Thesis (M.Sc.Eng.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Nanoparticle-based drug delivery has been explored to circumvent the often-toxic chemotherapy treatments used today by providing a more efficient and specific delivery to diseased tissues. Recently we have developed polymeric pH-responsive expansile nanoparticles (eNPs) for intracellular delivery of paclitaxel (Pax) as an improvement upon the traditional methods of delivery of Pax with using Cremophor/ethanol. As eNPs are internalized by the cell, the hydrophobic protecting groups found on side chains along the polymer backbone are hydrolyzed, leaving behind hydrophilic moieties that cause the eNPs to slowly swell with water. In this manner, the encapsulation and controlled release of a hydrophobic drug can be achieved. By altering the surface characteristics of the eNPs, one can change the behavior of the delivery vehicle as well as the biological response. To explore this approach, two surfactant strategies were employed. Specifically, the original sodium dodecyl sulfate (SDS) surfactant has been substituted with PEGylated surfactants (either lipids or poloxamer) to improve circulation and in vivo stability. In addition, these surfactants were functionalized to target the folate receptor (FR), which is overexpressed in several cancers, in order to increase cancer cell-specific localization and uptake. The resulting eNPs retained their swelling characteristics while demonstrating improved cellular uptake in folate receptor-expressing KB and MDA-MB-231 carcinoma cells with no change in uptake in A549 cells, which do not express the folate receptor. / 2031-01-01

Mechanically-activated delivery systems harness existing physiological and/or externally-applied forces to provide spatiotemporal control over the release of active agents. The presence and necessity of these forces in the human body and in the increasing use of mechanically-driven medical devices (e.g., stents, balloon catheters, gastric bands, tissue expanders) can serve as functional dynamic triggers. Therefore, this dissertation investigates the use of applied tensile strain and cyclic loading to control release of entrapped agents, and further translates the concept towards clinical applications by integrating the system with commercial medical devices that provide precise forces to trigger release. As an initial proof-of-concept, mechanoresponsive composites, consisting of highly-textured superhydrophobic barrier coatings over a hydrophilic substrate, are fabricated. The release of entrapped agents, controlled by the magnitude of applied strain, results in a graded response due to water infiltration through propagating patterned cracks in the coating. The strain-dependent delivery of anticancer agents with in vitro efficacy as well as the ex vivo delivery to esophageal tissue with an integrated stent system are demonstrated. Release is further modulated by barrier coating properties. Thicker coatings afford slower release rates with preserved in vitro activity for both a chemotherapeutic and an enzyme. Localizing coating crack patterns based on different geometric stress concentration factors further controls the selective sequential release of multiple agents. Finally, the development of a reversible mechanoresponsive system is investigated to provide cycle-mediated pulsatile release. Optimization of mechanical parameters results in delivery of multiple doses. To translate this concept towards the clinic, the system is integrated with commercial balloon catheters to provide multidose delivery of small molecules to ex vivo vessels. Using the inherent inflation and deflation of the catheter to trigger release, the system enhances existing capabilities to treat cardiovascular and peripheral artery diseases. In summary, the development of mechanoresponsive systems that respond to tensile strain and cycle number are described for the delivery of a wide-range of active agents (hydrophilic and hydrophobic small molecules as well as an enzyme), and their integration with existing medical devices. Furthermore, the comprehensive range of specific kinetic profiles, including triggered release, pulsatile delivery, and the sequential delivery of multiple agents, showcases the capabilities and versatility of these dynamic mechanoresponsive systems to modulate release for the treatment of various clinical diseases. / 2019-02-20T00:00:00Z

