Browsing by Subject "drug delivery"

Now showing 1 - 7 of 7
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    Attenuation of kindled seizures by intranasal delivery of neuropeptide-loaded nanoparticles.
    (Springer, 2009-04) Kubek, Michael J.; Domb, Abraham J.; Veronesi, Michael C.; Department of Anatomy and Cell Biology, IU School of Medicine
    Thyrotropin-releasing hormone (TRH; Protirelin), an endogenous neuropeptide, is known to have anticonvulsant effects in animal seizure models and certain intractable epileptic patients. Its duration of action, however, is limited by rapid tissue metabolism and the blood—brain barrier. Direct nose-to-brain delivery of neuropeptides in sustained-release biodegradable nanoparticles (NPs) is a promising mode of therapy for enhancing CNS neuropeptide bioavailability. To provide proof of principle for this delivery approach, we used the kindling model of temporal lobe epilepsy to show that 1) TRH-loaded copolymer microdisks implanted in a seizure focus can attenuate kindling development in terms of behavioral stage, after-discharge duration (ADD), and clonus duration; 2) intranasal administration of an unprotected TRH analog can acutely suppress fully kindled seizures in a concentration-dependent manner in terms of ADD and seizure stage; and 3) intranasal administration of polylactide nanoparticles (PLA-NPs) containing TRH (TRH-NPs) can impede kindling development in terms of behavioral stage, ADD, and clonus duration. Additionally, we used intranasal delivery of fluorescent dye-loaded PLA-NPs in rats and application of dye-loaded or dye-attached NPs to cortical neurons in culture to demonstrate NP uptake and distribution over time in vivo and in vitro respectively. Also, a nanoparticle immunostaining method was developed as a procedure for directly visualizing the tissue level and distribution of neuropeptide-loaded nanoparticles. Collectively, the data provide proof of concept for intranasal delivery of TRH-NPs as a viable means to 1) suppress seizures and perhaps epileptogenesis and 2) become the lead compound for intranasal anticonvulsant nanoparticle therapeutics.
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    Combined local delivery of tacrolimus and stem cells in hydrogel for enhancing peripheral nerve regeneration
    (Wiley, 2021-07) Saffari, Tiam M.; Chan, Katelyn; Saffari, Sara; Zuo, Kevin J.; McGovern, Renee M.; Reid, Joel M.; Borschel, Gregory H.; Shin, Alexander Y.; Medicine, School of Medicine
    The application of scaffold-based stem cell transplantation to enhance peripheral nerve regeneration has great potential. Recently, the neuroregenerative potential of tacrolimus (a U.S. Food and Drug Administration-approved immunosuppressant) has been explored. In this study, a fibrin gel-based drug delivery system for sustained and localized tacrolimus release was combined with rat adipose-derived mesenchymal stem cells (MSC) to investigate cell viability in vitro. Tacrolimus was encapsulated in poly(lactic-co-glycolic) acid (PLGA) microspheres and suspended in fibrin hydrogel, using concentrations of 0.01 and 100 ng/ml. Drug release over time was measured. MSCs were cultured in drug-released media collected at various days to mimic systemic exposure. MSCs were combined with (i) hydrogel only, (ii) empty PLGA microspheres in the hydrogel, (iii) 0.01, and (iv) 100 ng/ml of tacrolimus PLGA microspheres in the hydrogel. Stem cell presence and viability were evaluated. A sustained release of 100 ng/ml tacrolimus microspheres was observed for up to 35 days. Stem cell presence was confirmed and cell viability was observed up to 7 days, with no significant differences between groups. This study suggests that combined delivery of 100 ng/ml tacrolimus and MSCs in fibrin hydrogel does not result in cytotoxic effects and could be used to enhance peripheral nerve regeneration.
