Browsing by Subject "Rapamycin"

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    Improved inhalation therapies of brittle powders
    (2013-12) Carvalho, Simone Raffa; Williams, Robert O., 1956-
    Advancements in pulmonary drug delivery technologies have improved the use of dry powder inhalation therapy to treat respiratory and systemic diseases. Despite remarkable improvements in the development of dry powder inhaler devices (DPIs) and formulations in the last few years, an optimized DPI system has yet to be developed. In this work, we hypothesize that Thin Film Freezing (TFF) is a suitable technology to improve inhalation therapies to treat lung and systemic malignancies due to its ability to produce brittle powder with optimal aerodynamic properties. Also, we developed a performance verification test (PVT) for the Next Generation Cascade Impactor (NGI), which is one of the most important in vitro characterization methods to test inhalation. In the first study, we used TFF technology to produce amorphous and brittle particles of rapamycin, and compared the in vivo behavior by the pharmacokinetic profiles, to its crystalline counterpart when delivered to the lungs of rats via inhalation. It was found that TFF rapamycin presented higher in vivo systemic bioavailability than the crystalline formulation. Subsequently, we investigated the use of TFF technology to produce triple fixed dose therapy using formoterol fumarate, tiotropium bromide and budesonide as therapeutic drugs. We investigated applications of this technology to powder properties and in vitro aerosol performance with respect to single and combination therapy. As a result, the brittle TFF powders presented superior properties than the physical mixture of micronized crystalline powders, such as excellent particle distribution homogeneity after in vitro aerosolization. Lastly, we developed a PVT for the NGI that may be applicable to other cascade impactors, by investigating the use of a standardized pressurized metered dose inhaler (pMDI) with the NGI. Two standardized formulations were developed. Formulations were analyzed for repeatability and robustness, and found not to demonstrate significant differences in plate deposition using a single NGI apparatus. Variable conditions were introduced to the NGI to mimic operator and equipment failure. Introduction of the variable conditions to the NGI was found to significantly adjust the deposition patterns of the standardized formulations, suggesting that their use as a PVT could be useful and that further investigation is warranted.
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    The use of Rapamycin in reducing IL-10 and TGF [beta] expression in obesity-induced M2-like TAMs of the prostate tumor microenvironment
    (2019-12-05) Drake-Studstill, Margaret; deGraffenried, Linda
    Tumor-associated macrophages (TAMs) promote prostate cancer progression and aggressiveness in a variety of ways including promoting angiogenesis; upregulating tumoral survival; inducing EMT; and stimulating metastasis. Most importantly, they can suppress the immune system by expressing anti-inflammatory cytokines such as IL-10 and TGFβ. M2-like TAMs are polarized by a variety of signals, including from signaling factors expressed by adipocytes in the case of obese patients. It is crucial that we find ways to reduce immune suppression in cancer patients, so that patients’ immune systems may slow the cancer progression