Perflubron Research Articles

Targeted gold nanoshelled hybrid nanocapsules encapsulating doxorubicin for bimodal imaging and near-infrared triggered synergistic therapy of Her2-positve breast cancer.

A multifunctional targeted nanoplatform combining photothermal therapy and chemotherapy has emerged as a promising strategy for comprehensive therapies of breast cancer. In this study, we constructed human epidermal growth factor receptor 2 (Her2)-targeted gold nanoshelled poly(lactic-co-glycolic acid) hybrid nanocapsules encapsulating perfluorooctyl bromide, superparamagnetic iron oxide nanoparticles, and doxorubicin (Her2-GPDH nanocapsules) as theranostic agent for bimodal ultrasound/magnetic resonance imaging and synergistic photothermal-chemotherapy of Her2-postive breast cancer cells. Her2-GPDH nanocomposites possessed well-defined spherical morphology, and the average diameter was about 296 nm with good dispersion. Targeting assays demonstrated that Her2-GPDH nanocapsules exhibited higher targeting binding to Her2-positive SKBR3 cells than Her2-negative MDA-MB-231cells. The encapsulation efficiency and the loading content of doxorubicin in Her2-GPDH nanocapsules were 39 ± 1.45% and 3.8 ± 0.52%, respectively, and the agent exhibited pH-responsive and near-infrared light-triggered stepwise release behavior of doxorubicin. In vitro, the agent had potential to serve as feasible candidate for ultrasound imaging and T2-weighted magnetic resonance imaging with a relatively high relaxivity. Cell experiments confirmed that the agent had significant photothermal cytotoxicity on SKBR3 cells, and the combined photothermal-chemotherapy could significantly enhance the anti-tumor effect. In summary, the present Her2-GPDH nanocapsules, a novel multifunctional nanoplatform, will offer a new way for early bimodal molecular-level diagnosis and synergistic treatment of Her2-positve breast cancer.

Long‐Term Oxygen Storage Nanosystem for Near‐Infrared Light‐Triggered Oxygen Supplies to Antagonize Hypoxia‐Induced Therapeutic Resistance in Nasopharyngeal Carcinoma

AbstractO2‐delivering nanosystems have been used to antagonize hypoxia‐induced tumor therapeutic resistance. However, short‐time oxygen storage is still a bottleneck for these O2‐delivering nanosystems, which results in a decrease in blood circulation time and accumulation of oxygen in tumors, thus reducing the tumor therapeutic efficacy. Herein, a long‐term oxygen storage nanosystem (O2‐PIr@Si@PDA) is designed to overcome hypoxia for the treatment of nasopharyngeal carcinoma. This nanosystem is constructed by using perfluorooctyl bromide (PFOB) core as the oxygen carrier, functionalized with an oxygen sensitive probe (Ir(III) complex) and subsequently enclosed with an ultrathin‐walled silica shell. Due to the silica shell, this nanosystem can store oxygen for longer than 7 days. The oxygen in the O2‐PIr@Si@PDA nanosystem can be released quickly with the temperature‐responsive rupture of the silicon shell under near‐infrared (NIR) irradiation. The oxygen storage and release can be self‐monitored using the Ir(III) complex with its luminescence effect. As expected, this multifunctional nanosystem in combination with NIR irradiation not only inhibits tumor growth by alleviating hypoxia, but also enhances the effect of oxygen‐sensitized radiotherapy against nasopharyngeal carcinoma. Taken together, this study offers a novel strategy for designing long‐term oxygen storing nanosystem to relieve tumor hypoxia, thus improving the precise cancer therapeutic efficacy.

Silica nanoparticle coated perfluorooctyl bromide for ultrasensitive MRI.

MRI with hyperpolarized 129Xe can achieve low-concentration detection. Herein, nanoparticle-coated perfluorooctyl bromide (PFOB) was developed as a 129Xe MRI contrast agent with a moderate exchange rate, sufficient stability and feasible surface modification. The αvβ3 integrin overexpressed by non-small-cell lung cancer A549 cells was successfully detected by 129Xe MRI with high specificity through adequate surface modifications.

Small-scale preparation of perfluorocarbon-nanoemulsions utilizing dual centrifugation.

