Funded Research Projects

Permanent URI for this collectionhttps://hdl.handle.net/20.500.14641/189

An index of publicly funded research projects conducted by Texas A&M affiliated researchers.

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Browsing Funded Research Projects by Department "Cop-Pharmaceutical Sciences"

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    Research Project
    Improving tumor specificity and overcoming drug resistance of proteasome inhibitors by a dual-targeted drug delivery system
    Cop-Pharmaceutical Sciences; TAMHSC; https://hdl.handle.net/20.500.14641/209; National Institutes of Health
    Although targeting the ubiquitin-proteasome pathway by proteasome inhibitors, e.g. bortezomib (BTZ), is considered a targeted anticancer approach, its applications are hampered by poor drug solubility, low tumor specificity, drug resistance, side effects, and unsatisfying efficacy toward solid tumors. The current attempts, including the design of new proteasome inhibitors and drug delivery systems, focused mainly on improving drug bioavailability, but failed to address other important issues. Folate receptors (FRs) are overexpressed on many cancer cells as the major mechanism supportive of rapid cell growth, providing the rationale for the development of FR-targeted therapeutics. Unfortunately, some normal cells also express FRs, increasing the risk of off-tumor toxicity. The cancer targetability of these therapeutics has to be further improved. The matrix metalloproteinase 2 (MMP2) upregulation is highly associated with cancer growth, invasion and metastasis and emerged recently as a stimulus for the tumor-targeted drug delivery. To deal with the aforementioned issues of BTZ, in this application, a novel micellar nanopreparation is proposed, which contains a FR-targeted small-molecule drug conjugate (FA-Cat-BTZ) and an MMP2-sensitive self-assembling polymer (PEG2k-pp-PE). In the design, the MMP2-sensitive FR-targeting will improve the BTZ’s tumor specificity. In the tumor, the upregulated MMP2 will deshield the PEG layer and collapse the micellar nanoparticles, leading to the rapid release of FA-Cat-BTZ. Then, the released FA-Cat-BTZ will bind to the FRs on cancer cells for endocytosis. Therefore, this system undergoes the “two-stage” transition from a nanoparticle to a small molecule, which will satisfy the nanoparticles’ tumor accumulation, small molecules’ tissue penetration, and cancer cell-specific drug uptake. Additionally, PEG2k-pp-PE possesses the capability of overcoming the efflux-mediated drug resistance. As a result, the novel strategy will maximize BTZ’s anticancer activity, overcome drug resistance, and minimize side effects. The major goals of this proposal are to preclinically evaluate the strategy and gather the essential information/data for future clinical translation. Three specific aims are proposed: (i) Prepare and optimize the micelles; (ii) Evaluate the combinatorial effects of PEG2k-pp-PE and FA-Cat-BTZ; and (iii) Evaluate the in vivo tumor targeting and anticancer activity. The proposal is driven by the need to broaden the anticancer spectrum and improve the efficacy of proteasome inhibitors, and to develop a strategy that can be a stepping stone towards attaining the ultimate goal of cancer-specific drug delivery. This study will be the first exploration of the dual (MMP2 and FR) targeted delivery of targeted therapeutics to the solid tumor and the novel combination regimen (proteasome inhibitor and efflux inhibitor) for treating drug-resistant cancers. The positive findings from this study are expected to be translated into potential clinical progress. This AREA grant will also strengthen the research environment in the College of Pharmacy at TAMHSC and provide more research opportunities for PharmD, graduate, and undergraduate students.
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    Research Project
    Improving tumor specificity and overcoming drug resistance of proteasome inhibitors by a dual-targeted drug delivery system
    Cop-Pharmaceutical Sciences; TAMHSC; https://hdl.handle.net/20.500.14641/209; National Institutes of Health
    Although targeting the ubiquitin-proteasome pathway by proteasome inhibitors, e.g. bortezomib (BTZ), is considered a targeted anticancer approach, its applications are hampered by poor drug solubility, low tumor specificity, drug resistance, side effects, and unsatisfying efficacy toward solid tumors. The current attempts, including the design of new proteasome inhibitors and drug delivery systems, focused mainly on improving drug bioavailability, but failed to address other important issues. Folate receptors (FRs) are overexpressed on many cancer cells as the major mechanism supportive of rapid cell growth, providing the rationale for the development of FR-targeted therapeutics. Unfortunately, some normal cells also express FRs, increasing the risk of off-tumor toxicity. The cancer targetability of these therapeutics has to be further improved. The matrix metalloproteinase 2 (MMP2) upregulation is highly associated with cancer growth, invasion and metastasis and emerged recently as a stimulus for the tumor-targeted drug delivery. To deal with the aforementioned issues of BTZ, in this application, a novel micellar nanopreparation is proposed, which contains