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Medulloblastoma is the most common malignant paediatric brain tumour, with ~30% mediated by Sonic hedgehog signalling. Vismodegib-mediated inhibition of the Sonic hedgehog effector Smoothened inhibits tumour growth but causes growth plate fusion at effective doses. Here, we report a nanotherapeutic approach targeting endothelial tumour vasculature to enhance blood–brain barrier crossing. We use fucoidan-based nanocarriers targeting endothelial P-selectin to induce caveolin-1-dependent transcytosis and thus nanocarrier transport into the brain tumour microenvironment in a selective and active manner, the efficiency of which is increased by radiation treatment. In a Sonic hedgehog medulloblastoma animal model, fucoidan-based nanoparticles encapsulating vismodegib exhibit a striking efficacy and marked reduced bone toxicity and drug exposure to healthy brain tissue. Overall, these findings demonstrate a potent strategy for targeted intracranial pharmacodelivery that overcomes the restrictive blood–brain barrier to achieve enhanced tumour-selective penetration and has therapeutic implications for diseases within the central nervous system.

Amyloid-beta (Aβ) deposition occurs in the early stages of Alzheimer’s disease (AD), but the early detection of Aβ is a persistent challenge. Herein, we engineered a near-infrared optical nanosensor capable of detecting Aβ intracellularly in live cells and intracranially in vivo. The sensor is composed of single-walled carbon nanotubes functionalized with Aβ wherein Aβ-Aβ interactions drive the response. We found that the Aβ nanosensors selectively responded to Aβ via solvatochromic modulation of the near-infrared emission of the nanotube. The sensor tracked Aβ accumulation in live cells and, upon intracranial administration in a genetic model of AD, signaled distinct responses in aged mice. This technology enables the interrogation of molecular mechanisms underlying Aβ neurotoxicity in the development of AD in living systems.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor with ~30% mediated by Sonic hedgehog (SHH) signaling. While SHH effector Smoothened inhibition is promising, therapeutic index is reduced by high systemic doses required for sufficient intracranial drug concentrations. Treatment-related toxicities associated with radiation therapy result in lifelong morbidity, and SHH pathway inhibition in children notably results in permanent bone defects. Here, we found that nanoparticle-mediated P-selectin targeting on tumor vasculature induces caveolin-1-dependent transcellular passage across the blood-brain barrier. A vismodegib nanocarrier that targets P-selectin exhibited striking efficacy and markedly reduced both bone-related toxicities and drug exposure to healthy brain. These findings demonstrate a potent strategy and novel mechanism for targeted intracranial pharmacodelivery that overcomes the restrictive endothelial barrier to achieve enhanced tumor-selective penetration and has therapeutic implications for other diseases within the central nervous system.

In recent work, CuO nanofluid is prepared with and without PVA (poly(vinyl alcohol)) coated surfactant nanoparticles suspension in distilled water: ethylene glycol (DW:EG) (60:40) ratio for 0.1 wt% and 0.5 wt% concentration of fluid by two-step technique. Our work describes a simple and cost effective chemical precipitation method to synthesis CuO nanoparticles with the addition of synthetic polymer (PVA) allows the modification of physical properties of copper oxide (CuO) nanoparticles. The scanning electron microscopy (SEM) shows the morphological difference in nanocrystallite size and shape between without surfactant coated nanoparticles and with PVA coated particles. XRD pattern of CuO particles reveal that high crystal quality with the monoclinic crystal structure where PVA coated particles have crystallite size 15 nm and without coating it is 31 nm. UV-Vis (ultraviolet absorption spectroscopy) spectra confirmed that the CuO absorption peak at 292 nm and 445 nm for CuO+ PVA. Fourier transform infrared spectra (FTIR) spectroscopy studies show the interaction between PVA and CuO nanoparticles. Experimental results concluded that for CuO + PVA nanofluid, particle size is smaller and showing more stable fluid from zeta potential values. Thermal conductivity results are carried from sound velocity of fluid by Bridgman's equation. As the particle concentration increases in fluid, thermal enhancement is noted. It was found that the viscosity of nanofluid is lower with a larger size particle at the same temperature and for the same concentration. Therefore, our result shows that CuO nanofluids have good potential for effective heat transfer application.