Perfluorocarbon-nanoemulsions (PFC-NE) made of PFC and phospholipids (PL) by homogenization are optimal for in vivo-19F labelling of monocytes and subsequently of inflamed tissues in magnetic resonance imaging (MRI). Necessary requirements for in vivo use of PFC-NE are sterility, suitable droplet sizes and the absence of immune activating liposomes, which are a typical byproduct of the homogenization process. To meet these requirements, we developed an aseptic in-vial preparation technique for PFC-NE based on dual centrifugation (DC) by testing different PFC/phospholipid ratios as well as the application of additives. Two different PFC, perfluorooctylbromide (PFOB) and perfluoro-15-crown-5-ether (PFCE), were investigated. Particle sizes were assessed by dynamic light scattering and NE morphology by cryoTEM. DC homogenization was optimal when using an excess of PL (8.7 % (m/m) of utilized PFC, z-ave: 180 nm, pdi: 0.2). A purification approach by centrifugation was implemented to remove liposomes formed from the excess of PL during homogenization. The purification success was proven by phospholipid assay and PFC quantification via density and sound velocity measurements. DC in combination with a short centrifugation is a fast and reliable way of small-scale aseptic PFC-NE production for 19F MRI passive-targeting experiments of monocytes and inflamed tissues.

Imaging Rheumatoid Arthritis in Mice Using Combined Near Infrared and 19F Magnetic Resonance Modalities

Rheumatoid arthritis (RA) is an autoimmune disease that causes pain and tissue destruction in people worldwide. An accurate diagnosis is paramount in order to develop an effective treatment plan. This study demonstrates that combining near infrared (NIR) imaging and 19F MRI with the injection of labelled nanoparticles provides high diagnostic specificity for RA. The nanoparticles were made from poly(ethylene glycol)-block-poly(lactic-co-glycolic acid) (NP) or PLGA-PEG-Folate (Folate-NP), loaded with perfluorooctyl bromide (PFOB) and indocyanine green (ICG) and evaluated in vitro and in a collagen-induced arthritic (CIA) mouse model. The different particles had a similar size and a spherical shape according to dynamic light scattering (DLS) and transmission electron microscopy (TEM). Based on flow cytometry and 19F MRI analysis, Folate-NP yielded a higher uptake than NP in activated macrophages in vitro. The potential RA-targeting ability of the particles was studied in CIA mice using NIR and 19F MRI analysis. Both NP and Folate-NP accumulated in the RA tissues, where they were visible in NIR and 19F MRI for up to 24 hours. The presence of folate as a targeting ligand significantly improved the NIR signal from inflamed tissue at the early time point (2 hours), but not at later time points. Overall, these results suggest that our nanoparticles can be applied for combined NIR and 19F MRI imaging for improved RA diagnosis.

NIR-responsive nanoplatform for pre/intraoperative image-guided carcinoma surgery and photothermal ablation of residual tumor tissue

Local recurrence is common among patients with advanced cancer who have undergone surgery. Here, we developed a new surgical treatment for cancer based on a nanoparticle that loaded a near-infrared dye (IR780 iodide) and perfluorooctyl bromide into liposomes (NP-IR780). In an orthotopic breast cancer mouse model, NP-IR780 was demonstrated to have excellent tumor-targeting ability due to the selective tumor accumulation of IR780 iodide and the enhanced permeation and retention effect of the nanoparticle. With the excellent targeting ability, concurrent computed tomography and photoacoustic imaging were achieved for preoperative planning. In particular, NP-IR780 could serve as a tumor indicator for near-infrared fluorescence image-guided precise resection of lesions during surgery. Importantly, residual tumors could be ablated through intraoperative photothermal therapy without obvious recurrence. This work provides a theranostic strategy that significantly improved the survival of mice through pre/intraoperative image-guided tumor resection and subsequent photothermal therapy of residual lesions.

Noninvasive Monitoring of Allogeneic Stem Cell Delivery with Dual-Modality Imaging-Visible Microcapsules in a Rabbit Model of Peripheral Arterial Disease.