abstract: Mesoporous materials that possess large surface area, tunable pore size, and ordered structures are attractive features for many applications such as adsorption, protein separation, enzyme encapsulation and drug delivery as these materials can be tailored to host different guest molecules. Films provide a model system to understand how the pore orientation impacts the potential for loading and release of selectively sized molecules. This research work aims to develop structure-property relationships to understand how pore size, geometry, and surface hydrophobicity influence the loading and release of drug molecules. In this study, the pore size is systematically varied by incorporating pore-swelling agent of polystyrene oligomers (hPS) to soft templated mesoporous carbon films fabricated by cooperative assembly of poly(styrene-block-ethylene oxide) (SEO) with phenolic resin. To examine the impact of morphology, different compositions of amphiphilic triblock copolymer templates, poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (PEO-PPO-PEO), are used to form two-dimensional hexagonal and cubic mesostructures. Lastly, the carbonization temperature provides a handle to tune the hydrophobicity of the film. These mesoporous films are then utilized to understand the uptake and release of a model drug Mitoxantrone dihydrochloride from nanostructured materials. The largest pore size (6nm) mesoporous carbon based on SEO exhibits the largest uptake (3.5μg/cm2); this is attributed to presence of larger internal volume compared to the other two films. In terms of release, a controlled response is observed for all films with the highest release for the 2nm cubic film (1.45 μg/cm2) after 15 days, but this is only 56 % of the drug loaded. Additionally, the surface hydrophobicity impacts the fraction of drug release with a decrease from 78% to 43%, as the films become more hydrophobic when carbonized at higher temperatures. This work provides a model system to understand how pore morphology, size and chemistry influence the drug loading and release for potential implant applications. / Dissertation/Thesis / M.S. Chemical Engineering 2011

PURPOSE. To determine the intravitreal pharmacokinetic properties and to study the systemic biodistribution characteristics of 1-124-labeled bevacizumab, ranibizumab, and aflibercept with positron emission tomography-computed tomography (PET/CT) imaging in a nonhuman primate model. METHODS. Three groups with four owl monkeys per group underwent intravitreal injection with 1.25 mg/0.05 mL 1-124 bevacizumab, 0.5 mg/0.05 mL 1-124 ranibizumab, or 2.0 mg/0.05 mL 1-124 aflibercept in the right eye of each subject. All subjects were imaged using PET/CT on days 0, 1, 2, 4, 8, 14, 21, 28, and 35. Serum blood draws were performed at hours 1, 2, 4, 8, 12 and days 1, 2, 4, 8, 14, 21, 28, and 35. Radioactivity emission measurements were used to determine the intravitreal half-lives of each agent and to study the differences of radioactivity uptake in nonocular organs. RESULTS. The intravitreal half-lives were 3.60 days for 1-124 bevacizumab, 2.73 days for 1-124 ranibizumab, and 2.44 days for 1-124 aflibercept. Serum levels were highest and most prolonged for bevacizumab as compared to both ranibizumab and aflibercept. All agents were primarily excreted through the renal and mononuclear phagocyte systems. However, bevacizumab was also found in significantly higher levels in the liver, heart, and distal femur bones. CONCLUSIONS. Among the three anti-VEGF agents used in clinical practice, bevacizumab demonstrated the longest intravitreal retention time and aflibercept the shortest. Significantly higher and prolonged levels of bevacizumab were found in the serum as well as in the heart, liver, and distal bones. These differences may be considered by clinicians when formulating treatment algorithms for intravitreal therapies with these agents.

