Comparison of HFNC, Bubble CPAP, and SiPAP on Aerosol Delivery in Neonates: An In-Vitro Study

Background: Aerosol drug delivery via high flow nasal cannula (HFNC), bubble continuous positive airway pressure (CPAP), and synchronized inspiratory positive airway pressure (SiPAP) has not been quantified in spontaneously breathing premature infants. The purpose of this study was to compare HFNC, bubble CPAP, and SiPAP on aerosol delivery in a simulated spontaneously breathing preterm model. Methods: A breath simulator was set to preterm infant settings (VT: 9 ml, RR: 50 bpm and Ti: 0.5 sec) and connected to the trachea of an anatomical upper airway model of a preterm infant (DiBlasi) via collecting filter distal to the trachea. The HFNC (Fisher & Paykel), Bubble CPAP (Fisher & Paykel), and SiPAP (Carefusion) were attached to the model via their proprietary nasal cannula and set to deliver 5 cm H2O pressure. Albuterol sulfate (2.5 mg/0.5 mL) was aerosolized with a mesh nebulizer (Aeroneb Solo) positioned (1) proximal to the patient and (2) prior to the humidifier (n=5).The drug was eluted from the filter with 0.1 N HCl and analyzed via spectrophotometry (276 nm). Data were analyzed using descriptive statistics, t-tests, and analysis of variance (ANOVA), with p Results: At position 1, the trend of lower deposition across devices was not significant; however, in position 2, drug delivery with SiPAP was significantly lower compared to both HFNC (p=0.003) and bubble CPAP (p=0.008).Placement of the nebulizer prior to the humidifier increased deposition with all devices (p\u3c0.05). Conclusion: Aerosol can be delivered via all three devices used in this study; however, delivery efficiency of HFNC is better than the other CPAP devices tested. Device selection and nebulizer position impacted aerosol delivery in this simulated model of a spontaneously breathing preterm infant

Local Lung Targeting of Tumor Associated Macrophages Combined with Cytoreductive Therapy Decrease Tumor Burden in a Secondary Lung Cancer Model

Backgrounds. The efficacy of a locally administered small molecule colony stimulating factor 1 receptor inhibitor (CSF-1Ri), PLX3397, alone or in combination with cytoreductive therapy (paclitaxel) in reducing the tumor burden of an in vivo model of secondary lung cancer was investigated in this work. Local administration of immunotherapy to the lungs may enhance lung biodistribution of such therapies and reduce potential unwanted off-target toxicity. In addition, combination of such therapy with low dose standard of care chemotherapy may offer improved anti-tumor effects. Methods. Murine breast cancer cells (4T1, known to be highly metastasized to the lungs) were transduced to express the genes luciferase and tdTomato, and cells were injected to female Balb/c mice before being treated with PLX (intratracheally administered), paclitaxel (intravenously given), or the combination therapy. Both ex vivo bioluminescent imaging and lung weights were used to evaluate tumor burden. Western blot was performed using lung tumors to assess the effect of PLX3397 on its molecular target (phosphorylated CSF-1R). Immunofluorescence and Flowcytometry were utilized to examine the impact of treatment on tumorigenic tumor associated macrophages (M2 TAM). Results. Single-agent treatment partially decreased tumor burden, while combination therapy led to a significant reduction in tumor burden. PLX3397 significantly inhibited the expression of phosphorylated CSF-1R and reduced the number of M2 TAM without affecting the total macrophage population, thereby increasing the anti-tumorigenic (M1)/M2 ratio. Conclusion. Tumor burden reduction upon local administration of PLX3397 to the lungs correlates with the marked inhibition of the molecular target and the decrease in M2 TAM.https://scholarscompass.vcu.edu/gradposters/1065/thumbnail.jp

Remodeling the Lung Tumor Microenvironment with Locally Administered Nano-Immunochemotherapies for Osteosarcoma Lung Metastases

Osteosarcoma (OS) is the most common type of primary bone cancer and is primarily metastasized to the lungs. With lung metastasis (OSLM), the curability of disease and the overall survival rate diminish drastically. The standard of care has failed to improve the therapeutic outcomes of OSLM. The interplay between tumor cells and immune infiltrates in the tumor microenvironment (TME) is a critical determinant of metastasis growth. Gemcitabine (GMT) chemotherapy is used to treat OSLM. The combination therapy with colony-stimulating factor-1 receptor inhibitors (CSF-1Ris) to treat solid tumors has shown benefits in manipulating TME away from tolerance and is now in the clinic (PLX). A potential limitation of both therapies is the poor biodistribution and the off-target toxicity. Thus, there is an opportunity to develop novel combination therapies and delivery strategies to improve the therapeutic potential and decrease off-target toxicity of currently available therapeutics. In this work, we explain developing a reproducible, robust in vivo model of OSLM that enables screening of various therapeutics via local administration to the lungs and their influence on tumor foci. Then we evaluate the tolerability and efficacy of the local lung delivery of PLX in combination with GMT and their effect in tuning TME to prevent the growth of gross metastases. As lung tissue retention limit treatment potentials, sustained-release nanoformulation is a possible strategy to increase drugs\u27 retention and enhance their efficacy. Thus, we describe the optimization of GMT liposomal formulation. Combining these strategies can have translation potential to improve OSLM patients’ outcomes and survival