+publisher:"Georgia Tech" +contributor:("Dr. Niren Murthy")

1. Heffernan, Michael John. Biodegradable polymeric delivery systems for protein subunit vaccines.

Degree: PhD, Biomedical Engineering, 2008, Georgia Tech

► The prevention and treatment of cancer and infectious diseases requires vaccines that can mediate cytotoxic T lymphocyte-based immunity. A promising strategy is protein subunit vaccines… (more)

▼ The prevention and treatment of cancer and infectious diseases requires vaccines that can mediate cytotoxic T lymphocyte-based immunity. A promising strategy is protein subunit vaccines composed of purified protein antigens and immunostimulatory adjuvants, such as Toll-like receptor (TLR) agonists. In this research, we developed two new biodegradable polymeric delivery vehicles for protein antigens and TLR agonists, as model vaccine delivery systems. This work was guided by the central hypothesis that an effective vaccine delivery system would have stimulus-responsive degradation and release, biodegradability into excretable non-acidic degradation products, and the ability to incorporate various TLR-inducing adjuvants. The first vaccine delivery system is a cross-linked polyion complex micelle which efficiently encapsulates proteins, DNA, and RNA. The micelle-based delivery system consists of a block copolymer of poly(ethylene glycol) (PEG) and poly(L-lysine), cross-linked by dithiopyridyl side groups to provide transport stability and intracellular release. The second delivery system consists of solid biodegradable microparticles encapsulating proteins, nucleic acids, and hydrophobic compounds. The microparticles are composed of pH-sensitive polyketals, which are a new family of hydrophobic, linear polymers containing backbone ketal linkages. Polyketals are synthesized via a new polymerization method based on the acetal exchange reaction and degrade into non-acidic, excretable degradation products. In addition, the technique of hydrophobic ion pairing was utilized to enhance the encapsulation of ovalbumin, DNA, and RNA in polyketal microparticles via a single emulsion method. Using in vitro and in vivo immunological models, we demonstrated that the micelle- and polyketal-based vaccine delivery systems enhanced the cross-priming of cytotoxic T lymphocytes. The model vaccines were composed of ovalbumin antigen and various TLR-inducing adjuvants including CpG-DNA, monophosphoryl lipid A, and dsRNA. The results demonstrate that the cross-linked micelles and polyketal microparticles have considerable potential as delivery systems for protein-based vaccines. Advisors/Committee Members: Dr. Niren Murthy (Committee Chair), Dr. Carson Meredith (Committee Member), Dr. Julia Babensee (Committee Member), Dr. Mark Prausnitz (Committee Member), Dr. Ravi Bellamkonda (Committee Member).

Subjects/Keywords: Vaccine delivery; Drug delivery; Microencapsulation; Nanospheres; Microspheres; Nanoparticles; Polyacetal; PH-responsive; TLR ligands; Poly(I)-poly(C); Acid-degradable; Vaccines; Polymeric drug delivery systems; Biodegradable plastics

10 more images…

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Heffernan, M. J. (2008). Biodegradable polymeric delivery systems for protein subunit vaccines. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/24787

Chicago Manual of Style (16^th Edition):

Heffernan, Michael John. “Biodegradable polymeric delivery systems for protein subunit vaccines.” 2008. Doctoral Dissertation, Georgia Tech. Accessed January 16, 2021. http://hdl.handle.net/1853/24787.

MLA Handbook (7^th Edition):

Heffernan, Michael John. “Biodegradable polymeric delivery systems for protein subunit vaccines.” 2008. Web. 16 Jan 2021.

Vancouver:

Heffernan MJ. Biodegradable polymeric delivery systems for protein subunit vaccines. [Internet] [Doctoral dissertation]. Georgia Tech; 2008. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/1853/24787.

Council of Science Editors:

Heffernan MJ. Biodegradable polymeric delivery systems for protein subunit vaccines. [Doctoral Dissertation]. Georgia Tech; 2008. Available from: http://hdl.handle.net/1853/24787

2. Carpenedo, Richard L. Microsphere-mediated control of embryoid body microenvironments.

Degree: PhD, Biomedical Engineering, 2010, Georgia Tech

URL: http://hdl.handle.net/1853/33948

► Embryonic stem cells (ESCs) hold great promise for treatment of degenerative disorders such as Parkinson's and Alzheimer's disease, diabetes, and cardiovascular disease. The ability of… (more)

