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Browsing Data@TAMU by Subject "Cop - Pharmaceutical Sciences"

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    Research Project
    Oral delivery of insulin using ligand-directed nanoparticles that do not compete with physiological ligands
    Cop - Pharmaceutical Sciences; TAMU; https://hdl.handle.net/20.500.14641/447; DHHS-NIH-National Institute of Diabetes and Digestive and Kidney Disorders
    Project Summary The primary focus of managing type 2 diabetes (T2D) has traditionally been the strict control of blood glucose using one or multiple orally administered medications. Drugs currently used to treat T2D range from pharmaceutical agents that increase insulin secretion or sensitivity, to those that decrease hepatic gluconeogenesis or intestinal carbohydrate absorption. Agents that are more recent include glucagon-like peptide-1 (GLP-1) analogues, which inhibit the breakdown of endogenous GLP-1 by dipeptidyl peptidase-IV (DPP-IV), and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, which block normal glucose reabsorption in the kidneys. According to the United Kingdom Prospective Diabetes Study (UKPDS 33), even though the efficacy of these drugs in preventing microvascular complications of T2D (e.g., retinopathy, neuropathy and nephropathy) has been partially established, their role in preventing macrovascular complications (e.g., coronary heart disease and stroke) remains elusive. Moreover, the same study points out that 50 percent of patients originally controlled with a single drug acquired tolerance and needed the addition of a second drug after three years, and by nine years, about 75 percent of patients needed multiple therapies to achieve the target HbA1c value. There is significant evidence that in some T2D patients, despite taking medications, the ?-cell function undergoes continuous decline and eventually fails entirely, leaving these patients the only option of insulin therapy. Rather than being used as a treatment of last resort however, the clinical and research communities are recognizing that early initiation of insulin therapy in T2D patients will correct all of the underlying pathogenic mechanisms such as increased ?-cell apoptosis, glucotoxicity, lipotoxicity, and inflammation. Major drawbacks of early insulin injections for T2D include risks of cardiovascular disease, weight gain and hypoglycemia, stemming from irregular or incorrect dosing, lack of time in the physician's schedule to manage insulin therapy, and most importantly, patient non-compliance. Successful oral delivery of insulin is therefore a therapeutic Holy Grail as its inherent ease of administration mimicking natural secretion process potentially obviates or minimizes many of the drawbacks, and should reduce much of the burden of managing T2D by health care professionals. However, gastric instability and lack of transport across tightly packed epithelium and overlying mucus are formidable challenges to successful intestinal absorption of insulin. The work enabled by previous findings, in which oral delivery of insulin using ligand-directed nanoparticles that do not compete with physiological ligands led to improved therapeutic outcomes compared to conventional nanoparticles. In this project, the technology is further developed by investigating, how fine-tuning the nanoparticle composition affect the drug disposition and therapeutic outcomes, under the influence of commonly experienced physiological and pathophysiology conditions. In doing so, the project will establish 1) optimal non-competitive nanoparticle chemistry, 2) active drug delivery under pertinent physiological conditions, and 3) the therapeutic window of oral insulin in T2D.
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    Research Project
    Systemic Anti-Inflammatory Therapy to Prevent or Delay Diabetic Cataracts and Treat Post-Surgical Inflammation
    Cop - Pharmaceutical Sciences; TAMU; https://hdl.handle.net/20.500.14641/447; DHHS-NIH-National Eye Institute
    PROJECT SUMMARY Currently, surgical intervention is the only cure for cataracts, though this can be complicated in patients with diabetes. One of the most common postoperative complications in patients suffering from diabetes is persistent inflammation (uveitis) that can cause significant corneal edema, posterior synechia, and progression of diabetic retinopathy or neovascular glaucoma. There is substantial evidence that secondary cataract formation due to health conditions such as diabetes are associated with increased inflammation, oxidative stress, and sorbitol accumulation, along with covalent bonding of a protein or lipid molecule with a sugar molecule causing an increase in advanced glycosylation end products (AGE) formation that can cause significant damage to cells and tissues. The efforts to combat these effects using traditional drugs often leads to severe side effects outweighing the benefits. On the other hand natural compounds such as curcumin offer promise, but their progress is hampered due to lack of suitable dosage forms and poor bioavailability. In order to overcome inferior physicochemical and pharmacological attributes of curcumin we have prepared biodegradable nanosystems of polylactide-co-glycolide (PLGA) encapsulating curcumin (nCUR). These passively absorbed nCUR when given 8 mg/kg/day were significantly more effective than plain curcumin in delaying diabetic cataract in rodents, independent of glucose reduction. Despite the enhanced performance of passive nCUR, a significant dose remained unabsorbed in the intestine, indicating potential for further improvement through active-nanosystems. For the first time, we present a non-competitive active transport strategy to improve drug transport across biological barriers by developing carrier systems that have no equivalent in the world of competitive ligands. We hypothesize that transferrin receptor (TfR) mediated delivery across the intestinal barriers (IB) and blood ocular barriers (BOB) would significantly enhance the transport of the nanosystems making systemic anti-inflammatory therapy a reality. In this proposal, we will continue our studies on non-competitive active drug delivery strategy and understand how the systemic anti-inflammatory therapy will prevent or delay diabetic cataracts and manage post-surgical inflammation. To test this hypothesis, we propose the following specific aims: AIM #1. Establish the effectiveness of TfR in facilitating the transport of PLGA-GA NS across the IB and BOB in rat model. AIM #2. Establish the magnitude of desired or undesired effects in suitable rat models as a result of active transport. AIM #3. We will verify performance of this delivery strategy in a more man-like model. At the end of this study, we will have an effective systemic anti-inflammatory therapy to prevent or delay diabetic cataracts and treat post- surgical inflammation.