In the present work, we investigate the effect of nanoparticle crystallite size and shape on the thermal, rheological and optical properties of low-cost copper oxide nanofluid. Nanofluids are prepared by suspending 0.3% volume of nanoparticles in the 70:30 ethylene glycol:distilled water mixture using ultrasonic vibration, and followed by the microwave irradiation. Our results indicate that the zeta potential values of the nanofluids decrease as nanoparticle anisotropy or aspect ratio increases, zeta potential values decreases. Moreover, the increase in the thermal conductivity of the nanofluids is maximum for the nanofluids prepared using nanorods having the highest aspect ratio of 5.84. The rheology data of the CuO nanofluids with different shapes of nanoparticles at a particle volume fraction of 0.3% indicates that the nanofluids predominantly show Newtonian behaviour, exemplified by the shear rate independent viscosity. Moreover, the rheological behaviour is observed to depend on crystallite size and the nanoparticles shape as marked by an increase in the viscosity which follows the order, spherical

Objective: Due to COVID-19, patients who had sinus or skull base surgery in February and early March 2020 were unable toreceive standard postoperative care. Currently, there is a lack of data on the short- and long-term impacts of this. Wesought to examine the effects of the interruption of care due to COVID-19 on sinus and skull base surgery patientoutcomes. Study Design: Retrospective chart review. Methods: A retrospective review was conducted examining outcomes and healthcare utilization of patients at our institutionwho underwent sinus or skull base surgery in February and March of 2020, and who experienced an interruption inpostoperative care due to the pandemic. We then compared these measures with those of patients from the same timeperiod in 2019, who did not experience an interruption in care. Patient characteristics including age, indication for surgery,extent of surgery, polyps, preoperative Lund-Mackay and sinonasal outcome (SNOT22) scores and history of prior sinus orskull base surgery were recorded. Study outcomes included 3 and 6 month postoperative SNOT22 and Modified Lund-Kennedy endoscopy scores, antibiotic usage, sinonasal debridements performed, and number of telephone calls andtelehealth visits in the postoperative period. Results: A total of 107 patients were included. Of the SNOT22 scores available, the average change between preoperativeand 3 month postoperative SNOT22 scores for 2020 ( n = 15) compared to 2019 patients ( n = 30) was not significantlydifferent (a decrease of 17.27 and 19.93, respectively;p = 0.68). The average change between preoperative and 6-monthpostoperative SNOT22 scores for 2020 ( n = 13) compared to 2019 patients ( n = 26) was also not significantly different (adecrease of 18.69 and 20.77, respectively;p = 0.75). The average number of oral postoperative antibiotics received did notsignificantly differ between 2020 ( n = 52) and 2019 ( n = 55) cohorts (0.18 vs. 0.09, respectively;p = 0.53). The averagenumber of postoperative telephone calls did not significantly differ between 2020 and 2019 patients (1.51 vs. 1.19;p = 0.95). Patients in 2019 received an average of 2.35 postoperative sinonasal debridements compared to 1.90 in 2020 ( p =0.03). The average number of postoperative telehealth visits for 2020 patients was 0.72. Of the 2020 patients, 50% werelost to follow-up at 3 months postoperatively compared to 18% in 2019 ( p = 0.0005) and 71% were lost to follow-up at 6months postoperatively in 2020 compared to 36% in 2019 ( p = 0.0003). Conclusion: Although there was an interruption in postoperative care due to COVID-19, patients in 2020 who returned forfollow-up 3 and 6 months after surgery did not report significantly different subjective sinonasal outcomes compared topatients in 2019. A significantly greater number of patients have been lost to follow-up in 2020 compared to 2019 and havenot received routine postoperative care. Further study is required to determine the impact of the interruption of care due toCOVID-19 on sinus and skull base surgery outcomes.

Objective Nonphysician health care workers are involved in high-risk patient care during the COVID-19 pandemic, placing them at high risk of mental health burden. The mental health impact of COVID-19 in this crucial population has not been studied thus far. Thus, the objective of this study is to assess the psychosocial well-being of these providers. Study Design National cross-sectional online survey (no control group). Setting Academic otolaryngology programs in the United States. Subjects and Methods We distributed a survey to nonphysician health care workers in otolaryngology departments across the United States. The survey incorporated a variety of validated mental health assessment tools to measure participant burnout (Mini-Z assessment), anxiety (Generalized Anxiety Disorder–7), distress (Impact of Event Scale), and depression (Patient Health Questionnaire–2). Multivariable logistic regression analysis was performed to determine predictive factors associated with these mental health outcomes. Results We received 347 survey responses: 248 (71.5%) nurses, 63 (18.2%) administrative staff, and 36 (10.4%) advanced practice providers. A total of 104 (30.0%) respondents reported symptoms of burnout; 241 (69.5%), symptoms of anxiety; 292 (84.1%), symptoms of at least mild distress; and 79 (22.8%), symptoms of depression. Upon further analysis, development of these symptoms was associated with factors such as occupation, practice setting, and case load. Conclusion Frontline otolaryngology health care providers exhibit high rates of mental health complications, particularly anxiety and distress, in the wake of COVID-19. Adequate support systems must be put into place to address these issues.