Stem cell therapies, although promising for treating peripheral arterial disease (PAD), often suffer from low engraftment rates and the inability to confirm the delivery success and track cell distribution and engraftment. Stem cell microencapsulation combined with imaging contrast agents may provide a means to simultaneously enhance cell survival and enable cell tracking with noninvasive imaging. Here, we have evaluated a novel MRI- and X-ray-visible microcapsule formulation for allogeneic mesenchymal stem cell (MSC) delivery and tracking in a large animal model. Bone marrow-derived MSCs from male New Zealand White rabbits were encapsulated using a modified cell encapsulation method to incorporate a dual-modality imaging contrast agent, perfluorooctyl bromide (PFOB). PFOB microcapsules (PFOBCaps) were then transplanted into the medial thigh of normal or PAD female rabbits. In vitro MSC viability remained high (79 ± 5% at 4 weeks of postencapsulation), and as few as two and ten PFOBCaps could be detected in phantoms using clinical C-arm CT and 19F MRI, respectively. Successful injections of PFOBCaps in the medial thigh of normal (n = 15) and PAD (n = 16) rabbits were demonstrated on C-arm CT at 1-14 days of postinjection. Using 19F MRI, transplanted PFOBCaps were clearly identified as “hot spots” and showed one-to-one correspondence to the radiopacities on C-arm CT. Concordance of 19F MRI and C-arm CT locations of PFOBCaps with postmortem locations was high (95%). Immunohistological analysis revealed high MSC survival in PFOBCaps (>56%) two weeks after transplantation while naked MSCs were no longer viable beyond three days after delivery. These findings demonstrate that PFOBCaps could maintain cell viability even in the ischemic tissue and provide a means to monitor cell delivery and track engraftment using clinical noninvasive imaging systems.

Polyelectrolyte Coatings Can Control Charged Fluorocarbon Nanodroplet Stability and Their Interaction with Macrophage Cells

Fluorocarbon nanodroplets, ∼100 to ∼400 nm in diameter, are of immense interest in a variety of medical applications including the imaging and therapy of cancer and inflammatory diseases. However, fluorocarbon molecules are both hydrophobic and lipophobic; therefore, it is challenging to synthesize fluorocarbon nanodroplets with the optimal stability and surface properties without the use of highly specialized surfactants. Here, we hypothesize that we can decouple the control of fluorocarbon nanodroplet size and stability from its surface properties. We use a simple, two-step procedure where standard, easily available anionic fluorosurfactants are used to first stabilize the fluorocarbon nanodroplets, followed by electrostatically attaching functionalized polyelectrolytes to the nanodroplet surfaces to independently control their surface properties. Herein, we demonstrate that PEGylated polyelectrolyte coatings can effectively alter the fluorocarbon nanodroplet surface properties to reduce coalescence and its uptake into phagocytic cells in comparison with non-PEGylated polyelectrolyte coatings and uncoated nanodroplets, as measured by flow cytometry and fluorescence microscopy. In this study, perfluorooctyl bromide (PFOB) was used as a representative fluorocarbon material, and PEGylated PFOB nanodroplets with diameters between 250 and 290 nm, depending on the poly(ethylene glycol) block length, were prepared. The PEGylated PFOB nanodroplets had superior size stability in comparison with uncoated and non-PEGylated polyelectrolyte nanodroplets in saline and within macrophage cells. Of significance, non-PEGylated nanodroplets were rapidly internalized by macrophage cells, whereas PEGylated nanodroplets were predominantly colocalized on the cell membrane. This suggests that the PEGylated-polyelectrolyte coating on the charged PFOB nanodroplets may afford adjustable shielding from cells of the reticuloendothelial system. This report shows that using the same fluorosurfactant as a base layer, modularly assembled PFOB nanodroplets tailored for a variety of end applications can be created by selecting different polyelectrolyte coatings depending on their unique requirements for stability and interaction with phagocytic cells.

Effects of droplet size and perfluorocarbon boiling point on the frequency dependence of acoustic vaporization threshold.