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    A novel patient-specific three-dimensional drug delivery construct for regenerative endodontics
    (Wiley, 2018-10-03) Bottino, Marco C.; Albuquerque, Maria T. P.; Azabi, Asma; Münchow, Eliseu A.; Spolnik, Kenneth J.; Nör, Jacques E.; Edwards, Paul C.; Oral Pathology, Medicine and Radiology, School of Dentistry
    Evoked bleeding (EB) clinical procedure, comprising a disinfection step followed by periapical tissue laceration to induce the ingrowth of undifferentiated stem cells from the periodontal ligament and alveolar bone, is currently the only regenerative-based therapeutic approach to treating pulp tissue necrosis in undeveloped (immature) permanent teeth approved in the United States. Yet, the disinfection step using antibiotic-based pastes leads to cytotoxic, warranting a biocompatible strategy to promote root canal disinfection with no or minimal side-effects to maximize the regenerative outcomes. The purpose of this investigation was to develop a tubular three-dimensional (3D) triple antibiotic-eluting construct for intracanal drug delivery. Morphological (scanning electron microscopy), chemical (Fourier transform infrared spectroscopy), and mechanical (tensile testing) characteristics of the polydioxanone-based triple antibiotic-eluting fibers were assessed. The antimicrobial properties of the tubular 3D constructs were determined in vitro and in vivo using an infected (Actinomyces naeslundii) dentin tooth slice model and a canine method of periapical disease, respectively. The in vitro data indicated significant antimicrobial activity and the ability to eliminate bacterial biofilm inside dentinal tubules. In vivo histological findings demonstrated that, using the EB procedure, the tubular 3D triple antibiotic-eluting construct allowed the formation of an appropriate environment that led to apex closure and the ingrowth of a thin layer of osteodentin-like tissue into the root canal. Taken together, these findings indicate that our novel drug delivery construct is a promising biocompatible disinfection strategy for immature permanent teeth with necrotic pulps.
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    Pathophysiological role of microRNA-29 in pancreatic cancer stroma
    (Office of the Vice Chancellor for Research, 2015-04-17) Kwon, Jason J.; Nabinger, Sarah C.; Alluri, Ravi K.; Vega, Zachary; Sahu, Smiti S.; Abdul-Sater, Zahi; Yu, Zhangsheng; Gore, A. Jesse; Nalepa, Grzegorz; Saxena, Romil; Korc, Murray; Kota, Janaiah
    Background: Dense fibrotic stroma associated with pancreatic ductal adenocarcinoma (PDAC) has been a major obstacle for drug delivery to the tumor bed and may impede attempts to slow down PDAC progression and metastasis. However, current antistromal drugs have not improved tumor response to chemotherapy or patient survival. Thus, a better understanding of the molecular mechanisms associated with tumorstromal interactions is desperately needed to develop novel anti-stromal therapeutic approaches. MicroRNAs (miRNAs) are an abundant class of highly conserved, small non-coding RNAs that function as key regulators of eukaryotic gene expression and cellular homeostasis. miR-29 is known to play a paramount role in the fibrotic process of several organs by providing crucial functions downstream of pro-fibrotic signaling pathways such as TGF-β1 and regulates the expression of extracellular matrix (ECM) proteins, a major component in the PDAC stroma. Upregulation of TGF-β1 is associated with PDAC pathogenesis and is known to activate stromal cells. Furthermore, vascular endothelial growth factor (VEGF) that stimulates tumor angiogenesis is a predicted target of miR-29. We hypothesize that miR-29 may be misregulated in TGF-β1 activated PDAC stromal cells and lead to excessive accumulation of ECM proteins and VEGF. Kwon et al. 2015 Annual AACR Meeting Restored expression of miR-29 could be therapeutically beneficial to modulate tumorstromal interactions. Methods: Northern blot or qPCR techniques were used to assess miR-29 levels in vitro stromal cells, murine PDAC model, and PDAC patient biopsies, and stromal deposition/fibrosis was determined by Sirius red staining. In murine and human PDAC samples, stromal specific miR-29 expression was determined via in situ hybridization by co-staining pancreatic tissues with glial fibrillary acidic protein a marker for stromal cells and miR-29. miR-29 functional studies were conducted by transfection of stroma cells with synthetic miR-29 mimics and locked nucleic acid, a miR-29 inhibitor, and ECM protein/VEGF expression was analyzed by western blot analysis. The effect of miR-29 overexpression in stromal cells on cancer colony growth was evaluated by direct coculture of stromal cells ectopically expressing miR-29 with pancreatic cancer cells, and subsequently, cancer colony number and stromal accumulation was determined by crystal violet and sirius red stains respectively. Results: In both in vitro and in vivo models as well as PDAC patient biopsies, we observed loss of miR-29 is a common phenomenon of activated stromal cells, and is associated with a significant increase in ECM and VEGF accumulation. Restored expression of miR-29 in stromal cells reduced the deposition of matrix proteins, VEGF expression, and cancer colony formation in direct co-culture. Conclusion: These results provide insight into the mechanistic role of miR-29 in PDAC stroma and its potential use as an anti-stromal/angiogenic therapeutic agent.