Cisplatin-induced acute kidney injury (CI-AKI) is a significant co-morbidity of chemotherapeutic regimens. While this condition is associated with substantially lower survival and increased economic burden, there is no pharmacological agent to effectively treat CI-AKI. The disease is hallmarked by acute tubular necrosis of the proximal tubular epithelial cells primarily due to increased oxidative stress. In our prior work, we developed a highly-selective kidney-targeted mesoscale nanoparticle (MNP) that accumulates primarily in the renal proximal tubular epithelial cells while exhibiting no toxicity. Here, we found that MNPs exhibit renal-selective targeting in multiple mouse models of tumor growth with virtually no tumor accumulation. We then evaluated the therapeutic efficacy of MNPs loaded with the reactive oxygen species scavenger edaravone in a mouse model of CI-AKI. We found a marked and significant therapeutic effect with this approach as compared to free drug or empty control MNPs, including improved renal function, histology, and diminution of oxidative stress. These results indicated that renal-selective MNP edaravone delivery holds substantial potential in the treatment of acute kidney injury among patients undergoing cisplatin-based chemotherapy.

Direct targeting to the kidneys is a promising strategy to improve drug therapeutic index for the treatment of kidney diseases. We sought to investigate the renal selectivity and safety of kidney-targeted mesoscale nanoparticle technology. We found that direct intravenous administration of these particles resulted in 26-fold renal selectivity and localized negligibly in the liver or other organs. The nanoparticles targeted the renal proximal tubular epithelial cells, as evidenced by intravital microscopy and ex vivo imaging. Mice treated with the nanoparticles exhibited no negative systemic consequences, immune reaction, liver impairment, or renal impairment. The localization of material selectively to the renal tubules is uncommon, and this work portends the development of renal-targeted drugs for the treatment of kidney diseases.

Giant cell myocarditis (GCM), a rapidly progressive inflammation of the myocardium, is associated with fulminant heart failure, refractory ventricular arrhythmias, and conduction system abnormalities. Few case reports have noted orbital myositis as the initial clinical presentation. Our case demonstrates a unique presentation of GCM with only ocular symptoms, which unlike prior studies, rapidly progressed to heart failure, tachyarrhythmias, and conduction disease. Our case necessitated quick recognition and treatment with mechanical support making this the first known case of GCM with successful placement of biventricular assist devices and ultimately with heart transplantation.

OBJECTIVE The Sonic Hedgehog (SHH) medulloblastoma subgroup accounts for ~25% of all cases and has an intermediate prognosis. Current conventional therapies result in devastating morbidities including intellectual disability and secondary malignancies. Although molecularly targeted agents that inhibit the SHH pathway have demonstrated clinical efficacy, recent studies have shown on-target secondary toxicities on bone development suggesting new therapeutic approaches are needed. METHODS We investigated the efficacy of the SHH pathway inhibitor, Vismodegib packaged in a fucoidan-based nanoparticle (Fi-Vis) that targets P-selectin, a protein overexpressed on vascular endothelial cells and induced by low-dose ionizing radiation (XRT) in a time- and dose-dependent manner. This P-selectin targeting nanoparticle drug delivery system shows selectivity toward tumor vasculature and not normal brain vasculature in a genetic SHH medulloblastoma mouse model as assessed by ex vivo infrared imaging and two-photon intravital imaging. RESULTS Quantitative RT-PCR analysis of SHH medulloblastoma tissue following single dose XRT and Fi-Vis treatment (10mg/kg) showed a synergistic inhibition of Gli1 expression (>90% target inhibition). Furthermore, we demonstrate that very low dose XRT (0.25Gy) can induce P-selectin expression specifically within MB tumor vasculature and synergize with low dose Fi-Vis (10mg/kg) to significantly enhance mouse survival (p CONCLUSIONS These data suggest applicability of combined XRT and tumor vasculature-targeted nanotherapeutic dose de-escalation strategies for SHH medulloblastoma with implications for other pediatric and adult brain tumors.