Phase shift liquid perfluorocarbon (PFC) droplets vaporizable by ultrasound into echogenic microbubble above a threshold pressure, termed acoustic droplet vaporization (ADV), are used for therapeutic and diagnostic applications. This study systematically investigated the effect of excitation frequency (2.25, 10, and 15 MHz) on the ADV and inertial cavitation (IC) thresholds of lipid-coated PFC droplets of three different liquid cores-perfluoropentane (PFP), perfluorohexane (PFH), and perfluorooctyl bromide (PFOB)-and of two different sizes-average diameters smaller than 3 μm and larger than 10 μm-in a tubeless setup. This study found that the ADV threshold increases with frequency for the lowest boiling point liquid, PFP, for both large and small size droplets. For higher boiling point liquids, PFH and PFOB, this study did not detect vaporization for small size droplets at the excitation levels (maximum 4 MPa peak negative) studied here. The large PFOB droplets experienced ADV only at the highest excitation frequency 15 MHz. For large PFH droplets, ADV threshold decreases with frequency that could possibly be due to the superharmonic focusing being a significant effect at larger sizes and the higher excitation pressures. ADV thresholds at all the frequencies studied here occurred at lower rarefactional pressures than IC thresholds indicating that phase transition precedes inertial cavitation.

Overcoming hypoxia-induced chemoresistance to cisplatin through tumor oxygenation monitored by optical imaging.

Perfluorocarbon nanoparticles have been reported to deliver oxygen to tumors and reduce hypoxia-induced radioresistance, however few studies have been carried out to study its role in reducing hypoxia-induced chemoresistance. The oxygenation effect also varies dramatically between different perfluorocarbon formulations and protocols, and there have been no efficient tools to monitor dynamic changes of tumor oxygenation non-invasively. Our goal was to promote tumor oxygenation using perfluorooctyl bromide (PFOB) nanoemulsion and to assess its role in sensitizing tumors to cisplatin treatment. A novel optical imaging protocol was also created to monitor the dynamic changes of tumor oxygenation in real-time.Methods: PFOB nanoemulsion with high oxygen-carrying capacity was prepared and administered to tumor-bearing mice intravenously. Tumor oxygenation was monitored using optical imaging with a hypoxia probe injected intratumorally, thus the oxygenation dynamics and best oxygenation protocol were determined. Various treatment groups were studied, and the tumor growth was monitored to evaluate the role of oxygenation in sensitizing tumors to cisplatin treatment.Results: PFOB nanoemulsion with and without pre-oxygenation along with carbogen breathing resulted in much better tumor oxygenation compared to carbogen breathing alone, while PFOB with air breathing did not show significant increase in tumor oxygenation. Pre-oxygenated PFOB with carbogen breathing produced the most effective oxygenation as early as 5 min post administration. In vitro and in vivo data showed preoxygenated PFOB nanoemulsion with carbogen breathing could increase cisplatin-mediated apoptosis of cancer cells and inhibited tumor growth at a low dose of cisplatin (1 mg/kg) treatment. Furthermore, the treatment did not induce nephrotoxicity.Conclusions: Preoxygenated PFOB nanoemulsion with carbogen breathing can effectively increase tumor oxygenation, which has a great potential to prevent/overcome hypoxia-induced chemotherapy resistance. In addition, optical imaging with intratumoral injection of the hypoxia probe was an efficient tool to monitor tumor oxygenation dynamics during PFOB administration, providing better understanding on oxygenation effects under different protocols.

Perfluorocarbon nanodroplets can reoxygenate hypoxic tumors in vivo without carbogen breathing.

