Poly lactic-co-glycolic acid controlled delivery of Disulfiram to target liver cancer stem-like cells

Disulfiram (DS), an anti-alcoholism drug, shows very strong cytotoxicity in many cancer types. However its clinical application in cancer treatment is limited by the very short half-life in the bloodstream. In this study, we developed a poly lactic-co-glycolic acid (PLGA)-encapsulated DS protecting DS from the degradation in the bloodstream. The newly developed DS-PLGA was characterized. The DS-PLGA has very satisfactory encapsulation efficiency, drug-loading content and controlled release rate in vitro. PLGA encapsulation extended the half-life of DS from shorter than 2 minutes to 7 hours in serum. In combination with copper, DS-PLGA significantly inhibited the liver cancer stem cell population. CI-isobologram showed a remarkable synergistic cytotoxicity between DS-PLGA and 5-FU or Sorafenib. It also demonstrated very promising anticancer efficacy and antimetastatic effect in liver cancer mouse model. Both DS and PLGA are FDA approved products for clinical application. Our study may lead to repositioning of DS into liver cancer treatment.

Capillary siphons and their application in the fuel delivery system of direct methanol fuel cells

The objective of the work is to develop a fuel delivery system for potable direct methanol fuel cell. Currently, one of the most fundamental limitations of direct methanol fuel cells is that the fuel supplied to the anode of the DMFC must be a very dilute aqueous methanol solution (usually 0.5∼1.5 M). If a DMFC is filled with a dilute aqueous methanol solution, the fuel cell operation time per refuel would be very short, which would considerably diminish the advantage of a DMFC over a conventional battery. To overcome this difficulty, a complex fuel delivery system based on the modern micro system technology was proposed by the author. The proposed fuel delivery system would include micro-pumps, a methanol sensor, and a control unit. The fuel delivery system adds considerable costs to the fuel cell system and consume considerable amount of electricity from the fuel cell, which in turn significantly reduces the net power output of the fuel cell. As a result, the DMFC would have tremendous difficulty to compete with the conventional battery technology in terms of costs and power output. ^ This work presents a novel passive fuel delivery system for direct methanol fuel cells. In this particular system, a methanol fuel and an aqueous methanol solution are stored separately in two containers and a wick is disposed between the two containers in a siphon fashion, with the container of the aqueous methanol solution communicating with the anode of the DMFC. Methanol is siphoned from the methanol container to the aqueous solution container in-situ when the methanol in the aqueous methanol solution is consumed during the operation of the fuel cell. Through a proper selection of the wick and the containers, the methanol concentration near the anode of the DMFC could be maintained within a preferable range. ^

Integrated construction project delivery system in the U.S. public sector: An information modeling framework

Integrated project delivery (IPD) method has recently emerged as an alternative to traditional delivery methods. It has the potential to overcome inefficiencies of traditional delivery methods by enhancing collaboration among project participants. Information and communication technology (ICT) facilitates IPD by effective management, processing and communication of information within and among organizations. While the benefits of IPD, and the role of ICT in realizing them, have been generally acknowledged, the US public construction sector is very slow in adopting IPD. The reasons are - lack of experience and inadequate understanding of IPD in public owner as confirmed by the results of the questionnaire survey conducted under this research study. The public construction sector should be aware of the value of IPD and should know the essentials for effective implementation of IPD principles - especially, they should be cognizant of the opportunities offered by advancements in ICT to realize this.^ In order to address the need an IPD Readiness Assessment Model (IPD-RAM) was developed in this research study. The model was designed with a goal to determine IPD readiness of a public owner organization considering selected IPD principles, and ICT levels, at which project functions were carried out. Subsequent analysis led to identification of possible improvements in ICTs that have the potential to increase IPD readiness scores. Termed as the gap identification, this process was used to formulate improvement strategies. The model had been applied to six Florida International University (FIU) construction projects (case studies). The results showed that the IPD readiness of the organization was considerably low and several project functions can be improved by using higher and/or advanced level ICT tools and methods. Feedbacks from a focus group comprised of FIU officials and an independent group of experts had been received at various stages of this research and had been utilized during development and implementation of the model. Focus group input was also helpful for validation of the model and its results. It was hoped that the model developed would be useful to construction owner organizations in order to assess their IPD readiness and to identify appropriate ICT improvement strategies.^