Microalbuminuria is an important clinical marker of several cardiovascular, metabolic, and other diseases such as diabetes, hypertension, atherosclerosis, and cancer. The accurate detection of microalbuminuria relies on albumin quantification in the urine, usually via an immunoturbidity assay; however, like many antibody-based assessments, this method may not be robust enough to function in global health applications, point-of-care assays, or wearable devices. Here, we develop an antibody-free approach using synthetic molecular recognition by constructing a polymer to mimic fatty acid binding to the albumin, informed by the albumin crystal structure. A single-walled carbon nanotube, encapsulated by the polymer, as the transduction element produces a hypsochromic (blue) shift in photoluminescence upon the binding of albumin in clinical urine samples. This complex, incorporated into an acrylic material, results in a nanosensor paint that enables the detection of microalbuminuria in patient samples and comprises a rapid point-of-care sensor robust enough to be deployed in resource-limited settings., Microalbuminuria, a clinical marker associated with cancer and hypertension, defined by low albumin levels in the urine, is normally detected by immunoassay. Herein, a nanosensor paint was developed using a polymer to mimic fatty acid binding to albumin, transduced by carbon nanotube fluorescence.

OBJECTIVE The Sonic Hedgehog (SHH) medulloblastoma subgroup accounts for ~25% of all cases and has an intermediate prognosis. Current therapies result in devastating morbidities including intellectual disability and secondary malignancies. Although molecularly targeted agents against the SHH pathway have demonstrated efficacy, on-target bone toxicities suggest new therapeutic approaches are needed. METHODS We investigated the SHH pathway inhibitor, vismodegib, packaged in a fucoidan-based nanoparticle (Fi-Vis) that targets P-selectin expressed on endothelial cells and induced by low-dose ionizing radiation (XRT) in a time- and dose-dependent manner. This P-selectin targeting nanoparticle shows selectivity toward tumor and not normal brain vasculature in a GEM SHH medulloblastoma model as assessed by ex vivo infrared imaging and molecular studies. RESULTS Quantitative RT-PCR analysis of SHH medulloblastoma following single dose XRT and Fi-Vis treatment (10mg/kg) showed synergistic reduction of Gli1 expression (>90% target inhibition). We demonstrate that low-dose XRT (0.25Gy) can induce P-selectin expression specifically on medulloblastoma tumor endothelium and synergize with low-dose Fi-Vis (10mg/kg) to significantly enhance mouse survival (p CONCLUSIONS These data suggest applicability of combined XRT and tumor vasculature-targeted nanotherapeutic dose de-escalation strategies for SHH medulloblastoma with implications for other pediatric brain tumors.

Acute kidney injury (AKI) develops in up to 30% of patients who receive cisplatin-based chemotherapy. In this setting, AKI can result in delays in completion of treatment and/or the need to switch to other potentially less effective therapeutic regimens. Despite its high incidence and associated increased morbidity and mortality, there is no effective pharmacologic intervention to treat AKI of any etiology, including AKI resulting from cisplatin or any other nephrotoxic treatments. In the case of cisplatin-induced AKI, it is also imperative that any pharmacologic intervention that could be effective for AKI will not interfere with the systemic chemotherapeutic effects of cisplatin. In prior studies (Nano Letters, 2015), we reported the development of mesoscale nanoparticles (MNPs), composed of poly(lactic-co-glycolic acid) and polyethylene glycol (PLGA-PEG) that localize to the kidneys with a high affinity, primarily to the proximal tubules (the site of injury in AKI), and persist at that location for up to a week. Herein, we encapsulated a small molecule reactive oxygen species scavenger, (edaravone) in the MNPs. Experiments were performed in male C57BL/6 mice with cisplatin-induced AKI (25 mg/kg IP). To assess therapeutic efficacy, tail vein injections of 50 mg/kg edaravone-containing MNPs, 50 mg/kg empty control MNPs, or 30 mg/kg free edaravone were performed 24 hours after cisplatin injection (n=6-8 per group). Mice were euthanized at 72 hours post-cisplatin administration, and kidney and serum were saved for analysis. In a separate group of mice bearing metastatic small cell lung cancer, fluorescent MNPs were injected to determine whether MNPs still localize to the kidneys rather than to the tumor as has been described for other types of nanoparticles. Mice receiving cisplatin had a ~5 fold increase in serum creatinine and severe acute tubular necrosis as compared to controls. In contrast to mice receiving cisplatin alone, mice receiving edaravone-containing MNPs along with cisplatin had normal creatinine and histology similar to controls. Neither treatment with free edaravone nor empty MNPs resulted in a significant improvement in renal function or severity of tubular necrosis in mice with cisplatin-induced AKI. In the presence of AKI, the distribution of MNPs was still highly selective to the renal proximal tubules. In mice with metastatic lung tumors, we determined that MNPs maintain their specific renal distribution and do not localize to tumors as has been described with other smaller nanoparticle systems. These studies demonstrate that edaravone-containing MNPs can be an effective treatment for cisplatin-induced AKI while avoiding the possible therapeutic abatement associated with tumor deposition of reactive oxygen species scavengers. We anticipate that these studies will constitute the basis for the development of novel strategies for the treatment and prevention of cisplatin-induced AKI in humans. Citation Format: Daniel A. Heller, Edgar Jaimes, Ryan Williams, Janki Shah. Renal tubule-targeted supportive care nanotherapy for cisplatin-induced acute kidney injury [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 2032.