Nanoscale perfluorocarbon (PFC) droplets have enormous potential as clinical theranostic agents. They are biocompatible and are currently used in vivo as contrast agents for a variety of medical imaging modalities, including ultrasound, computed tomography, photoacoustic and 19F-magnetic resonance imaging. PFC nanodroplets can also carry molecular and nanoparticulate drugs and be activated in situ by ultrasound or light for targeted therapy. Recently, there has been renewed interest in using PFC nanodroplets for hypoxic tumor reoxygenation towards radiosensitization based on the high oxygen solubility of PFCs. Previous studies showed that tumor oxygenation using PFC agents only occurs in combination with enhanced oxygen breathing. However, recent studies suggest that PFC agents that accumulate in solid tumors can contribute to radiosensitization, presumably due to tumor reoxygenation without enhanced oxygen breathing. In this study, we quantify the impact of oxygenation due to PFC nanodroplet accumulation in tumors alone in comparison with other reoxygenation methodologies, in particular, carbogen breathing.Methods: Lipid-stabilized, PFC (i.e., perfluorooctyl bromide, CF3(CF2)7Br, PFOB) nanoscale droplets were synthesized and evaluated in xenograft prostate (DU145) tumors in male mice. Biodistribution assessment of the nanodroplets was achieved using a fluorescent lipophilic indocarbocyanine dye label (i.e., DiI dye) on the lipid shell in combination with fluorescence imaging in mice (n≥3 per group). Hypoxia reduction in tumors was measured using PET imaging and a known hypoxia radiotracer, [18F]FAZA (n≥ 3 per group).Results: Lipid-stabilized nanoscale PFOB emulsions (mean diameter of ~250 nm), accumulated in the xenograft prostate tumors in mice 24 hours post-injection. In vivo PET imaging with [18F]FAZA showed that the accumulation of the PFOB nanodroplets in the tumor tissues alone significantly reduced tumor hypoxia, without enhanced oxygen (i.e., carbogen) breathing. This reoxygenation effect was found to be comparable with carbogen breathing alone.Conclusion: Accumulation of nanoscale PFOB agents in solid tumors alone successfully reoxygenated hypoxic tumors to levels comparable with carbogen breathing alone, an established tumor oxygenation method. This study confirms that PFC agents can be used to reoxygenate hypoxic tumors in addition to their current applications as multifunctional theranostic agents.

Imaging Assessment of Partial Liquid Ventilation in Bronchopulmonary Dysplasia

Partial liquid ventilation is proposed as an alternative ventilation strategy to reduce surface tension, increase alveolar recruitment, and decrease inflammation. Studied in acute respiratory distress and other indications, liquid ventilation is being revisited for infants with bronchopulmonary dysplasia. Perfluorooctyl bromide used for liquid ventilation is radiopaque, allowing radiographic visualization of lung liquid ventilation patterns that may provide additional insight into pulmonary pathophysiology. Current protocols utilize reduced liquid dosing, resulting in unique imaging features. We discuss optimal radiographic technique and report initial ultrasound evaluation results. With renewed interest in partial liquid ventilation, it may be helpful for pediatric radiologists to familiarize themselves with the clinical use and radiographic appearance of liquid ventilation material.

Fluorous-Soluble Metal Chelate for Sensitive Fluorine-19 Magnetic Resonance Imaging Nanoemulsion Probes.

Fluorine-19 MRI is an emerging cellular imaging approach, enabling lucid, quantitative "hot-spot" imaging with no background signal. The utility of 19F-MRI to detect inflammation and cell therapy products in vivo could be expanded by improving the intrinsic sensitivity of the probe by molecular design. We describe a metal chelate based on a salicylidene-tris(aminomethyl)ethane core, with solubility in perfluorocarbon (PFC) oils, and a potent accelerator of the 19F longitudinal relaxation time ( T1). Shortening T1 can increase the 19F image sensitivity per time and decrease the minimum number of detectable cells. We used the condensation between the tripodal ligand tris-1,1,1-(aminomethyl)ethane and salicylaldehyde to form the salicylidene-tris(aminomethyl)ethane chelating agent (SALTAME). We purified four isomers of SALTAME, elucidated structures using X-ray scattering and NMR, and identified a single isomer with high PFC solubility. Mn4+, Fe3+, Co3+, and Ga3+ cations formed stable and separable chelates with SALTAME, but only Fe3+ yielded superior T1 shortening with modest line broadening at 3 and 9.4 T. We mixed Fe3+ chelate with perfluorooctyl bromide (PFOB) to formulate a stable paramagnetic nanoemulsion imaging probe and assessed its biocompatibility in macrophages in vitro using proliferation, cytotoxicity, and phenotypic cell assays. Signal-to-noise modeling of paramagnetic PFOB shows that sensitivity enhancement of nearly 4-fold is feasible at clinical magnetic field strengths using a 19F spin-density-weighted gradient-echo pulse sequence. We demonstrate the utility of this paramagnetic nanoemulsion as an in vivo MRI probe for detecting inflammation macrophages in mice. Overall, these paramagnetic PFC compounds represent a platform for the development of sensitive 19F probes.

Perfluorocarbon Nanocapsules Improve Hypoxic Microenvironment for the Tumor Ultrasound Diagnosis and Photodynamic Therapy.