Integrated Construction Project Delivery System in the U.S. Public Sector: An Information Modeling Framework

Integrated project delivery (IPD) method has recently emerged as an alternative to traditional delivery methods. It has the potential to overcome inefficiencies of traditional delivery methods by enhancing collaboration among project participants. Information and communication technology (ICT) facilitates IPD by effective management, processing and communication of information within and among organizations. While the benefits of IPD, and the role of ICT in realizing them, have been generally acknowledged, the US public construction sector is very slow in adopting IPD. The reasons are - lack of experience and inadequate understanding of IPD in public owner as confirmed by the results of the questionnaire survey conducted under this research study. The public construction sector should be aware of the value of IPD and should know the essentials for effective implementation of IPD principles - especially, they should be cognizant of the opportunities offered by advancements in ICT to realize this. In order to address the need an IPD Readiness Assessment Model (IPD-RAM) was developed in this research study. The model was designed with a goal to determine IPD readiness of a public owner organization considering selected IPD principles, and ICT levels, at which project functions were carried out. Subsequent analysis led to identification of possible improvements in ICTs that have the potential to increase IPD readiness scores. Termed as the gap identification, this process was used to formulate improvement strategies. The model had been applied to six Florida International University (FIU) construction projects (case studies). The results showed that the IPD readiness of the organization was considerably low and several project functions can be improved by using higher and/or advanced level ICT tools and methods. Feedbacks from a focus group comprised of FIU officials and an independent group of experts had been received at various stages of this research and had been utilized during development and implementation of the model. Focus group input was also helpful for validation of the model and its results. It was hoped that the model developed would be useful to construction owner organizations in order to assess their IPD readiness and to identify appropriate ICT improvement strategies.

Improving the Utilization of Front-Line Service Delivery System Personnel

There are two types of work typically performed in services which differ in the degree of control management has over when the work must be done. Serving customers, an activity that can occur only when customers are in the system is, by its nature, uncontrollable work. In contrast, the execution of controllable work does not require the presence of customers, and is work over which management has some degree of temporal control. This paper presents two integer programming models for optimally scheduling controllable work simultaneously with shifts. One model explicitly defines variables for the times at which controllable work may be started, while the other uses implicit modeling to reduce the number of variables. In an initial experiment of 864 test problems, the latter model yielded optimal solutions in approximately 81 percent of the time required by the former model. To evaluate the impact on customer service of having front-line employees perform controllable work, a second experiment was conducted simulating 5,832 service delivery systems. The results show that controllable work offers a useful means of improving labor utilization. Perhaps more important, it was found that having front-line employees perform controllable work did not degrade the desired level of customer service.

Dual stimulation of antigen presenting cells using carbon nanotube-based vaccine delivery system for cancer immunotherapy

Although anti−cancer immuno−based combinatorial therapeutic approaches have shown promising results, efficient tumour eradication demands further intensification of anti−tumour immune response. With the emerging field of nanovaccinology, multi−walled carbon nanotubes (MWNTs) have manifested prominent potentials as tumour antigen nanocarriers. Nevertheless, the utilization of MWNTs in co−delivering antigen along with different types of immunoadjuvants to antigen presenting cells (APCs) has not been investigated yet. We hypothesized that harnessing MWNT for concurrent delivery of cytosine−phosphate−guanine oligodeoxynucleotide (CpG) and anti-CD40 Ig (αCD40), as immunoadjuvants, along with the model antigen ovalbumin (OVA) could potentiate immune response induced against OVA−expressing tumour cells. We initially investigated the effective method to co−deliver OVA and CpG using MWNT to the APC. Covalent conjugation of OVA and CpG prior to loading onto MWNTs markedly augmented the CpG−mediated adjuvanticity, as demonstrated by the significantly increased OVA−specific T cell responses in vitro and in C57BL/6 mice. αCD40 was then included as a second immunoadjuvant to further intensify the immune response. Immune response elicited in vitro and in vivo by OVA, CpG and αCD40 was significantly potentiated by their co−incorporation onto the MWNTs. Furthermore, MWNT remarkably improved the ability of co−loaded OVA, CpG and αCD40 in inhibiting the growth of OVA−expressing B16F10 melanoma cells in subcutaneous or lung pseudo−metastatic tumour models. Therefore, this study suggests that the utilization of MWNTs for the co−delivery of tumour−derived antigen, CpG and αCD40 could be a competent approach for efficient tumours eradication.