The abnormal accumulation of lipids within the endolysosomal lumen occurs in many conditions, including lysosomal storage disorders, atherosclerosis, non-alcoholic fatty liver disease (NAFLD), and drug induced phospholipidosis. Current methods cannot monitor endolysosomal lipid content in vivo, hindering preclinical drug development and research into the mechanisms linking endolysosomal lipid accumulation to disease progression. We developed a single-walled carbon nanotube-based optical reporter that non-invasively measures endolysosomal lipid accumulation via bandgap modulation of its intrinsic near-infrared emission. The reporter detected lipid accumulation in Niemann-Pick disease, atherosclerosis, and NAFLD models in vivo. By applying the reporter to the study of NAFLD, we found that elevated lipid quantities in hepatic macrophages caused by a high fat diet persist long after reverting to a normal diet. The reporter dynamically monitored endolysosomal lipid accumulation in vivo over time scales ranging from minutes to weeks, indicating its potential to accelerate preclinical research and drug development processes.

Blood vessels, the extracellular space, and the cell membrane represent physiologic barriers to nanoparticle-based drug delivery for cancer therapy. We demonstrate that electroporation (EP) can assist in the delivery of dye stabilized sorafenib nanoparticles (SFB-IR783) by increasing the permeability of endothelial monolayers, improving diffusion through the extracellular space in tumorspheres, and by disrupting plasma membrane function in cancer cells. These changes occur in a dose-dependent fashion, increasing proportionally with electric field strength. Cell death from irreversible electroporation (IRE) was observed to contribute to the persistent transport of SFB-IR783 through these physiologic barriers. In a model of mice bearing bilateral xenograft HCT116 colorectal tumors, treatment with EP resulted in the immediate and increased uptake of SFB-IR783 when compared with the untreated contralateral tumor. The uptake of SFB-IR783 was independent of direct transfection of cells through EP and was mediated by changes in vascular permeability and extracellular diffusion. The combination of EP and SFB-IR783 was observed to result in 40% reduction in mean tumor diameter when compared with sham treatment (p < 0.05) at the time of sacrifice, which was not observed in cohorts treated with EP alone or SFB-IR783 alone. Treatment of tumor with EP can augment the uptake and increase the efficacy of nanoparticle therapy.

Medulloblastoma, the most common pediatric malignant brain tumor, is divided into at least four molecular subtypes. The Sonic Hedgehog (SHH) subtype, accounts for approximately 30% of all cases and has an intermediate prognosis (5-year overall survival of 60%). Current treatments involve surgery, adjuvant radiotherapy for older children, and chemotherapy, however, lead to devastating morbidity, including decline in cognition and intellect, endocrine deficiencies, and secondary malignancies. More recently, targeted treatment options that inhibit the Hedgehog pathway have demonstrated clinical efficacy, including the Smoothened inhibitor, Vismodegib, however result studies have also shown secondary toxicities including effects on bone development. Here we investigated the efficacy of Vismodegib packaged in a fucoidan-based nanoparticle (Fi-Vis) that targets P-selectin, a protein overexpressed on vascular endothelial cells and is induced by 2Gy ionizing radiation (XRT) in a time- and dose-dependent manner. This p-selectin targeting nanoparticle drug delivery system shows selectivity toward tumor vasculature and not normal brain vasculature in a genetically relevant SHH-driven medulloblastoma mouse model as assessed by ex vivo infrared imaging. Quantitative RT-PCR analysis on SHH medulloblastoma tumor tissue following 2Gy XRT and Fi-Vis single dose treatment (as low as 10mg/kg) showed a synergistic inhibition of Gli1 expression (up to ~90% target inhibition). Furthermore, we demonstrate that lower single fraction XRT doses as low as 1Gy also induce P-selectin expression within medulloblastoma tumor vasculature. These data suggest applicability of combined XRT and tumor vasculature-targeted nanotherapeutic dose de-escalation strategies for medulloblastoma and potentially other pediatric brain tumors.