▼ Embryonic stem cells (ESCs) hold great promise for treatment of degenerative disorders such as Parkinson's and Alzheimer's disease, diabetes, and cardiovascular disease. The ability of ESCs to differentiate to all somatic cell types suggests that they may serve as a robust cell source for production of differentiated cells for regenerative medicine and other cell-based therapeutics. In order for ESCs to be used effectively in clinical settings, efficient and reproducible differentiation to targeted cell types must be demonstrated. The overall objective of this project was to engineer microenvironmental control over differentiating ESCs through the formation of embryoid bodies (EBs) uniform in size and shape, and through the incorporation of morphogen-containing polymer microspheres within the interior of EBs. The central hypothesis was that morphogen delivery through incorporated polymer microspheres within a uniform population of EBs will induce controlled and uniform differentiation of ESCs. Rotary suspension culture was developed in order to efficiently produce uniform EBs in high yield. Compared to static suspension culture, rotary suspension significantly improved the production of differentiating cells and EBs over the course of 7 days, while simultaneously improving the homogeneity of EB size and shape compared to both hanging drop and static EBs. The diffusive transport properties of EBs formed via rotary suspension were investigated using a fluorescent, cell permeable dye to model the movement of small morphogenic molecules within EBs. Confocal microscopy, cryosections and EB dissociation all demonstrated that the dye was not able to fully penetrate EB, and that the larger EBs at later time points (7 days) retarded dye movement to a greater extent than earlier EBs (days 2 and 4). Polymer microspheres capable of encapsulating morphogenic factors were incorporated into EBs in order to overcome the diffusional limitations of traditional soluble delivery. The size of microspheres, microsphere coating, microsphere to cell ratio, and rotary mixing speed were all observed to influence incorporation within EBs. The use of microsphere-mediated delivery within EBs to direct cell differentiation was examined. Microsphere-mediated delivery of retinoic acid (RA) induced formation of uniquely cystic spheroids with a visceral endoderm layer enveloping a pseudo-stratified columnar epithelium, and with spatial localization of transcriptional profiles similar to the early primitive streak stage of mouse development. Continued differentiation of RA MS EBs in defined media conditions was assessed. Gene expression demonstrated that regular serum enhanced endoderm induction, serum-free media supported ectoderm differentiation, while mesoderm was most prominent in untreated EBs in full serum. In summary, this work has realized a unique approach for stem cell differentiation through modification of the internal microenvironment of ESC spheroids. This novel inside-out method toward engineering EBs demonstrated that… Advisors/Committee Members: Dr. Todd McDevitt (Committee Chair), Dr. Andrew Lyon (Committee Member), Dr. Michelle LaPlaca (Committee Member), Dr. Niren Murthy (Committee Member), Dr. Ravi Bellamkonda (Committee Member), Dr. Steve Stice (Committee Member).

Subjects/Keywords: Microsphere; Retinoic acid; Embryoid body; Embryonic stem cell; Stem cells; Tretinoin; Degeneration (Pathology); Regenerative medicine

…Spain. While work has made up a significant portion of my time at Georgia Tech and in Atlanta… …thank you for all his support. Many friends from my first few years at Georgia Tech have…

11 more images…

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Carpenedo, R. L. (2010). Microsphere-mediated control of embryoid body microenvironments. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/33948

Chicago Manual of Style (16^th Edition):

Carpenedo, Richard L. “Microsphere-mediated control of embryoid body microenvironments.” 2010. Doctoral Dissertation, Georgia Tech. Accessed January 16, 2021. http://hdl.handle.net/1853/33948.

MLA Handbook (7^th Edition):

Carpenedo, Richard L. “Microsphere-mediated control of embryoid body microenvironments.” 2010. Web. 16 Jan 2021.

Vancouver:

Carpenedo RL. Microsphere-mediated control of embryoid body microenvironments. [Internet] [Doctoral dissertation]. Georgia Tech; 2010. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/1853/33948.

Council of Science Editors:

Carpenedo RL. Microsphere-mediated control of embryoid body microenvironments. [Doctoral Dissertation]. Georgia Tech; 2010. Available from: http://hdl.handle.net/1853/33948

Georgia Tech

3. Gotz, Marion Gabriele. Design, synthesis, and evaluation of irreversible peptidyl inhibitors for clan CA and clan CD cysteine proteases.