Submitted by Luiz Felipe Barbosa (luiz.fbabreu2@ufpe.br) on 2015-04-17T14:27:33Z No. of bitstreams: 2 TESE Flávia Lucena.pdf: 1461854 bytes, checksum: c95dfad3364a7959e3f68649485b4dfb (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) / Made available in DSpace on 2015-04-17T14:27:33Z (GMT). No. of bitstreams: 2 TESE Flávia Lucena.pdf: 1461854 bytes, checksum: c95dfad3364a7959e3f68649485b4dfb (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Previous issue date: 2013 / Relatos na literatura vêm utilizando nanoparticulas com o objetivo de carrear drogas e diminuir seus efeitos colaterais. Dentro dessa perspectiva estão às redes coordenadas a metais orgânicos ou MOFs. Este trabalho teve como objetivo realizar a incorporação de um fármaco antitumoral em uma rede de coordenação, visando melhorar sua biodisponibilidade para o organismo, bem como avaliar a toxicidade deste sistema in vitro e in vivo. Para isso foi realizado estudo teórico-computacional que nos permitiu a escolher o melhor fármaco a ser utilizado (5-fluorouracil) e a melhor rede de coordenação (Cu-BTC MOF), levando em consideração os tamanhos das moléculas dos mesmos em relação ao tamanho dos poros das MOFs Cu-BTC e MIL-53(Al). Os resultados das caracterizações químicas realizadas (UV-VIS, IV, CNHS, DRX, TGA/DTG e DSC) indicaram uma incorporação de 0,82 g de 5-fluorouracil para cada 1 g de MOF Cu-BTC após sete dias de agitação. A cultura celular in vitro demonstrou que o sistema 5-FU + Cu-BTC MOF apresentou atividade citotóxica significante quando comparado ao fármaco em solução. O teste de verificação do mecanismo de morte celular utilizando a citometria de fluxo indicou ser a apoptose o mecanismo de ação responsável para eliminação das células tumorais. O estudo de dissolução indicou uma liberação lenta e controlada de 39% do fármaco nos primeiros 30 minutos seguida da liberação de 82% do fármaco em 48 horas. Alterações histológicas só foram evidenciadas quando utilizada a dose de 750mg/kg sendo esta, a dose letal (DL50) encontrada. O teste da peritonite, verificação dos níveis de citocinas pro-inflamatórias e produção de óxido demonstraram que o sistema 5-FU + Cu-BTC MOF reduziu o número de leucócitos, os níveis de citocinas pró-inflamatórias e óxido nítrico, indicando que o sistema apresentou também atividade antiinflamatória para os testes realizados. Os resultados indicaram ser o sistema 5-FU+Cu-BTC MOF um excelente carreador de fármaco, com indicação de atividade anti-inflamatória, excelente atividade citotóxica via mecanismo de apoptose e liberação lenta e gradual do fármaco, o que possibilitou a diminuição na toxicidade do mesmo acompanhado de uma significante melhora terapêutica.

Made available in DSpace on 2018-06-27T18:56:02Z (GMT). No. of bitstreams: 3 Jacieli Evangelho de Figueiredo.pdf: 2905042 bytes, checksum: 577b7716deef90f233a689cb2e861976 (MD5) Jacieli Evangelho de Figueiredo.pdf.txt: 123610 bytes, checksum: 2d86310cb91039f2eb8ce3e716d0a1c7 (MD5) Jacieli Evangelho de Figueiredo.pdf.jpg: 3372 bytes, checksum: 5504b695397c5fd50208bde8ed91789f (MD5) Previous issue date: 2010-08-25 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Cyclodextrins, macrocyclic polymers, built up of units of D-()-α-glucopyranose (1-4). Have toroidal shape of truncated cone with a hydrophobic cavity in the form of donut in which various types of drugs may be included to form inclusion complexes. The cyclodextrin are three different types of structures that occur by enzymatic modification of six, seven or eight glucose units, called, respectively, α, β and γ-cyclodextrin. Recent studies show the possibility of using these substances in various biomedical applications as vehicles for delivering drugs and biological agents, and its goal of targeting drugs to carry the desired amount for the target and releasing it at a controlled rate. Additionally, by including the compounds can be protected against oxidation, degradation by light, heat losses and volatility, in addition, can prevent unpleasant tastes or odors. Considering possible biological applications of these compounds, this study aims to evaluate, through computer simulations based on first-principles Density Functional Theory (DFT), the interaction of α and β - cyclodextrin with drugs: aspirin, nimesulide and vitamin E. We will show that the α and β - cyclodextrins can include these compounds maintain their structures unchanged, with binding energies between -1.17 and -0.06 eV. Analyzing the structural and electronic properties, we can see what settings are most conducive to the carrying of drugs and thereby further demonstrated the potential of cyclodextrins for pharmaceutical and related applications. / As ciclodextrinas são polímeros macrocíclicos construídas por unidades de D-(+)-glucopiranose α-(1-4). Têm forma toroidal de cone truncado, com uma cavidade hidrofóbica na forma de donut, no qual vários tipos de fármacos podem ser incluídos, formando complexos de inclusão. A ciclodextrina apresenta três diferentes tipos de estruturas que ocorrem por modificação enzimática de seis, sete ou oito unidades de glicose, denominadas, respectivamente, α, β e γ-ciclodextrina. Estudos recentes demonstram a possibilidade de utilizar essas substâncias em diversas aplicações biomédicas, como veículos para entrega de fármacos e agentes biológicos, tendo como propósito o direcionamento da droga para transportar a quantidade desejada para o alvo e disponibilizá-la a uma taxa controlada. Adicionalmente, através da inclusão, os compostos podem ficar protegidos contra oxidação, degradação pela luz, calor, perdas por volatilidade e, além disso, podem previnir gostos ou odores desagradáveis. Considerando possíveis aplicações biológicas desses compostos, esse trabalho tem o objetivo de avaliar, através de simulações computacionais de primeiros princípios, baseadas na Teoria do Funcional da Densidade (DFT), a interação de α e β - ciclodextrinas com os fármacos: ácido acetilsalicílico, nimesulida e vitamina E. Mostraremos que a α e β - ciclodextrinas podem incluir estes compostos mantendo suas estruturas inalteradas, com energias de ligação entre -1,17 e -0,06 eV. Analisando as propriedades estruturais e eletrônicas, se pode observar quais configurações são mais propícias para o carreamento de fármacos e, através disso, demonstramos o potencial das ciclodextrinas para aplicações farmacêuticas e relacionadas.