Snakebite is an environmental hazard associated with a significant morbidity and mortality. Two main types of toxicity occur due to snakebite, namely vasculotoxicity and neurotoxicity. Neurotoxic snakebites present mainly with bilateral ptosis with dilated pupils and/or difficulty in breathing. Jatropha curcas belongs to the family Euphorbiaceae and is commonly referred to as " Ratanjyot" in Gujarati. It has got many medicinal uses such as anticancerous properties and bio-oil. There are very few cases of its toxicity in adults. Toxicity from it causes meiosis, vomiting, diarrhea, etc., We will hereby discuss one such patient who consumed J. curcas seeds intentionally, became drowsy and accidentally got bit by a snake, and then, the patient started having bilateral ptosis, but with normal-sized pupils. There is no case reported yet in the literature mentioning the combined toxicity of snakebite and J. curcas, so we thought to publish this first case report of its kind in the world, thus discussing its diagnosis, symptoms, and treatment modalities.

Ovarian cancer biomarker detection using a novel nanosensor implant in live mice., Patients with high-grade serous ovarian carcinoma (HGSC) exhibit poor 5-year survival rates, which may be significantly improved by early-stage detection. The U.S. Food and Drug Administration–approved biomarkers for HGSC—CA-125 (cancer antigen 125) and HE4 (human epididymis protein 4)—do not generally appear at detectable levels in the serum until advanced stages of the disease. An implantable device placed proximal to disease sites, such as in or near the fallopian tube, ovary, uterine cavity, or peritoneal cavity, may constitute a feasible strategy to improve detection of HGSC. We engineered a prototype optical sensor composed of an antibody-functionalized carbon nanotube complex, which responds quantitatively to HE4 via modulation of the nanotube optical bandgap. The complexes measured HE4 with nanomolar sensitivity to differentiate disease from benign patient biofluids. The sensors were implanted into four models of ovarian cancer, within a semipermeable membrane, enabling the optical detection of HE4 within the live animals. We present the first in vivo optical nanosensor capable of noninvasive cancer biomarker detection in orthotopic models of disease.

A unilaterally fixed mydriasis, also known as a 'blown pupil,' is considered an ominous sign concerning for intracranial pathology. Causes of anisocoria can range from benign to immediately life-threatening. When a patient presents with anisocoria, the concern for a fatal diagnosis leads the clinician to obtain numerous tests, many of which may be unnecessary. The authors present a case of a healthy woman in her 30s who presented with an acute unilateral mydriasis likely secondary to inadvertent contact with a scopolamine patch. On examination, she had no other neurological deficits. Further investigation did not reveal any abnormality. In the event of a patient with an isolated mydriasis in an otherwise healthy and conversant patient with no other neurological deficits, it is essential to rule out other causes before pursuing aggressive and unnecessary testing and treatment.

Alterations in PIK3CA, the gene encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3Kα), are frequent in head and neck squamous cell carcinomas. Inhibitors of PI3Kα show promising activity in various cancer types, but their use is curtailed by dose-limiting side effects such as hyperglycaemia. In the present study, we explore the efficacy, specificity and safety of the targeted delivery of BYL719, a PI3Kα inhibitor currently in clinical development in solid tumours. By encapsulating BYL719 into P-selectin-targeted nanoparticles, we achieve specific accumulation of BYL719 in the tumour milieu. This results in tumour growth inhibition and radiosensitization despite the use of a sevenfold lower dose of BYL719 compared with oral administration. Furthermore, the nanoparticles abrogate acute and chronic metabolic side effects normally observed after BYL719 treatment. These findings offer a novel strategy that could potentially enhance the efficacy of PI3Kα inhibitors while mitigating dose-limiting toxicity in patients with head and neck squamous cell carcinomas., Head and neck squamous cell carcinomas (HNSCC) often harbour PIK3CA mutations but PI3Kα inhibitors can cause some side effects. Here, the authors develop P-selectin targeted nanoparticles to enhance tumour-specific delivery of a PI3Kα inhibitor to HNSCC PDX and orthotopic xenograft models.

A series of pateamine A (1) derivatives were synthesized for structure/activity relationship (SAR) studies and a selection of previous generation analogs were re-evaluated based on current information regarding the mechanism of action of these translation inhibitors. Structural modifications in the new generation of derivatives focused on alterations to the C19–C22 Z,E-diene and the trienyl side chain of the previously described simplified, des-methyl, des-amino pateamine A (DMDAPatA, 2). Derivatives were tested for anti-proliferative activity in cell culture and for inhibition of mammalian cap-dependent translation in vitro. Activity was highly dependent on the rigidity and conformation of the macrolide and the functionality of the side chain. The only well tolerated substitutions were replacement of the N,N-dimethyl amino group found on the side chain of 2 with other tertiary amine groups. SAR reported here suggests that this site may be modified in future studies to improve serum stability, cell-type specificity, and/or specificity towards rapidly proliferating cells.

