence and phototherapeutic properties of the SiNc–based theranostic agent. RESULTS: As a theranostic agent, the developed SiNc polymeric nanoparticles were evaluated by DLS, TEM (around 20 nm), NIR absorbance and fluorescence spectroscopies, ROS and hyperthermia production. The safety and effectiveness of SiNc–nanoparticles as a bioimaging agent was confirm in vitro and in vivo. In addition, high photostability of SiNc–nanoparticles have been detected. The efficiency of SiNc–nanoparticles as an NIR bioimaging agent was confirmed by recording the strong fluorescence signal in the ovarian cancer tumors. The in vitro and in vivo studies demonstrated that, after efficient tumor accumulation via i.v. administration, phototherapy mediated by SiNc can efficiently destroy ovarian cancer tumors. CONCLUSIONS: We have developed a photostable NIR theranostic nanomedicine platform that provides florescence detection of subcutaneous and orthotopic tumor xenographs as well as effective phototherapy resulting in complete tumor eradication. This theranostic agent can be potentially employed concurrently for tumor delineation with real–time NIR fluorescence signal during surgery and intraoperative targeted treatment to further eliminate non–surgically removable disease sites by non–toxic phototherapy. Citation Format: Oleh Taratula, Olena Taratula, Xiaoning Li, Canan Schumann, Shay Bracha, Milan Milovancev, Adam W. G. Alani. THERANOSTIC NANOPLATFORM FOR IMAGE–GUIDED SURGERY AND INTRAOPERATIVE PHOTOTHERAPY FOR OVARIAN CANCER TREATMENT [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-012.

The (+) and (−) enantiomers for a cryptophane-7-bond-linker-benzenesulfonamide biosensor (C7B) were synthesized and their chirality confirmed by electronic circular dichroism (ECD) spectroscopy. Biosensor binding to carbonic anhydrase II (CAII) was characterized for both enantiomers by hyperpolarized (hp) 129Xe NMR spectroscopy. Our previous study of the racemic (+/−) C7B biosensor-CAII complex [Chambers, et al., J. Am. Chem. Soc. 2009, 131, 563–569], identified two “bound” 129Xe@C7B peaks by hp 129Xe NMR (at 71 and 67 ppm, relative to “free” biosensor at 64 ppm), which led to the initial hypothesis that (+) and (−) enantiomers produce diastereomeric peaks when coordinated to Zn2+ at the chiral CAII active site. Unexpectedly, the single enantiomers complexed with CAII also identified two “bound” 129Xe@C7B peaks: (+) 72, 68 ppm and (−) 68, 67 ppm. These results are consistent with X-ray crystallographic evidence for benzenesulfonamide inhibitors occupying a second site near the CAII surface. As illustrated by our studies of this model protein-ligand interaction, hp 129Xe NMR spectroscopy can be useful for identifying supramolecular assemblies in solution.

Multifunctional theranostic platforms capable of concurrent near-infrared (NIR) fluorescence imaging and phototherapies are strongly desired for cancer diagnosis and treatment. However, the integration of separate imaging and therapeutic components into nanocarriers results in complex theranostic systems with limited translational potential. A single agent-based theranostic nanoplatform, therefore, was developed for concurrent NIR fluorescence imaging and combinatorial phototherapy with dual photodynamic (PDT) and photothermal (PTT) therapeutic mechanisms. The transformation of a substituted silicon naphthalocyanine (SiNc) into a biocompatible nanoplatform (SiNc-NP) was achieved by SiNc encapsulation into the hydrophobic interior of a generation 5 polypropylenimine dendrimer following surface modification with polyethylene glycol. Encapsulation provides aqueous solubility to SiNc and preserves its NIR fluorescence, PDT and PTT properties. Moreover, an impressive photostability in the dendrimer-encapsulated SiNc has been detected. Under NIR irradiation (785 nm, 1.3 W cm(-2)), SiNc-NP manifested robust heat generation capability (ΔT = 40 °C) and efficiently produced reactive oxygen species essential for PTT and PDT, respectively, without releasing SiNc from the nanopaltform. By varying the laser power density from 0.3 W cm(-2) to 1.3 W cm(-2) the therapeutic mechanism of SiNc-NP could be switched from PDT to combinatorial PDT-PTT treatment. In vitro and in vivo studies confirmed that phototherapy mediated by SiNc can efficiently destroy chemotherapy resistant ovarian cancer cells. Remarkably, solid tumors treated with a single dose of SiNc-NP combined with NIR irradiation were completely eradicated without cancer recurrence. Finally, the efficiency of SiNc-NP as an NIR imaging agent was confirmed by recording the strong fluorescence signal in the tumor, which was not photobleached during the phototherapeutic procedure.

