Thesis (Ph.D.)--University of Wisconsin--Madison, 2006. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D. in Chemical Engineering)--Vanderbilt University, Dec. 2006. / Title from title screen. Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xvi, 218 p.; also includes graphics (some col.). Includes bibliographical references (p. 200-218). Available online via OhioLINK's ETD Center

Thesis (M. Sc. (Pharmacy))--Rhodes University, 2006.

Tierärztl. Hochsch., Diss., 2003--Hannover.

Thesis (Ph.D.)--University of Wisconsin--Madison, 2006 / Includes bibliographical references (p. 186-199). Also available on the Internet.

A targeted, stimuli-responsive, polymeric drug delivery vehicle has been developed to help alleviate the severe side-effects caused by narrow therapeutic window drugs. Doxorubicin, a commonly used chemotherapeutic agent has been conjugated to dextran by two different techniques. In the first method, doxorubicin and hepatocyte-targeting galactosamine were attached to dextran through amine bonds. Conjugation efficiency based on the amount loaded of each reactant varied from 1% to 50% for doxorubicin and from 2% to 20% for galactosamine, depending on various synthesis parameters. For the second conjugate, doxorubicin was attached to dextran through an acid-labile hydrazide bond. Fluorescence quenching indicated that all our conjugates can bind to DNA. The degree of binding was improved with increasing polymer molecular weight and substitution of doxorubicin, and also with hydrazide-bonded conjugate. In cell culture experiments, we have found that the uptake of conjugates was much lower than that of free doxorubicin. Lower uptake of conjugates decreased the toxicity of doxorubicin. Also, the uptake of non-galactosylated conjugate was lower than that of the galactosylated conjugate. Microscopy studies indicated that doxorubicin was localized almost exclusively at the nucleus, whereas the amine-bonded conjugates were present throughout the cell. Targeted amine-linked conjugates and hydrazide-bonded conjugates achieved greatly improved cytotoxicity. Following uptake, the doxorubicin was dissociated from the hydrazide conjugate in an endosomal compartment and diffused to the nucleus. The LC₅₀ values of non-targeted amine-linked, targeted amine-linked, and hydrazide-linked doxorubicin were 19.81 μg/mL, 7.33 μg/mL and 4.39 μg/mL, respectively. The amine-linked conjugates were also tested on a multidrug-resistant cell line; the LC₅₀ values of doxorubicin and the non-targeted amine-linked conjugate were 8.60 μg/mL and 36.02 μg/mL, respectively. / Singapore-MIT Alliance (SMA)

Ph.D.

Insulin, a relatively low molecular weight protein has been used for decades in the treatment of diabetes; it has well-defined properties and delivery requirements. Due to the current increase of diabetes in the world improved insulin delivery systems could significantly influence the treatment of diabetes and the quality of life of the affected people. The main objective of this work was to encapsulate insulin in polymer nanoparticles of Poly (DL-Lactic-Co-Glycolic Acid) (PLGA) and poly vinyl alcohol (PVA). Preliminary results of these functional therapeutic nanoparticles prepared with PVA and PLGA by using a double emulsion method (water/oil/water) were obtained in terms of encapsulation efficiency and effective insulin release from the nanoparticles. Assessing the bioactivity of insulin once encapsulated and released is not trivial, thus an indirect protein assay was developed to effectively and easily assess the activity of proteins going through these processes. Trypsin, a proteolitic enzyme was used as model protein to investigate the biological activity of encapsulated and released biomolecules. The activity of trypsin towards a synthetic substrate, DL-BAPNA was used to measure the enzyme kinetics and activity before encapsulation, while encapsulated and after the enzyme was released from the nanoparticles. Results show that the enzyme maintained substantial activity while encapsulated and after its release. It is anticipated that the biological activity after being released from the nanoparticles will remain biologically active, however, biological assays remain to be performed to corroborate this argument. In addition to release experiments with trypsin and insulin, other proteins were also studied. In all cases the release form the nanoparticles at 37 °C exhibited a three stage release process, The release process will be modeled according to developed mathematical models that consider initial burst of molecules, degradation of polymer and diffusion of molecules from the nanoparticles.