Disseminated tumors are poorly accessible to nanoscale drug delivery systems because of the vascular barrier, which attenuates extravasation at the tumor site. We investigated P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, for its potential to target metastases by arresting nanomedicines at the tumor endothelium. We found that P-selectin is expressed on cancer cells in many human tumors. To develop a targeted drug delivery platform, we used a fucosylated polysaccharide with nanomolar affinity to P-selectin. The nanoparticles targeted the tumor microenvironment to localize chemotherapeutics and a targeted MEK (mitogen-activated protein kinase kinase) inhibitor at tumor sites in both primary and metastatic models, resulting in superior antitumor efficacy. In tumors devoid of P-selectin, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression. Radiation concomitantly produced an abscopal-like phenomenon wherein P-selectin appeared in unirradiated tumor vasculature, suggesting a potential strategy to target disparate drug classes to almost any tumor.

The near-infrared photoluminescence from non-covalently dispersed single-walled carbon nanotubes (SWCNT) is optimally suited to probe distinct classes of biological environments. With aspect ratios of >100:1, nanotubes present an opportunity to observe atypical interactions between linear filamentous particles and three-dimensional biological environments. A pressing concern in therapeutic biomedicine is the inability of drug-carrying nanoparticles that function well in two dimensional cell cultures, to show efficacy in vivo. The inability of spherical nanoparticles to penetrate dense three-dimensional structures in a well defined point of failure. By exploiting the ability to image single carbon nanotubes via widefield fluorescence microscopy, we quantified the relative permeability of multi cellular tumor spheroids to a linear nanoparticle1. The results indicate the ability of nanoparticles to penetrate tumor spheroids depends strongly on the nanoparticle shape. Additionally, this platform portends a new approach to characterize the permeability of living multicellular environments. References: Photoluminescent carbon nanotubes interrogate the permeability of multicellular tumor spheroids, Yosef Shamay*, Prakit V. Jena*, et al, Carbon 97 (2016) 99-109

Development of targeted nanoparticle drug carriers often requires complex synthetic schemes involving both supramolecular self-assembly and chemical modification. These processes are generally difficult to predict, execute, and control. We describe herein a targeted drug delivery system that is accurately and quantitatively predicted to self-assemble into nanoparticles based on the molecular structures of precursor molecules, which are the drugs themselves. The drugs assemble with the aid of sulfated indocyanines into particles with ultrahigh drug loadings of up to 90%. We devised quantitative structure-nanoparticle assembly prediction (QSNAP) models to identify and validate electrotopological molecular descriptors as highly predictive indicators of nano-assembly and nanoparticle size. The resulting nanoparticles selectively targeted kinase inhibitors to caveolin-1-expressing human colon cancer and autochthonous liver cancer models to yield striking therapeutic effects while avoiding pERK inhibition in healthy skin. This finding enables the computational design of nanomedicines based on quantitative models for drug payload selection. Molecular simulations reveal the self-assembly of small molecules into nanoparticle drug carriers. Targeting of colon and liver cancer cells by the nanoparticles via kinase inhibitors is employed in anti-tumour therapy in vivo.

Neuronal differentiation of PC12 cells in response to NGF is a prototypical model in which signal duration determines a biological response. Sustained ERK activity induced by NGF, as compared with transient activity induced by EGF, is critical to the differentiation of these cells. To characterize the transcriptional program activated preferentially by NGF, we compared global gene expression profiles between cells treated with NGF and EGF for 2–4 h, when sustained ERK signaling in response to NGF is most distinct from the transient signal elicited by EGF. This analysis identified 69 genes that were preferentially up-regulated in response to NGF. As expected, up-regulation of these genes was mediated by sustained ERK signaling. In addition, they were up-regulated in response to other neuritogenic treatments (pituitary adenylate cyclase-activating polypeptide and 12-O-tetradecanoylphorbol-13-acetate plus dbcAMP) and were enriched for genes related to neuronal differentiation/function. Computational analysis and chromatin immunoprecipitation identified binding of CREB and AP-1 family members (Fos, FosB, Fra1, JunB, JunD) upstream of >30 and 50%, respectively, of the preferentially NGF-induced genes. Expression of several AP-1 family members was induced by both EGF and NGF, but their induction was more robust and sustained in response to NGF. The binding of Fos family members to their target genes was similarly sustained in response to NGF and was reduced upon MEK inhibition, suggesting that AP-1 contributes significantly to the NGF transcriptional program. Interestingly, Fra1 as well as two other NGF-induced AP-1 targets (HB-EGF and miR-21) function in positive feedback loops that may contribute to sustained AP-1 activity.