Evaluation Of An Extended Duct Air Delivery System For Spaces Conditioned By Rooftop Units

Traditional air delivery to high-bay buildings involves ceiling level supply and return ducts that create an almost-uniform temperature in the space. Problems with this system include potential recirculation of supply air and higher-than-necessary return air temperatures. A new air delivery strategy was investigated that involves changing the height of conventional supply and return ducts to have control over thermal stratification in the space. A full-scale experiment using ten vertical temperature profiles was conducted in a manufacturing facility over one year. The experimental data was utilized to validated CFD and EnergyPlus models. CFD simulation results show that supplying air directly to the occupied zone increases stratification while holding thermal comfort constant during the cooling operation. The building energy simulation identified how return air temperature offset, set point offset, and stratification influence the building’s energy consumption. A utility bill analysis for cooling shows 28.8% HVAC energy savings while the building energy simulation shows 19.3 – 37.4% HVAC energy savings.

Methotrexate nanoparticle delivery system for treatment of inflammatory bowel disease in pediatric patients

Purpose: To evaluate the efficacy and safety of methotrexate (MTX) nanoparticles in pediatric patients with inflammatory bowel disease (IBD). Methods: In this randomized, open-label clinical study, 28 pediatric patients with moderate to severe IBD were randomly assigned to treatment (MTX nanoparticles,15 mg/week) or control (azathioprine, AZA, 2 mg/kg/day) group. Nanoparticles were synthesized by adding calcium chloride to sodium alginate solution containing MTX, and was further treated with poly-L-lysine aqueous solution. The nanoparticles were evaluated for particle size, zeta potential and drug encapsulation efficacy. Erythrocyte sedimentation rate, C-reactive protein, aspartate aminotransferase, alanine transaminase, and disease activity scores were used to assess IBD remission. Results: Nanoparticle size, zeta potential and encapsulation efficacy were 164.4 ± 6.9 nm, -32.6 ± 3.7 mV, and 97.8 ± 4.2 %, respectively. After 12 weeks of therapy, the mean Pediatric Crohn\'s Disease Activity Index (PCDAI) scores for control and treatment groups were 22.3 ± 2.14 and 16.8 ± 1.87, respectively, while mean Pediatric Ulcerative Colitis Activity (PUCAI) Index scores were 24.3 ± 1.47 and 18.7 ± 1.92, respectively. Eight patients in the treatment and five patients in the control group achieved remission. Biochemical parameters varied significantly between the groups. Conclusion: MTX nanoparticles are safe and more effective than standard first-line IBD therapy. However, further studies are required to determine the suitability of the formulation for therapeutic use.

Development of a polyplexes-based miRNA delivery system in a 3D-bioplotted osteoarthritis cellular model.