a FR-targeted small-molecule drug conjugate (FA-Cat-BTZ) and an MMP2-sensitive self-assembling polymer (PEG2k-pp-PE). In the design, the MMP2-sensitive FR-targeting will improve the BTZ’s tumor specificity. In the tumor, the upregulated MMP2 will deshield the PEG layer and collapse the micellar nanoparticles, leading to the rapid release of FA-Cat-BTZ. Then, the released FA-Cat-BTZ will bind to the FRs on cancer cells for endocytosis. Therefore, this system undergoes the “two-stage” transition from a nanoparticle to a small molecule, which will satisfy the nanoparticles’ tumor accumulation, small molecules’ tissue penetration, and cancer cell-specific drug uptake. Additionally, PEG2k-pp-PE possesses the capability of overcoming the efflux-mediated drug resistance. As a result, the novel strategy will maximize BTZ’s anticancer activity, overcome drug resistance, and minimize side effects. The major goals of this proposal are to preclinically evaluate the strategy and gather the essential information/data for future clinical translation. Three specific aims are proposed: (i) Prepare and optimize the micelles; (ii) Evaluate the combinatorial effects of PEG2k-pp-PE and FA-Cat-BTZ; and (iii) Evaluate the in vivo tumor targeting and anticancer activity. The proposal is driven by the need to broaden the anticancer spectrum and improve the efficacy of proteasome inhibitors, and to develop a strategy that can be a stepping stone towards attaining the ultimate goal of cancer-specific drug delivery. This study will be the first exploration of the dual (MMP2 and FR) targeted delivery of targeted therapeutics to the solid tumor and the novel combination regimen (proteasome inhibitor and efflux inhibitor) for treating drug-resistant cancers. The positive findings from this study are expected to be translated into potential clinical progress. This AREA grant will also strengthen the research environment in the College of Pharmacy at TAMHSC and provide more research opportunities for PharmD, graduate, and undergraduate students.
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    Research Project
    In Utero Third-Hand Smoke Impact on Platelet Function and Thrombogenesis
    Cop-Pharmaceutical Sciences; TAMHSC; https://hdl.handle.net/20.500.14641/689; DHHS-NIH-National Institute of Environmental Health Sciences
    While the involvement of in utero exposure to first-hand smoke (FHS) and second-hand smoke (SHS) in the pathogenesis of thrombotic diseases is well documented, the contribution of the newly “discovered” third-hand form (THS) in such disease processes remains unknown. This derives, in part, from: (1) initial lack of knowledge of THS existence; (2) lack of appreciation for its “real” negative health consequences; (3) lack of a THS-exposure animal model that mimics real-world scenarios; and (4) lack of studies regarding such consequences on platelet biology. The present application proposes experiments that address fundamental, mechanistic, epigenetic and clinically-relevant translational aspects of the adverse-health effects of the newly “realized” form of smoking, THS, in utero and in the context of thrombotic disease and platelet biology, and gender. Studies are also proposed to investigate, in a similar fashion, the toxicants that underlie THS effects on platelets and associated diseases. These studies are of paramount significance given that the dangers of THS are underestimated/unappreciated, despite evidence that it is more toxic than SHS, especially in vulnerable populations such as children and minorities (e.g., Hispanic Americans). The Aims of our proposal are: Aim 1. Investigate the impact of in utero THS-exposure on platelet-dependent diseases. While in utero exposure to the well-known FHS and SHS was found to contribute to the genesis of myocardial infarctions, whether in utero exposure to THS is also associated with an increased risk of thrombotic disorders, is yet to be determined. To address this issue, we will determine the ramifications of in utero THS exposure on normal hemostasis, platelet counts, as well as on clotting factors and other thrombosis mediators, in a dose-, and time dependent fashion. Subsequent studies will examine whether in utero THS participates in the development of thrombotic disorders. Aim 2. Investigate the mechanism by which in utero THS-exposure modulates platelet function. Our recently published findings show, for the first time, that adult THS exposure modulates physiological hemostasis, and increases the risk of thrombogenesis, via enhancing platelet activation. However, whether in utero THS is associated with similar effects, and if so, the mechanism by which it modulates platelet function remain to be investigated. Thus, the overall goal of the experiments proposed in this section is to determine the significance, toxicants and mechanism of the impact of in utero THS-exposure on various platelet functional responses, platelet epigenetics, its effect on other blood cells (e.g., leukocytes) and thrombosis “markers”, as well as its major route of exposure. Collectively, these experiments will make significant contributions to our understanding of the consequences of in utero THS exposure on platelet activation and cardiovascular human health, its epigenetics, and the mechanism and toxicants by which THS exerts its effects