We synthesized “mesoscale” nanoparticles, approximately 400 nm in diameter, which unexpectedly localized selectively in renal proximal tubules and up to 7 times more efficiently in the kidney than other organs. Although nanoparticles typically localize in the liver and spleen, modulating their size and opsonization potential allowed for stable targeting of the kidneys through a new proposed uptake mechanism. Applying this kidney targeting strategy, we anticipate use in the treatment of renal disease and the study of renal physiology.

Purpose: PI3K-pathway activation is the second most common genetic abnormality occurring in head and neck squamous cell carcinoma (HNSCC). Mutation or amplification of PIK3CA, the gene coding for the p110α subunit of PI3K, occur in 34%-56% of HNSCC and there is evidence that targeting PI3Kα in these tumors can be radiosensitizing. Small molecule kinase inhibitors of PI3Kα are showing promising activity. However, the use of this molecule is limited by serious side effects such as hyperglycemia, diarrhea and rush. In this study we aimed to apply novel nanotechnology for targeted drug delivery via the cell adhesion molecule P-selectin, which was previously shown to be overexpressed in tumor microvasculature. Furthermore, P-selectin is up regulated following radiation therapy (RT), which could enhance drug delivery using targeted nanoparticles. Experimental design: We explored the efficacy and specificity of targeted delivery of BYL719, a potent alpha-specific PI3K inhibitor, using nanoparticles that selectively target P-selectin present in the tumor microvasculature in PIK3CA-mutated HNSCC. We compared the antitumor effects of nanoparticle delivery versus standard oral gavage with free drug in PIK3CA mutated HNSCC cell line- and patient-derived xenografts (PDXs). In addition, we compared blood glucose and insulin levels between standard BYL719 administration and nanoparticle drug delivery at different time points after treatment. Furthermore, we sought to evaluate the radiosensitizing properties of BYL719 when combined with fractionated RT of 5X4Gy. Results: P-selectin targeted delivery of 50 mg/kg/week BYL719 resulted in a significant tumor growth delay, which was comparable to the standard drug administration of 350 mg/kg/week (50 mg/kg/daily). While blood glucose and insulin levels were spiking after standard oral gavage of BYL719, these parameters were virtually unchanged upon nanoparticle administration of the drug. The radiosensitizing abilities of low-dose nanoparticle-linked BYL719 were comparable to the drug concentrations used in standard daily BYL719 administration. When given concomitantly with fractionated RT, both methods showed robust enhancement of radiotherapy response in all the models tested resulting in durable control of tumor growth. Conclusions: P-selectin targeted delivery of a PI3Kα inhibitor resulted in inhibition of the PI3K/Akt/mTOR pathway without affecting glucose or insulin levels. The magnitude of pathway inhibition was sufficient to radiosensitize several HNSCC animal models. This novel targeting strategy could be translated to the clinic to treat patients with PIK3CA activated and radioresistant HNSCC tumors sparing most of the systemic adverse effects of PI3K inhibition. Citation Format: Aviram Mizrachi, Yosi Shamay, Janki Shah, Samuel I. Brook, Joanne Soong, Vinagolu K. Rajasekhar, John L. Humm, Simon N. Powell, José Baselga, Daniel A. Heller, Adriana Haimovitz-Friedman, Maurizio Scaltriti. Tumor-specific PI3K inhibition via nanoparticle targeted delivery in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4122. doi:10.1158/1538-7445.AM2017-4122

Gabapentin (1-aminomethyl-cyclohexaneacetic acid) is an amino acid that has the structure of the neurotransmitterγ-aminobutyric acid (GABA). It is a novel drug used for the treatment of postoperative pain with antihyperalgesic properties and a unique mechanism of action. Gabapentin and the related, more potent compound pregabalin have been shown to be beneficial in the treatment of neuropathic pain as well as postoperative pain following spinal surgery and hysterectomy. This study reviews five aspects of gabapentin: (1) chemical and structural characteristics; (2) pharmacokinetics and pharmacodynamics; (3) application in acute pain management; (4) adverse effects; and (5) drug safety. Overall, gabapentin has been reported to be a safe and efficacious drug for the treatment of postoperative pain.