Herein, we report the successful development of a novel nanosystem capable of an efficient delivery and temperature-triggered drug release specifically aimed at cancer. The water-soluble 130.1 ± 0.2 nm iron oxide nanoparticles (IONPs) were obtained via synthesis of a monodispersed iron oxide core stabilized with tetramethylammonium hydroxide pentahydrate (TMAOH), followed by coating with the thermoresponsive copolymer poly-(NIPAM-stat-AAm)-block-PEI (PNAP). The PNAP layer on the surface of the IONP undergoes reversible temperature-dependent structural changes from a swollen to a collapsed state resulting in the controlled release of anticancer drugs loaded in the delivery vehicle. We demonstrated that the phase transition temperature of the prepared copolymer can be precisely tuned to the desired value in the range of 36°C–44°C by changing the monomers ratio during the preparation of the nanoparticles. Evidence of modification of the IONPs with the thermoresponsive copolymer is proven by ATR-FTIR and a quantitative analysis of the polymeric and iron oxide content obtained by thermogravimetric analysis. When loaded with doxorubicin (DOX), the IONPs-PNAP revealed a triggered drug release at a temperature that is a few degrees higher than the phase transition temperature of a copolymer. Furthermore, an in vitro study demonstrated an efficient internalization of the nanoparticles into the cancer cells and showed that the drug-free IONPs-PNAP were nontoxic toward the cells. In contrast, sufficient therapeutic effect was observed for the DOX-loaded nanosystem as a function of temperature. Thus, the developed temperature-tunable IONPs-based delivery system showed high potential for remotely triggered drug delivery and the eradication of cancer cells.

A multifunctional tumor-targeting delivery system was developed and evaluated for an efficient treatment of drug-resistant ovarian cancer by combinatorial therapeutic modality based on chemotherapy and mild hyperthermia. The engineered iron oxide nanoparticle (IONPs)-based nanocarrier served as an efficient delivery vehicle for doxorubicin and provided the ability to heat cancer cells remotely upon exposure to an alternating magnetic field (AMF). The nanocarrier was additionally modified with polyethylene glycol and LHRH peptide to improve its biocompatibility and ability to target tumor cells. The synthesized delivery system has an average size of 97.1 nm and a zeta potential close to zero, both parameters favorable for increased stability in biological media and decreased elimination by the immune system. The nanocarrier demonstrated faster drug release in acidic conditions that mimic the tumor environment. It was also observed that the LHRH targeted delivery system could effectively enter drug resistant ovarian cancer cells, and the fate of doxorubicin was tracked with fluorescence microscope. Mild hyperthermia (40 °C) generated by IONPs under exposure to AMF synergistically increased the cytotoxicity of doxorubicin delivered by the developed nanocarrier to cancer cells. Thus, the developed IONPs-based delivery system has high potential in the effective treatment of ovarian cancer by combinatorial approach.

Recently, we identified 1-aminoanthracene as a fluorescent general anesthetic. To investigate the mechanism of action, a photoactive analogue, 1-azidoanthracene, was synthesized. Administration of 1-azidoanthracene to albino stage 40-47 tadpoles was found to immobilize animals upon near-UV irradiation of the forebrain region. The immobilization was often reversible, but it was characterized by a longer duration consistent with covalent attachment of the ligand to functionally important targets. IEF/SDS-PAGE examination of irradiated tadpole brain homogenate revealed labeled protein, identified by mass spectrometry as β-tubulin. In vitro assays with aminoanthracene-cross-linked tubulin indicated inhibition of microtubule polymerization, similar to colchicine. Tandem mass spectrometry confirmed anthracene binding near the colchicine site. Stage 40-47 tadpoles were also incubated 1 h with microtubule stabilizing agents, epothilone D or discodermolide, followed by dosing with 1-aminoanthracene. The effective concentration of 1-aminoanthracene required to immobilize the tadpoles was significantly increased in the presence of either microtubule stabilizing agent. Epothilone D similarly mitigated the effects of a clinical neurosteroid general anesthetic, allopregnanolone, believed to occupy the colchicine site in tubulin. We conclude that neuronal microtubules are "on-pathway" targets for anthracene general anesthetics and may also represent functional targets for some neurosteroid general anesthetics.