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    Patient preferences in retinal drug delivery
    (Nature, 2021) Jacobs, Brandon; Palmer, Nicholas; Shetty, Trupti; Dimaras, Helen; Hajrasouliha, Amir; Jusufbegovic, Denis; Corson, Timothy W.; Ophthalmology, School of Medicine
    Retinal vascular diseases (RVDs) are often treated with intravitreally (IVT) injected drugs, with relatively low patient compliance and potential risks. Ongoing research explores alternative RVD treatments, including eye drops and oral tablets. This study surveyed RVD patients treated with IVT injections to establish factors influencing low compliance rates while gauging treatment delivery method preferences. Demographics, perspectives, and treatment preferences were collected via IRB-approved, self-administered survey sent to Glick Eye Institute patients treated via IVT injections. Demographics, diagnoses, and treatments were ascertained from respondents’ medical records. Gender, age, and number of IVT injections received were used as stratifications. Five-level Likert-style scales and t-tests evaluated responses and stratification comparisons. The most common diagnoses in the respondent population (n = 54; response rate = 5%) were age-related macular degeneration, macular edema, and diabetic retinopathy. Respondents had varying levels of education, income, and age. Most (83%) admitted feeling anxious prior to their first IVT injection, but 80% reported willingness to receive IVT injections indefinitely, with a preference for ophthalmologist visits every 1–3 months. Eye drops would be preferred over IVT injections by 76% of respondents, while 65% preferred oral tablets, due to several perceived negative factors of IVT injections and positive factors for eye drops. Stratified groups did not differ in responses to survey questions. RVD patients will accept IVT injections for vision preservation, but alternative delivery methods like eye drops or oral tablets would be preferred. Thus, development of eye drop and oral therapeutics for RVD treatment is further emphasized by these findings.
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    The quest for optimal labour induction drug delivery
    (Wiley, 2019-08) Grasch, Jennifer L.; Haas, David M.; Obstetrics and Gynecology, School of Medicine
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    Rationally engineered nanoparticles target multiple myeloma cells, overcome cell-adhesion-mediated drug resistance, and show enhanced efficacy in vivo
    (Nature, 2012-04) Kiziltepe, T.; Ashley, J. D.; Stefanick, J. F.; Qi, Y. M.; Alves, Nathan J.; Handlogten, Michael W.; Suckow, M. A.; Navari, R. M.; Bilgicer, B.
    In the continuing search for effective cancer treatments, we report the rational engineering of a multifunctional nanoparticle that combines traditional chemotherapy with cell targeting and anti-adhesion functionalities. Very late antigen-4 (VLA-4) mediated adhesion of multiple myeloma (MM) cells to bone marrow stroma confers MM cells with cell-adhesion-mediated drug resistance (CAM-DR). In our design, we used micellar nanoparticles as dynamic self-assembling scaffolds to present VLA-4-antagonist peptides and doxorubicin (Dox) conjugates, simultaneously, to selectively target MM cells and to overcome CAM-DR. Dox was conjugated to the nanoparticles through an acid-sensitive hydrazone bond. VLA-4-antagonist peptides were conjugated via a multifaceted synthetic procedure for generating precisely controlled number of targeting functionalities. The nanoparticles were efficiently internalized by MM cells and induced cytotoxicity. Mechanistic studies revealed that nanoparticles induced DNA double-strand breaks and apoptosis in MM cells. Importantly, multifunctional nanoparticles overcame CAM-DR, and were more efficacious than Dox when MM cells were cultured on fibronectin-coated plates. Finally, in a MM xenograft model, nanoparticles preferentially homed to MM tumors with ∼10 fold more drug accumulation and demonstrated dramatic tumor growth inhibition with a reduced overall systemic toxicity. Altogether, we demonstrate the disease driven engineering of a nanoparticle-based drug delivery system, enabling the model of an integrative approach in the treatment of MM.