Degree: PhD, Chemistry and Biochemistry, 2004, Georgia Tech

URL: http://hdl.handle.net/1853/8072

► Cysteine proteases are a class of proteolytic enzymes, which are involved in a series of metabolic and catabolic processes, such as protein turnover, digestion, blood… (more)

▼ Cysteine proteases are a class of proteolytic enzymes, which are involved in a series of metabolic and catabolic processes, such as protein turnover, digestion, blood coagulation, apoptosis, fertilization and cell differentiation, and the immune response system. The development of novel potent and selective inhibitors for cysteine proteases has therefore gained increasing attention among medicinal chemists. In this thesis we have reported the design, synthesis, and evaluation of several peptidyl inhibitors for clan CA and clan CD cysteine proteases. We have continued the investigation of dipeptidyl vinyl sulfones as potent and selective inhibitors for dipeptidyl peptidase I (DPPI), a lysosomal cysteine protease, which is involved in the processing of intracellular proteases, such as granzymes. We have found that DPPI tolerates negatively charged amino acid residues in the P2 position with inhibition rates of 7,600 M-1s-1. Dipeptidyl vinyl sulfones with positively charged amino acid residues at the P1 position, however, do not inhibit DPPI at all. A second project focused on the epoxidation of the double bond of the vinyl sulfone moiety of the dipeptidyl vinyl sulfones. Instead of epoxidizing the double bond, we found that an isomerization had occurred. The newly formed compounds were determined to be allyl sulfones. We tested this new class of inhibitors with clan CA proteases and obtained inhibition rates of 560 M-1s-1 for Cbz-Leu-Phe-AS-Ph with calpain I. Two new classes of compounds for the clan CD protease S. mansoni legumain were designed, synthesized, and evaluated. Aza-peptidyl epoxides were found to be potent and selective inhibitors of S. mansoni legumain with IC50’s as low as 45 nM. Aza-peptide Michael acceptors were derived from the aza-peptide epoxide design and synthesized in an analogous fashion. The aza-peptide Michael acceptors inhibited S. mansoni legumain with even lower IC50’s, as low as 10 nM. However, the aza-peptide Michael acceptors react with thioalkylating agents contained in the buffer, such as DTT. The rates of degradation were determined spectroscopically, and half-lives of 3 to 20 minutes were measured. This observation gave us insights into the enzymatic mechanism and allowed us to determine the point of attack for the legumain active site cysteine thiol. Advisors/Committee Members: Dr. James C. Powers (Committee Chair), Dr. Donald Doyle, Dr. Nicholas Hud, Dr. Niren Murthy, and Dr. Suzanne Shuker (Committee Members).

Subjects/Keywords: Allyl sulfone; Aza-peptide; Biosynthesis; Cysteine protease; Cysteine proteinases; Irreversible inhibitors; Protease inhibitors; Sulphones; Vinyl sulfone

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gotz, M. G. (2004). Design, synthesis, and evaluation of irreversible peptidyl inhibitors for clan CA and clan CD cysteine proteases. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/8072

Chicago Manual of Style (16^th Edition):

Gotz, Marion Gabriele. “Design, synthesis, and evaluation of irreversible peptidyl inhibitors for clan CA and clan CD cysteine proteases.” 2004. Doctoral Dissertation, Georgia Tech. Accessed January 16, 2021. http://hdl.handle.net/1853/8072.

MLA Handbook (7^th Edition):

Gotz, Marion Gabriele. “Design, synthesis, and evaluation of irreversible peptidyl inhibitors for clan CA and clan CD cysteine proteases.” 2004. Web. 16 Jan 2021.

Vancouver:

Gotz MG. Design, synthesis, and evaluation of irreversible peptidyl inhibitors for clan CA and clan CD cysteine proteases. [Internet] [Doctoral dissertation]. Georgia Tech; 2004. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/1853/8072.

Council of Science Editors:

Gotz MG. Design, synthesis, and evaluation of irreversible peptidyl inhibitors for clan CA and clan CD cysteine proteases. [Doctoral Dissertation]. Georgia Tech; 2004. Available from: http://hdl.handle.net/1853/8072

Georgia Tech

4. Foster, Michael Scott. Design, synthesis, kinetic analysis, molecular modeling, and pharmacological evaluation of novel inhibitors of peptide amidation.

Degree: PhD, Chemistry and Biochemistry, 2008, Georgia Tech

URL: http://hdl.handle.net/1853/31816

► Novel, rationally-designed acrylate analogs of various known dipeptide substrates were found to be mechanism-based inactivators of the enzyme peptidylglycine alpha-amidating monooxygenase (PAM, EC 1.14.17.3). This… (more)

Subjects/Keywords: Molecular modeling; Stereochemistry; Molecules Models; Peptides; Chemical structure; Peptide hormones; Neuropeptides

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Foster, M. S. (2008). Design, synthesis, kinetic analysis, molecular modeling, and pharmacological evaluation of novel inhibitors of peptide amidation. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/31816

Chicago Manual of Style (16^th Edition):

Foster, Michael Scott. “Design, synthesis, kinetic analysis, molecular modeling, and pharmacological evaluation of novel inhibitors of peptide amidation.” 2008. Doctoral Dissertation, Georgia Tech. Accessed January 16, 2021. http://hdl.handle.net/1853/31816.

