Browsing by Subject "Drug Carriers"
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Item Beta-Lapachone Nanotherapeutics for Lung Cancer Therapy(2009-01-08) Blanco, Elvin; Gao, JinmingA rising trend in lung cancer chemotherapy involves the development of agents that exploit molecular targets overexpressed in tumors, with hopes of increasing specificity, and in turn, efficacy. β-Lapachone (β-lap) is a novel anticancer drug whose mechanism of action relies on its bioactivation by the enzyme NAD(P)H:quinone oxidoreductase-1, NQO1, found overexpressed in NSCLC. While promising, its low water solubility limits its clinical translation. Moreovoer, a clinical formulation of the drug proves highly hemolytic and relatively ineffective. Our objective was to develop β-lapachone polymer micelles for lung cancer treatment, in hopes of targeting tumors: 1) pharmacokinetically, through the use of a platform that will ensure drug stability, bioavailability, and targeted localized delivery; and 2) pharmacodynamically, through the use of an anticancer drug that is bioactivated by a tumor-specific enzyme. We hypothesize that β-lapachone polymer micelles will result in a highly specific and effective nanotherapeutic platform for the treatment of lung cancer. Studies involving the clinical formulation of β-lap demonstrated that the vehicle, hydroxypropyl-β-cyclodextrin (HPβ-CD), causes hemolysis. The rapid dissociation of β-lap with HPβ-CD led to short blood circulation times and rapid distribution among all organs. By contrast, a micellar formulation of β-lap did not cause hemolysis, and displayed increased blood circulation times and relatively high and sustained accumulation in tumors. β-Lap micelles were small in size (~30 nm), possessed core-shell morphology, and displayed favorable release kinetics. In vitro examination of β-lap micelle efficacy in cancer cell lines demonstrated an NQO1-dependent mechanism of cell death. Upon translation to in vivo models of lung cancer in mice, β-lap micelles hindered tumor growth in subcutaneous lung tumors. It is important to note at this time that the clinical formulation of β-lap displayed no antitumor effects when compared to control tumors. Upon examination in an orthotopic model of lung cancer in mice, β-lap micelles were shown to prolong animal survival. Results from this study point toward the therapeutic potential of β-lap micelles for lung cancer treatment. Future studies involve optimization of the basic platform, as well as adjuvant use with current therapeutic strategies, to help propel this technology to preclinical studies and eventual clinical use.Item Development of Poly(Lactide-Co-Glycolide) Microspheres for Controlled Release of Thymosin Beta-4 in the Heart(2012-07-17) Thatcher, Jeffrey Edward; DiMaio, J. MichaelThymosin beta-4 is of great importance because it improves heart function after heart attack in animal models. In order to limit the number of interventions in Thymosin beta-4 therapy, a localized and controlled release formulation is necessary. Our goal was to generate controlled release microsphere formulations of poly(lactic-co-glycolic acid) that overcame a common problem of burst-release and to establish a method to modulate the release rates between formulations. Burst-release is the rapid release of drug from the formulation occurring in the initial 24 hours of elution. This event causes undesirable loss and potentially toxic levels of therapeutic from the microsphere. Modulation of release is of particular importance in these studies because little is known regarding the therapeutic dose of Thymosin beta-4 in humans. A class of non-ionic surfactants, alkyl glucosides, were used as excipients in preparation of poly(lactic-co-glycolic acid) double-emulsion microspheres for controlled release of the protein albumin or the peptide Thymosin beta-4. We specifically chose octyl-glucopyranoside and decyl-glucopyranoside for their ability to stabilize the primary emulsion step during microsphere synthesis. We demonstrate that the addition of alkyl glucosides of differing hydrocarbon chain length can modulate the rate of protein and peptide release from these microspheres. In albumin formulations, octyl-glucopyranoside reduced overall release compared to decyl-glucopyranoside and formulations prepared without surfactant, whereas in TB4 formulations decyl-glucopyranoside reduced overall release. In albumin containing microspheres burst release was high in formulations that did not contain any surfactant, 23%. Addition of decyl-glucopyranoside reduced burst release to 6% while addition of octyl-glucopyranoside further reduced burst release to 3%. Thin sections revealed smaller and more uniform internal porosity in microspheres containing surfactant, of which octyl-glucopyranoside porosity was less than decyl-glucopyranoside porosity. This difference in porosity corresponds with the reduction in initial burst release and overall release of albumin. With these surfactants we established a group of formulations with differing drug release rates. This research suggests that formulations containing Thymosin beta-4 can be beneficially used in future in vivo testing to determine a controlled release profile capable of generating a therapeutic response in ischemic heart disease.Item Lipid formulations of Amphotericin B(1999-10-07) Gregg, Clark R.Item Stimuli-Responsive Polymer Systems that Respond to Redox Potential and pH for Controlled Drug Release(2018-04-13) Elkassih, Sussana Ahmed; MacMillan, John; Siegwart, Daniel J.; Lux, Jacques; Stefan, Mihaela C.Nanocarriers are widely investigated drug delivery systems that can overcome physiological barriers by tuning nanocarrier size, shape, surface chemistry, targeting ligand conjugation, and material composition. Furthermore, they have stimuli-responsive moieties that translate physiological signals, such as pH and redox potential, at the tumor microenvironment into nanocarrier behaviors, like swelling, degradation, morphological change, and charge reversal. Stimuli-responsive nanocarriers exhibit better pharmacokinetic profiles with reduced premature cargo leakage during circulation time and improved tumor targeting efficacies. pH is the most commonly explored stimuli for designing nanocarriers, however there has been a recent interest in redox stimuli-responsive nanocarriers. Redox stimuli-responsive nanocarriers are often incorporated with a glutathione (GSH) sensitive bond, typically disulfide bonds, for intracellular activation or degradation. In these documented series of experiments, I first focus on poly(disulfide)s and report on the synthesis of fully degradable poly(disulfide) cross-linked nanogel drug carriers formed by oxidative radical polymerization of 2,2'-(ethylenedioxy)diethanethiol (EDDET) as a monomer with different cross-linkers, including pentaerythritol tetramercaptoacetate (PETMA), via a single- electron transfer mechanism. Because the poly(EDDET) backbone repeat structure and cross- linking junctions are composed entirely of disulfide bonds, these nanogels specifically degrade to small molecule dithiols intracellularly in response to the reducing agent glutathione present inside of cells. Due to the ease of synthesis, rapid gelation times, and tunable functionality, these non-toxic and fully degradable nanogels offer excellent potential for use in a variety of drug delivery applications. In addition to disulfide bonds, esters are another attractive functional group for the synthesis of degradable polymers for drug delivery, therefore I later discuss experiments and research that I worked on with Dr. Jing Hao, a postdoc in the Siegwart lab, that describes how polyesters can be synthesized in a controlled fashion and how they can be used to deliver siRNA molecules in vitro and in vivo. Specifically, the synthesis of a lipocationic polyester library via ring-opening polymerization (ROP) of functional valerlactones for efficacious siRNA delivery is described. The 139 polymers in the lipocationic polyester library were synthesized in high yield, fast time (minutes), and gram scale. Precise monomer incorporation ratios were achieved to enable tunable hydrophobicity and pKa. Nanoparticles formulated with these polymers were able to enable gene silencing in vitro and in vivo at low doses.