The efficient synthesis of enantiopure, trisubstituted cryptophane-A derivatives, organic host molecules with unusually high xenon affinity, is reported. Synthesis and chromatographic separation of (±) tri-Mosher's acid substituted cryptophane diastereomers gave ready access to the enantiopure cryptophanes, which are critical components in the design of enantiomerically pure (129)Xe biosensors. Hyperpolarized (129)Xe NMR spectroscopy identified single resonances for both trisubstituted cryptophane diastereomers that were separated by 9.5 ppm. This highlights opportunities for using enantiopure xenon biosensors in the simultaneous detection of (129)Xe in different biochemical environments.

Efficient syntheses of trisubstituted cryptophane-A derivatives that are versatile host molecules for many applications are reported. Trihydroxy cryptophane was synthesized in six or seven steps with yields as high as 9.5%. By a different route, trihydroxy cryptophane modified with three propargyl, allyl, or benzyl protecting groups was synthesized with yields of 4.1-5.8% in just six steps. Hyperpolarized (129)Xe NMR chemical shifts of 57-65 ppm were measured for these trisubstituted cryptophanes.

A gyroscope-inspired tribenzylamine hemicryptophane provides a vehicle for exploring the structure and properties of multiple p-phenylene rotators within one molecule. The hemicryptophane was synthesized in three steps in good overall yield using mild conditions. Three rotator-forming linkers were cyclized to form a rigid cyclotriveratrylene (CTV) stator framework, which was then closed with an amine. The gyroscope-like molecule was characterized by (1)H NMR and (13)C NMR spectroscopy, and the structure was solved by X-ray crystallography. The rigidity of the two-component CTV-trismethylamine stator was investigated by (1)H variable-temperature (VT) NMR experiments and molecular dynamics simulations. These techniques identified gyration of the three p-phenylene rotators on the millisecond time scale at -93 °C, with more dynamic but still hindered motion at room temperature (27 °C). The activation energy for the p-phenylene rotation was determined to be ~10 kcal mol(-1). Due to the propeller arrangement of the p-phenylenes, their rotation is hindered but not strongly correlated. The compact size, simple synthetic route, and molecular motions of this gyroscope-inspired tribenzylamine hemicryptophane make it an attractive starting point for controlling the direction and coupling of rotators within molecular systems.

Cryptophane-A, comprised of two cyclotriguaiacylenes joined by three ethylene linkers, is a prototypal organic host molecule that binds reversibly to neutral small molecules via London forces. Of note are trifunctionalized, water-soluble cryptophane-A derivatives, which exhibit exceptional affinity for xenon in aqueous solution. In this paper, we report high-resolution X-ray structures of cryptophane-A and trifunctionalized derivatives in crown–crown and crown–saddle conformations, as well as in complexes with water, methanol, xenon or chloroform. Cryptophane internal volume varied by more than 20% across this series, which exemplifies 'induced fit' in a model host–guest system., Cryptophane-A is a prototypical organic host molecule that binds reversibly to neutral guest molecules. Taratula et al. report X-ray structures of cryptophane-A complexed with a range of host molecules to show that the cryptophane host–guest system exhibits ‘induced fit’.

Charge transport and recombination in nanostructured semiconductors are poorly understood key processes in dye-sensitized solar cells. We have employed time-resolved spectroscopies in the terahertz and visible spectral regions supplemented with Monte Carlo simulations to obtain unique information on these processes. Our results show that charge transport in the active solar cell material can be very different from that in nonsensitized semiconductors, due to strong electrostatic interaction between injected electrons and dye cations at the surface of the semiconductor nanoparticle. For ZnO, this leads to formation of an electron-cation complex which causes fast charge recombination and dramatically decreases the electron mobility even after the dissociation of the complex. Sensitized TiO2 does not suffer from this problem due to its high permittivity efficiently screening the charges.

The concept of 'xenon biosensor' for magnetic resonance imaging (MRI) was first proposed by a Berkeley team in 2001, with evidence that hyperpolarized 129Xe bound to a biotin-labeled cryptophane can detect streptavidin at much lower concentrations (nM-microM) than is typical for contrast-enhanced MRI experiments. 129Xe biosensors have undergone many recent developments to address challenges in molecular imaging. For example, cryptophanes that exhibit 10-fold higher xenon affinity with distinct 129Xe magnetic resonance spectra have been synthesized. Also relevant are dendrimeric cryptophane assemblies and inorganic zeolites that localize many 129Xe atoms to rare targets. Finally, this article considers biosensors that produce measurable changes in 129Xe chemical shift based upon the activity of oligonucleotides, proteins, or enzymes, and includes the first cell studies.