MLA Handbook (7^th Edition):

Foster, Michael Scott. “Design, synthesis, kinetic analysis, molecular modeling, and pharmacological evaluation of novel inhibitors of peptide amidation.” 2008. Web. 16 Jan 2021.

Vancouver:

Foster MS. Design, synthesis, kinetic analysis, molecular modeling, and pharmacological evaluation of novel inhibitors of peptide amidation. [Internet] [Doctoral dissertation]. Georgia Tech; 2008. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/1853/31816.

Council of Science Editors:

Foster MS. Design, synthesis, kinetic analysis, molecular modeling, and pharmacological evaluation of novel inhibitors of peptide amidation. [Doctoral Dissertation]. Georgia Tech; 2008. Available from: http://hdl.handle.net/1853/31816

Georgia Tech

5. Nitin, Nitin. Optical and MR Molecular Imaging Probes and Peptide-based Cellular Delivery for RNA Detection in Living Cells.

Degree: PhD, Biomedical Engineering, 2005, Georgia Tech

URL: http://hdl.handle.net/1853/7458

► Detection, imaging and quantification of gene expression in living cells can provide essential information on basic biological issues and disease processes. To establish this technology,… (more)

▼ Detection, imaging and quantification of gene expression in living cells can provide essential information on basic biological issues and disease processes. To establish this technology, we need to develop molecular probes and cellular delivery methods to detect specific RNAs in live cells with potential for in vivo applications. In this thesis work, the major focus is placed on the development of molecular beacons and biochemical approaches (peptides etc.) to deliver such probes to different cellular compartments. These approaches are then employed to study the expression and localization of mRNAs, co-localization of mRNAs with cytoplasmic organelles and cytoskeleton, and co-localization of RNA molecules in the nuclei of living cells. Further along this direction, we were interested in developing a better understanding of the functional states of mRNAs and the fluorescent signal observed in optical imaging experiments. To acheive this goal, we altered the translational process and studied its effect on the detection of mRNAs in living cells. The results of these studies indicate that the translational state of mRNAs favors the hybridization of molecular beacon with its target sequence. This study has also provided the evidence that molecular beacons are reversibly bound to target mRNAs and the repression of the translational process can prevent molecular beacon from binding to its target mRNA. Further, using these approaches in combination with FRAP based biophysical analysis, the dynamics of endogenous RNA in living cells are studied. These studies revealed the possible subcellular organization of RNA molecules and their dynamics in living cells. The results also demonstrated the role of cytoskeleton and ATP in the mobility of specific mRNAs in the cytoplasm. In addition to optical probes, studies have been carried out to develop an MRI contrast agent using iron-oxide nanoparticles for deep tissue molecular imaging. Specifically, we have functionalized magnetic nanoparticles that are water-soluble, mono-dispersed, biocompatible, and easily adaptable for multifunctional bioconjugation of probes and ligands. We have successfully delivered magnetic nanoparticle bioconjugates into live cells and demonstrated their effect on relaxivity. We have further studied the role of coating thickness for optimization of contrast and further enhance the fundamental understanding of contrast mechanisms. Advisors/Committee Members: Dr Gang Bao (Committee Chair), Dr Al Merrill (Committee Member), Dr Nicholas Hud (Committee Member), Dr Niren Murthy (Committee Member), Dr X. Hu (Committee Member).

Subjects/Keywords: Magnetic nanoparticles; RNA; MRI; Optical; Molecular beacons; Molecular imaging; RNA Detection; Nanoparticles Magnetic properties; Molecular spectroscopy; Molecular probes; Magnetic resonance imaging; Diagnostic imaging

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Nitin, N. (2005). Optical and MR Molecular Imaging Probes and Peptide-based Cellular Delivery for RNA Detection in Living Cells. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/7458

Chicago Manual of Style (16^th Edition):

Nitin, Nitin. “Optical and MR Molecular Imaging Probes and Peptide-based Cellular Delivery for RNA Detection in Living Cells.” 2005. Doctoral Dissertation, Georgia Tech. Accessed January 16, 2021. http://hdl.handle.net/1853/7458.

MLA Handbook (7^th Edition):

Nitin, Nitin. “Optical and MR Molecular Imaging Probes and Peptide-based Cellular Delivery for RNA Detection in Living Cells.” 2005. Web. 16 Jan 2021.

Vancouver:

Nitin N. Optical and MR Molecular Imaging Probes and Peptide-based Cellular Delivery for RNA Detection in Living Cells. [Internet] [Doctoral dissertation]. Georgia Tech; 2005. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/1853/7458.