Amelioration of hypoxia is an important factor increasing the effects of anti-tumor therapies. In the present experiments, nanocapsules of poly(lactide-co-glycolide)-poly(ethylene glycol)/perfluorooctyl bromide (PFOB)/photosensitizers (IR780) have been developed to increase oxygen concentration inside the tumor and improve the outcome of photodynamic therapy (PDT). PFOB has high oxygen solubility, and IR780 is a photosensitizer particularly suited for a highly effective photodynamic therapy under the 808-nm laser irradiation. Thus, PFOB provides sufficient oxygen for the reaction with the photosensitizer, producing more singlet oxygen to induce cell apoptosis. The photodynamic effect of nanocapsules was confirmed to be enhanced after addition of PFOB through simulation experiments in vitro in the hypoxic microenvironment. The results have demonstrated that due to the addition of PFOB the nanocapsules can provide a contrast-enhanced ultrasound diagnosis and ensure more notable inhibition of the growth of lung tumors following the 808 nm laser irradiation. Furthermore, the nanocapsules allowed the photosensitizers to achieve sufficient therapeutic potential, which was optimal under the conditions of modest hypoxia with about 5% oxygen concentration.

In vivo 19F MR inflammation imaging after myocardial infarction in a large animal model at 3T.

Fluorine-19 (19F) MRI with intravenously applied perfluorocarbons allows the in vivo monitoring of infiltrating immune cells as demonstrated in small animal models at high field. Here, we aimed to transfer this approach to a clinical scanner for detection of inflammatory processes in the heart after acute myocardial infarction (AMI) in a large animal model. Optimization of coil and sequence performance was carried out on phantoms and in vivo at a 3T Philips Achieva. AMI was induced in Munich mini pigs by 90-min occlusion of the left anterior descending artery. At day 3 after AMI, pigs received a body weight-adjusted intravenous dose of a perfluorooctyl bromide nanoemulsion followed by 1H/19F MRI at day 6 after AMI. A balanced steady-state free precession turbo gradient echo sequence using an ellipsoidal 19F/1H surface coil provided the best signal-to-noise ratio and a superior localization of 19F patterns in vivo. This approach allowed the reliable detection of 19F signals in the injured myocardium within less than 20min. The 19F signal magnitude correlated significantly with the functional impairment after AMI. This study demonstrates the feasibility of in vivo 19F MR inflammation imaging after AMI at 3T within a clinically acceptable acquisition time.

Thin-Shelled PEGylated Perfluorooctyl Bromide Nanocapsules for Tumor-Targeted Ultrasound Contrast Agent.

Shell thickness determines the acoustic response of polymer-based perfluorooctyl bromide (PFOB) nanocapsule ultrasound contrast agents. PEGylation provides stealth property and arms for targeting moieties. We investigated a modulation in the polymer formulation of carboxy-terminated poly(d,l-lactide-co-glycolide) (PLGA) and poly(d,l-lactide-co-glycolide)-block-polyethylene glycol (PLGA-b-PEG) to produce thin-shelled PFOB nanocapsules while keeping its echogenicity, stealth property, and active targeting potential. Polymer formulation contains 40% PLGA-PEG that yields the PEGylated PFOB nanocapsules of approximately 150 nm size with average thickness-to-radius ratio down to 0.15, which adequately hindered phagocytosis. Functionalization with antibody enables in vitro tumor-specific targeting. Despite the acoustic response improvement, the in vivo tumor accumulation was inadequate to generate an observable acoustic response to the ultrasound power at the clinical level. The use of PLGA and PLGA-PEG polymer blend allows the production of thin-shelled PFOB nanocapsules with echogenicity improvement while maintaining its potential for specific targeting.