Thesis (MEng)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Bacterial colonisation and biofilm formation onto total hip replacement femoral stems remain a serious complication detrimental to the success of total hip arthroplasty. Current treatment procedures are accompanied by a heavy financial burden and morbidity for the patient while failing to guarantee a successful outcome with no reinfection. In fact, infection rates after revision surgeries are typically higher than those for primary hip arthroplasties. This study investigates conceptual drug delivery channels to be incorporated within cementless femoral stems by applying additive manufacturing as enabler technology. Drug delivery from these features is aimed at both prophylaxis and treatment of infection, with the latter emphasising the concept of creating a reinforceable antimicrobial depot inside the implant. The novelty lies in facilitating the administration of multiple drug dosages from within the implant instead of the once-off implant-based release strategies currently employed. Samples containing internal channels were designed based on analogies to drug delivery studies reporting on the commercial antibiotic loaded bone cement, Palacos R+G loaded with gentamicin. These samples were manufactured by LaserCUSING® from Ti-6Al-4V ELI powder. For prophylactic proof of concept, testing the channels were filled with Palacos R+G and challenged with two clinical isolates of Staphylococcus aureus in a bacterial growth inhibition study. Gentamicin-susceptible S.aureus Xen 36 was prevented from colonising for a minimum of 72 hours, whereas gentamicin resistant S.aureus Xen 31 reached the material within 24 h, signifying the importance of drug selection according to pathogen. Hence, a solution of vancomycin in phosphate buffered saline pH 7.4 was used during in vitro reservoir release testing. Three dosage injections were made into each of six samples during a cumulative incubation period of 100 h. A biocompatible 5,000 Da molecular weight cut off polyethersulfone nanoporous membrane was employed as release rate-controlling device. Released vancomycin was quantified with reversed phase high performance liquid chromatography. The resulting release profile was characterised by means of the Korsmeyer-and-Peppas model for diffusion based drug delivery. Constraint diffusion was identified as the mechanism controlling release, implying interplay between Fickian diffusion and polymer relaxation for effecting vancomycin release from within the reservoir. The concept created in this study provides a basis towards the development of full scale intelligent implants with multiple dose in situ drug delivery capabilities. Implants incorporating this concept could aid in the perpetual struggle against infection by providing a new strategy for delivery of high level antibiotics directly to the site of infection. / AFRIKAANSE OPSOMMING: Kolonisering van bakterieë en die vorming van biofilms op totale heupvervanging femorale stamme bly ʼn ernstige komplikasie tot die sukses van ʼn totale heupvervanging. Huidige behandelingsprosedures gaan gepaard met ʼn swaar finansiële las en infeksies vir die pasiënt sonder versekering van ʼn suksesvolle uitkoms. Die voorkoms van infeksie is tipies hoër vir revisie prosedures as vir primêre heupvervangings. Hierdie studie ondersoek konseptuele dwelmvoorsieningskanale wat in sementvrye femorale stamme geïnkorporeer kan word deur middel van toevoegingsvervaardiging as bemagtigingstegnologie. Dwelmtoediening deur hierdie strukture is gemik op beide voorkoming en behandeling van infeksie met ʼn klem op die konsep van ʼn herlaaibare antimikrobiese depot in die implantaat. Die nuwigheid lê in die fasilitasie van toediening van veelvuldige dwelm dosisse vanaf binne die implantaat in plaas van die huidige eenmalige implantaatgebaseerde toedieningstrategieë. Die ontwerp van monsters wat interne kanale bevat is baseer op vergelykings met literatuur op kommersiële beensement, Palacos R+G, wat met gentamisien belaai is. Hierdie monsters is vervaardig met LaserCUSING® van Ti-6Al-4V ELI poeier. Kanale is gevul met Palacos R+G en uitgedaag met twee kliniese isolate van Staphylococcus aureus in ʼn bakteriële groei inhibisie studie. Gentamisien-sensitiewe S.aureus Xen 36 is verhoed tot kolonisasie vir ʼn minimum van 72 uur, terwyl gentamisien-weerstandige S.aureus Xen 31 die materiaal binne 24 uur bereik het. Vervolgens was ‘n oplossing van vankomisien in fosfaatbuffer soutoplossing pH 7.4 gebruik tydens in vitro vrystellingstoetse. Drie dosisse inspuitings is in elk van ses monsters oor ʼn inkubasietydperk van 100 uur toegedien. ʼn Biokompatibiele 5,000 Da molekulêre massa afsnypunt polietersulfoon nanoporeuse membraan is as vrystellingskoers regulerende apparaat gebruik. Vrygestelde vankomisien is gekwantifiseer met omgekeerde fase hoë verrigting vloeistof-chromatografie. Die vrystellingsprofiel is gekarakteriseer met die Korsmeyer-en-Peppas model vir diffusie gebaseerde dwelmtoediening. Beperkte diffusie is geïdentifiseer as die meganisme wat vrystelling beheer. Dit impliseer ʼn tussenspel in Fickiaanse diffusie en polimeer verslapping vir die tot stand bring van vankomisien vrystelling vanaf binne die reservoir. Hierdie konsep van die studie verskaf ʼn basis vir die ontwikkeling van volskaalse intelligente implantate met ʼn veelvuldige in situ dwelmtoedienings vermoë. Implantate met hierdie konseptuele strukture kan steun gee aan die voortdurende stryd teen infeksie deur ʼn nuwe strategie daar te stel vir die toediening van hoë vlak antibiotika direk by die infeksie area.