Council of Science Editors:

Nitin N. Optical and MR Molecular Imaging Probes and Peptide-based Cellular Delivery for RNA Detection in Living Cells. [Doctoral Dissertation]. Georgia Tech; 2005. Available from: http://hdl.handle.net/1853/7458

Georgia Tech

6. Gill, Harvinder Singh. Coated microneedles and microdermabrasion for transdermal delivery.

Degree: PhD, Bioengineering, 2007, Georgia Tech

URL: http://hdl.handle.net/1853/24711

► The major hurdle in the development of transdermal route as a versatile drug delivery method is the formidable transport barrier provided by the stratum corneum.… (more)

▼ The major hurdle in the development of transdermal route as a versatile drug delivery method is the formidable transport barrier provided by the stratum corneum. Despite decades of research to overcome the stratum corneum barrier, limited success has been achieved. The objectives of this research were to develop and characterize two different strategies to overcome the stratum corneum barrier for transdermal delivery of biopharmaceuticals and vaccines. In the first strategy, coated microneedles (sharp-tipped, micron-sized structures) were developed to enable delivery of drugs directly into the skin by bypassing the stratum corneum barrier. In the second strategy, instead of bypassing the barrier, microdermabrasion was used to selectively abrade stratum corneum with sharp microparticles for topical drug application. Coated microneedles For developing painless microneedles, the first detailed study was performed to characterize the effect of microneedle geometry on pain caused by microneedle insertions in human volunteers. This study demonstrated that microneedles are significantly less painful than a 26-gage hypodermic needle and that decreasing microneedle length and numbers reduces pain. Next, the first in-depth study of microneedle coating methods and formulations was performed to (i) develop a novel micron-scale dip-coating process, (ii) test the breadth of compounds that can be coated onto microneedles, and (iii) develop a rational basis to design novel coating formulations based on the physics of dip-coating. Finally, a plasmid DNA-vaccine was coated onto microneedles to immunize mice, to provide the first evidence that microneedle-based skin immunization can generate a robust in vivo antigen-specific cytotoxic-T-lymphocyte response using similar, or lower, DNA doses on microneedles as when using the gene gun or intramuscular injection. Microdermabrasion We demonstrated for the first time that microdermabrasion in monkeys and humans can selectively, yet completely remove the stratum corneum layer. Using a mobile mode of microdermabrasion, an increase in the number of treatment passes led to greater tissue removal. Furthermore, topical application of Modified Vaccinia Ankara virus after microdermabrasion induced virus-specific antibodies in monkeys. In conclusion, both coated microneedles and microdermabrasion were developed to enable delivery of biomolecules into the skin, indicating their potential for transdermal delivery of a wide range of biopharmaceuticals and vaccines. Advisors/Committee Members: Dr. Mark R. Prausnitz (Committee Chair), Dr. Mark Feinberg (Committee Co-Chair), Dr. Mark Allen (Committee Member), Dr. Niren Murthy (Committee Member), Dr. Peter Hesketh (Committee Member), Dr. Robert Swerlick (Committee Member).

Subjects/Keywords: Microneedle coatings; Protein delivery; Protein coatings; Hepatitis C virus; Dip coating; Removal of stratum corneum; Microdermabrasion; DNA delivery; Vaccine delivery; Coating formulation; Microfabricated microneedles; Pocketed microneedles; Stainless steel microneedles; Transdermal medication; Drug delivery devices; Skin absorption; Dermabrasion

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gill, H. S. (2007). Coated microneedles and microdermabrasion for transdermal delivery. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/24711

Chicago Manual of Style (16^th Edition):

Gill, Harvinder Singh. “Coated microneedles and microdermabrasion for transdermal delivery.” 2007. Doctoral Dissertation, Georgia Tech. Accessed January 16, 2021. http://hdl.handle.net/1853/24711.

MLA Handbook (7^th Edition):

Gill, Harvinder Singh. “Coated microneedles and microdermabrasion for transdermal delivery.” 2007. Web. 16 Jan 2021.

Vancouver:

Gill HS. Coated microneedles and microdermabrasion for transdermal delivery. [Internet] [Doctoral dissertation]. Georgia Tech; 2007. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/1853/24711.

Council of Science Editors:

Gill HS. Coated microneedles and microdermabrasion for transdermal delivery. [Doctoral Dissertation]. Georgia Tech; 2007. Available from: http://hdl.handle.net/1853/24711

		in
And / Or
		in
And / Or
		in
And / Or
		in

Open Access Theses and Dissertations