Molecular oxygen loading in candidate theranostic droplets stabilized with biocompatible fluorinated surfactants: Particle size effect and application to in situ19F MRI mapping of oxygen partial pressure

ObjectivePerfluorocarbon nano- and micron-sized emulsions are a new field of investigation in cancer treatment due to their ability to be used as imaging contrast agents, or as delivery vectors for pharmaceuticals. They also demonstrated capability to enhance the efficiency of high intensity focused ultrasound thermo-therapy. In the context of new biomedical applications we investigated perfluorooctyl bromide (PFOB) theranostic droplets using 19F NMR. Each droplet contains biocompatible fluorinated surfactants composed of a polar Tris(hydroxymethyl)aminomethane head unit and hydrophobic perfluorinated tail (abbreviated as F-TAC). The influence of the droplet size on the oxygen loading capacity was determined from longitudinal relaxation (T1) data of 19F NMR signal. Material and methodsLiquid PFOB and five samples of PFOB droplets of average diameter 0.177, 0.259, 1.43, 3.12 and 4.53 µm were tested with different oxygen levels. A dedicated gas exchange system was validated to maintain steady state oxygen concentrations, including a spatial gradient of oxygen concentration. A prototyped transmit-receive switchable 19F/1H quadrature coil was integrated on a 3 T clinical scanner. The coil is compatible with focused ultrasound sonication for future application. A spectroscopy FID inversion-recovery (IR) sequence was used to measure the T1 value per sample and per value of equilibrium oxygen pressure. Pixel wise, spatial T1 mapping was performed with magnetization prepared 2D gradient echo sequences in tissue mimicking gels doped with theranostic droplets. ResultsExperimental data indicated that the longitudinal relaxation rate of 19F signal of the investigated theranostic droplets depended approximately linearly on the oxygen level and its slope decreased with the particle size according to a second order polynomial over the investigated range. This semi-empirical model was derived from general thermodynamics and weak electrostatic forces theory and fitted the experimental data within 0.75% precision. The capacity of oxygen transportation for the described theranostic droplets tended to that of pure PFOB, while micron-sized droplets lost up to 50% of this capacity. In a specific setup producing a steady state gradient of oxygen concentration, we demonstrated spatial mapping of oxygen pressure gradient of 6 kPa/mm with 1 mm in-plane resolution. ConclusionThe size-tunable PFOB theranostic droplets stabilized with F-TAC surfactants could be characterized by 19F MRI in a clinical setup readily compatible with interventional in vivo studies under MR guidance. Current precision and spatial resolution of T1 mapping are promising. A potential challenge for further in vivo studies is the reduction of the imaging time.

Investigating the efficacy of a new intravenous (IV) nanoemulsified sevoflurane/arginine formulation for maintenance of general anesthesia for embolization of cerebral aneurysm

The aim of this research investigation was to profound analysis the mitigating impact of sevoflurane/arginine post-molding on cerebral ischemia-reperfusion damage in rats. The authors fabricated emulsions fusing sevoflurane, perfluorooctyl bromide as a settling specialist, and mixes of arginine polymer. Cell suitability and gene expression of tubulin and NeuN were assessed. The stability, morphology and functional group were evaluated utilizing dynamic light scattering (DLS), Transmission Electron Microscope (TEM), atomic force microscopy (AFM), and Fourier-transform infrared spectroscopy (FTIR). Cerebral aneurysms were prompted through hypertension and a solitary stereotactic infusion of elastase into the basal storage in rat. The capacity of the emulsions to decreased cerebral aneurysm was tried in vivo by regulating them IV delivery of Se/Arg samples to rats. Se/Arg pre-conditioning expanded cell feasibility in neuroblast (SK-N-DZ) cells. Se/Arg pre-conditioning diminished infarct volume and enhanced neurological result in rats subjected to cerebral hypoxia–ischemia. Se/Arg preconditioning expanded levels of tubulin and NeuN. The prepared sevoflurane/arginine material pre-conditioning-incited neuroprotective impacts in vitro as well as in vivo analyses. Sevoflurane/arginine post-molding decreased cerebral tissue misfortune detected 7 days after cerebrum hypoxia–ischemia. This impact was prompted by clinically significant focuses and canceled by Sevoflurane/arginine. These outcomes recommend that Sevoflurane/arginine post-conditioning ensures neonatal cerebrum against cerebrum hypoxia–ischemia.

Comb-Like Fluorophilic-Lipophilic-Hydrophilic Polymers for Nanocapsules as Ultrasound Contrast Agents.