The treatment of epidermal wounds, particularly chronic wounds, is one of the most ubiquitous medical challenges and has imposed a considerable financial burden on the global health care system. Several factors in epidermal wounds lead to severe medical conditions among which infection comprises a large number of mortalities. To tackle this issue, great efforts have been made in the last decades to incorporate antimicrobial agents into wound dressings in order to inhibit microorganism colonization. Additionally, various wound monitoring systems have been developed to detect and track infections using different indicators such as bacterial by-products. However, the integration of these infection sensors with wound dressings – most of which have benefited from electrochemical detectors – has been a major bottleneck due to the electrode failure in the wound environment and the need for electrical power supply. Other approaches have focused on the development of point-of-care devices that simplify the detection of infection. This study aims to address the aforementioned challenge by developing a multifunctional hydrogel-based wound dressing – made of alginate 1.5% (w/v) – for on-site infection monitoring via colourimetric and image processing methods. Taking advantage of wound acidity as an indicator of bacterial infection, the developed wound dressing was composed of an array of pH sensors, fabricated by 3-dimensional (3D) bioprinting. Brilliant Yellow and cabbage juice as two pH-responsive dyes were immobilized in the pH sensors to facilitate a wireless wound monitoring. In this system, Brilliant Yellow afforded a higher accuracy in image processing while cabbage juice provided a better visual observation of the wound condition. The functionality of the developed dressing in detecting bacterial infection was evaluated via an ex-vivo test on pig skin samples, infected by Pseudomonas aeruginosa, and the presence of bacteria was detected within 30 minutes after the placement of the dressings on the skin samples. Moreover, the inclusion of gentamicin-loaded components into the wound dressing facilitated the inhibition of bacterial growth, which was evaluated in vitro on the same strain of bacteria. In this experiment, 2 mg/ml of gentamicin in the hydrogel led to the eradication of P. aeruginosa. This incorporation of antibiotic delivery along with the simple colourimetric infection detection holds a great promise for managing acute and chronic wounds by inhibition of bacterial growth and monitoring infection in real-time without a need for dressing removal. / Graduate / 2018-08-16