A series of “rigid-rod” dyes with an organic chromophore (pyrene or coumarin) attached through an oligophenylenethynylene (OPE) rigid bridge, linear or branched, to an anchoring isopthalic acid unit (Ipa) were synthesized and studied for solar cells (DSSCs) applications. The new dyes were attached to metal oxide (MOn = TiO2, ZrO2 and ZnO) nanoparticles films via the two COOH binding groups on the Ipa unit to investigate their binding and photophysical properties at the semiconductor surface. FTIR-ATR spectra show that all dyes did bind to the metal oxide films through carboxylate bonds. Fluorescence emission on insulating ZrO2 films was employed to study aggregation of the organic rigid-rods. Studies of the pyrene rigid-rods in solar cells showed near quantitative conversation of absorbed photons into electricity.

Olena Taratula,1 Mehulkumar Patel,2 Canan Schumann,1 Michael A Naleway,1 Addison J Pang,1 Huixin He,2 Oleh Taratula1 1Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR, USA; 2Department of Chemistry, Rutgers University-Newark, Newark, NJ, USA Abstract: We report a novel cancer-targeted nanomedicine platform for imaging and prospect for future treatment of unresected ovarian cancer tumors by intraoperative multimodal phototherapy. To develop the required theranostic system, novel low-oxygen graphene nanosheets were chemically modified with polypropylenimine dendrimers loaded with phthalocyanine (Pc) as a photosensitizer. Such a molecular design prevents fluorescence quenching of the Pc by graphene nanosheets, providing the possibility of fluorescence imaging. Furthermore, the developed nanoplatform was conjugated with poly(ethylene glycol), to improve biocompatibility, and with luteinizing hormone-releasing hormone (LHRH) peptide, for tumor-targeted delivery. Notably, a low-power near-infrared (NIR) irradiation of single wavelength was used for both heat generation by the graphene nanosheets (photothermal therapy [PTT]) and for reactive oxygen species (ROS)-production by Pc (photodynamic therapy [PDT]). The combinatorial phototherapy resulted in an enhanced destruction of ovarian cancer cells, with a killing efficacy of 90%–95% at low Pc and low-oxygen graphene dosages, presumably conferring cytotoxicity to the synergistic effects of generated ROS and mild hyperthermia. An animal study confirmed that Pc loaded into the nanoplatform can be employed as a NIR fluorescence agent for imaging-guided drug delivery. Hence, the newly developed Pc-graphene nanoplatform has the significant potential as an effective NIR theranostic probe for imaging and combinatorial phototherapy. Keywords: graphene nanosheets, phthalocyanine, photothermal therapy, photodynamic therapy, theranostic&nbsp

Two bifunctional linkers, a rigid-rod p-ethynyl-isophthalic acid capped with a Ru(II)-polypyridyl complex and 3-mercaptopropionic acid, were covalently bound to ZnO nanotip films grown by metal-organic chemical vapor deposition (MOCVD) technology. This highly vertically aligned, crystalline form of ZnO had not been functionalized before. The binding was studied by Fourier transform (FT) IR and UV spectroscopies and probed, in the case of the Ru complex, by static and dynamic fluorescence quenching. The molecules did bind through the carboxylic acid groups, and the FT-IR attenuated total reflectance spectra are indicative of a bidentate carboxylate binding mode. Other molecules (heptanoic acid, isophthalic acid, and trimethoxy(2-phenylethyl)silane) were also bound to the ZnO nanotips. A comparison was made with epitaxial ZnO films grown by MOCVD and ZnO mesoporous films prepared from colloidal solutions to investigate the effect of the ZnO morphology. The ZnO nanotips were excellent binding substrates, particularly for the rigid-rod linker. Since ZnO films are etched at low pH (4), novel nanotip films made of ternary MgxZn1-xO, which is formed by alloying ZnO with MgO and is more resistant to acids, were developed. The MgxZn1-xO nanotip films were employed to use linkers with acidic groups and to study the effect of pH pretreatment of the surface on the binding.

We used time-resolved spectroscopies in terahertz and visible ranges complemented with Monte-Carlo simulations to assess the connection between ultrafast charge injection and formation and transport of mobile charge carriers in dye-sensitized nano-structured semiconductors.