Imaging the enhanced permeation and retention effect by ultrasound is hindered by the large size of commercial ultrasound contrast agents (UCAs). To obtain nanosized UCAs, triblock copolymers of poly(ethylene glycol)-polylactide-poly(1 H,1 H,2 H,2 H-heptadecafluorodecyl methacrylate) (PEG-PLA-PFMA) with distinct numbers of perfluorinated pendant chains (5, 10, or 20) are synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization. Nanocapsules (NCs) containing perfluorooctyl bromide (PFOB) intended as UCAs are obtained with a 2-fold increase in PFOB encapsulation efficiency in fluorinated NCs as compared with plain PEG-PLA NCs thanks to fluorous interactions. NC morphology is strongly influenced by the number of perfluorinated chains and the amount of polymer used for formulation, leading to peculiar capsules with several PFOB cores at high PEG-PLA-PFMA20 amount and single-cored NCs with a thinner shell at low fluorinated polymer amount, as confirmed by small-angle neutron scattering. Finally, fluorinated NCs yield higher in vitro ultrasound signal compared with PEG-PLA NCs, and no in vitro cytotoxicity is induced by fluorinated polymers and their degradation products. Our results highlight the benefit of adding comb-like fluorinated blocks in PEG-PLA polymers to modify the nanostructure and enhance the echogenicity of nanocapsules intended as UCAs.

Abstract 2689: Nanoformulated mellitin from bee venom exhibits excellent anti-prostate cancer efficacy

Abstract Melittin, a major peptide component of bee venom, has shown chemopreventive as well as chemotherapeutic effects against many cancers both in cell culture and preclinical animal model systems. However, several issues including nonspecificity, degradation, inefficient systemic delivery, bioavailability, and more importantly its enhanced hemolytic activity have hampered its translation to humans. We recently reviewed the literature on bee venom (Cancer Letters, 2017;402:16-31) and suggested that the use of nanotechnology mediated delivery of melittin can enhance significantly its systemic delivery to target cancer cells and with minimal hemolytic effect. We employed nanotechnology to improve the therapeutic outcome of bee venom by using perfluorocarbon nanoemulsion vesicles to deliver melittin, hereafter referred to as ‘NanoBees'. The nano carriers were synthesized as an oil-in-water emulsion composed of a liquid perfluorooctyl bromide core having a monolayer of phospholipid forming a stabilizing interface with the aqueous media. We concentrated our studies on prostate cancer (PCa) because it is an attractive candidate and suitable target because of its long latency which offers a relatively long period of time for pharmacological interventions. We assessed the effectiveness of delivery of melittin, encapsulated in nanoformulation in vitro against PCa cells and in vivo in animal models. Treatment of PCa cells DU-145, C42 and PC3 PCa cells with formulated NanoBees (0-40 μg/ml) inhibited cell viability and proliferation and induced apoptosis. We observed an increase in the levels of proapototic Bax and concomitant decrease in the levels of antiapoptotic Bcl-2 resulting in a shift in the ratio of these molecules that favored apoptosis. We also observed an increase in poly(ADP-ribose) polymerase (PARP) cleavage and significant increase in the activation of cleaved caspases 3,7,8,9 in all tested PCa cell lines. These proteins were more than two fold up-regulated in the cells treated with NanoBees when compared to native melittin. Treatment of PCa cells with NanoBees inhibited cell proliferation in vitro through inhibition of the PI3K/Akt pathway and simultaneous downregulation in the expression of CyclinD1 and CDK4. We next tested the effect of NanoBees in a xenograft mouse model implanted with PCa PC3 cells. Intraperitoneal administration of NanoBees (5, 10 and 15 mg/Kg) significantly decreased tumor volume and growth rate compared to saline and void nanoparticle treatment. Incorporation of melittin in nanoemulsion prevented side effects associated with native melittin such hemolysis. These data support our hypothesis that nanotechnology could enhance the outcome of cancer therapy of melittin derived from bee venom through boosting bioavailability and limiting toxicity thus leading to a significant potential for possible clinical outcome. Citation Format: Islam R. Abdelaal, Imtiaz A. Siddiqui, Vaqar M. Adhami, Hazem F. Abdelaal, Hadir Mohamed, Mohamad Rady, Hasan Mukhtar. Nanoformulated mellitin from bee venom exhibits excellent anti-prostate cancer efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2689.