Consumers of topical formulations apply a wide spectrum of preparations, both cosmetic and dermatological, to their healthy or diseased skin. These formulations range in physicochemical nature from solid through semisolid to liquid. Pharmaceutical foams are pressurized dosage forms containing one or more active ingredients that, upon valve actuation, emit a fine dispersion of liquid and/or solid materials in a gaseous medium. Foam formulations are generally easier to apply, are less dense, and spread more easily than other topical dosage forms. Foams may be formulated in various ways to provide emollient or drying functions to the skin, depending on the formulation constituents. Therefore, this delivery technology should be a useful addition to the spectrum of formulations available for topical use; however, as yet, only a few are commercially available. Probably the most convincing argument for the use of foams is ease of use by the patient, and consumer acceptance. Most foam dosage forms used in dermatology to date have incorporated corticosteroids, although some products have also been used to deliver antiseptics, antifungal agents, anti-inflammatory agents, local anesthetic agents, skin emollients, and protectants. Although there is no clinical evidence that foam formulations are currently superior to other conventional delivery vehicles, these formulations have a clear application advantage and with continued developments in the science of supersaturation technology, it seems certain that foam delivery systems will retain their place in the dermatological and cosmetic armamentarium.

Two specific drug-delivery applications were sought in this work using polyamidoamine (PAMAM) dendrimers. One drug-delivery system used a novel dendrimer hydrogel (DH) for sustained delivery of anti-glaucoma drugs. In this work, PAMAM G3.0 dendrimers were covalently bonded with poly(ethylene glycol) (PEG­12000) molecules which were subsequently acrylated, resulting in photocurable DH conjugates. For pharmacological studies, DH were loaded with a solution of intraocular pressure lowering drugs, brimonidine and timolol maleate, and were characterized for in vitro release and ex vivo transport and uptake. DH formulations were shown to increase the loading of drug molecules, increase transcorneal drug delivery, and exhibit sustained-delivery of drug molecules. A second drug-delivery system, utilizing cell-surface engineering, intended to increase the targeting ability of highly toxic anti-cancer drugs to curtail systemic effects. In particular, Qdots and 5-(aminoacetamido) fluorescein-labeled polyamidoamine dendrimer G4.5, both of which were coated with amine-derivatized polyethylene glycol, were immobilized to the sodium periodate-treated surface of RAW264.7 macrophages through a transient Schiff base linkage. Further, a reducing agent sodium cyanoborohydride was applied to reduce Schiff bases to stable secondary amine linkages. The distribution of nanoparticles on the cell surface was observed by fluorescence microscopy and was found to be dependent on the stability of the linkages tethering nanoparticles to the cell surface.

Ph.D. (Chemistry) / Alchornea species (Euphorbiaceae) have been used in traditional medicine across Africa and are well known to display broad spectrum biological activities including anti‐microbial, antiinflammatory and anti‐cancer activities. This project is aimed at discovering bioactive compounds for anti‐microbial and anti‐cancer therapy from plants of the Alchornea species and developing suitable nanocarrier drug delivery systems (DDS) as drug or compound transporters using gold nanoparticles and natural polymers. The plant material (roots, stems and leaves) was collected in bulk from an uncultivated farmland of the Elounden Mount, in the Yaoundé central region of Cameroon. The extracts were prepared using solvents of varying polarity in order to extract a wide range of phytochemicals. The extracts of A. cordifolia, A. floribunda and A. laxiflora as well as those isolated compounds that were sufficiently pure, were screened for antibacterial activity against four Gram‐positive bacteria (Bacillus cereus, Enterococcus faecalis, Staphylococcus aureus and S. saprophyticus) and four Gram‐negative bacteria (Escherichia coli, Klebsiella pneumonia, Moraxella catarrhalis and Proteus mirabilis), as well as antimycobacterial activity (Mycobacterium aurum and M. smegmatis). The anti‐cancer properties were similarly tested against SNO oesophageal cancer, breast cancer (MDA‐MB‐231 and MCF‐7), and leukemia HL‐60 cell lines. The antimicrobial activities were evaluated using the micro‐dilution assay while the anticancer activity was evaluated by means of cell viability (MTT assay, Alamar blue, trypan blue and an ATP assays). The isolation of compounds and synthesis of derivatives were performed by exhaustive chromatographic techniques and suitable organic reactions. The structures of the compounds were determined by means of spectroscopic methods (FT‐IR, MS, 1D and 2D NMR). Three compounds (AC3.1, AC2.4 and 3HB) were used to synthesize DDS and were characterized using UV‐Vis, FT‐IR, TEM, SEM, XRD, EDS, DLS and zeta potential.