L'osteoartrite (OA) è una patologia infiammatorio/degenerativa ossea per la quale non sono disponibili terapie causali efficaci ma solo approcci palliativi per la riduzione del dolore cronico. E’ quindi giustificato un investimento per individuare nuove strategie di trattamento. In quest’ottica, lo scopo di questa tesi è stato quello di indagare l’efficacia di polyplexi a base di chitosano o di PEI-g-PEG in un modello cellulare 3D in vitro basato su un hydrogel di Gellan Gum Metacrilato (GGMA) con a bordo condrociti in condizioni simulate di OA. Inizialmente sono state studiate la dimensione e il potenziale-Z di un pool di formulazioni di poliplexi. Quindi se ne è valutata la citocompatibilità utilizzando cellule staminali mesenchimali immortalizzate Y201. Infine, una miscela di GGMA, cellule e polyplexi è stata utilizzata per la stampa 3D di campioni che sono stati coltivati fino a 14 giorni. La condizione OA è stata simulata trattando le cellule con una miscela di citochine implicate nello sviluppo della malattia. Tutte le formulazioni a base di chitosano e due basate su PEI-g-PEG si sono dimostrate citocompatibili e sono hanno veicolato i miRNA nelle cellule (come mostrato dai risultati di analisi in fluorescenza). I risultati delle colorazioni H&E e AlcianBlue hanno confermato che il terreno condizionato ha ben ricreato le condizioni di OA. I polyplexi a base di chitosano e PEI-g-PEG hanno controbilanciato gli effetti delle citochine. Risultati incoraggianti, anche se da approfondire ulteriormente, provengono anche dall’analisi di espressione (RT-PCR) di cinque geni specifici della cartilagine. Concludendo, questo modello ha ben riprodotto le condizioni di OA in vitro; il chitosano ha mostrato di essere un adeguato veicolo per un trattamento a base di miRNA; il PEI-g-PEG si propone come un'alternativa più economica e ragionevolmente affidabile, sebbene il rischio di citotossicità alle concentrazioni più elevate richieda una più esteva validazione sperimentale.

Biocompatibilidade e biodegradabilidade de micropartículas de poli-lactato-co-glicolato na ceratite infecciosa em coelhos

Avaliaram-se a biocompatibilidade e a biodegradabilidade do sistema de liberação controlada de poli-lactato-co-glicolato (PLGA) no tratamento com ciprofloxacina das ceratites por Staphylococcus aureus em coelhos. Foram utilizados 20 coelhos, distribuídos em quatro grupos (G). Os animais dos G1, G3 e G4 foram inoculados com 2,5µL da bactéria - 108UFC, no estroma corneano. Os do G2 não receberam a aplicação do inóculo. O tratamento foi realizado com solução salina básica para os animais do G1, micropartículas de PLGA contendo ciprofloxacina nos animais dos G2 e G4 e colírio de ciprofloxacina naqueles do G3. Suabe e biópsia da superfície ocular foram coletados para cultura. Apenas um animal do G1 apresentou cultura positiva para S. aureus. Exame histológico revelou a presença bacteriana em todos os animais do G1 e em dois animais do G3. Também foi constatada reação inflamatória no local da aplicação do sistema de liberação controlada. O tratamento com micropartículas de PLGA foi eficiente no tratamento de ceratites bacterianas, ao eliminar por completo a presença do S. aureus, mas entretanto não foi completamente biocompatível e biodegradável após cinco dias.

Tratamento da ceratite infecciosa experimental em coelhos com o sistema de liberação controlada subconjuntival de ciprofloxacina

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Sistemas de liberação controlada de quitosana contendo antigeno capsular Vi de Salmonella Typhi

A utilização do antígeno Vi em vacinas é bastante promissor devido a este proporcionar um alto nível de imunidade em vacinas parenterais. A necessidade pela busca por alternativas para administração de vacinas levou à aplicação da tecnologia da liberação controlada de fármacos no campo da imunização. Nestes sistemas de liberação controlada, as doses administradas são diminuídas, porém o período de imunidade aumenta, já que prolonga a quantidade liberada do antígeno ao longo do tempo. O presente estudo propôs desenvolver e caracterizar um sistema de liberação controlada contendo antígeno Vi, utilizando como polímero veiculador a quitosana. As técnicas de RMN H^-1 e espectroscopia de infravermelho mostraram que o método de extração do antígeno Vi empregado foi satisfatório qualitativamente. A caracterização da quitosana e das nanopartículas através de ensaios de análise térmica mostrou maior estabilidade das partículas em relação à quitosana, além do aumento da temperatura de degradação nas nanopartículas à medida que aumenta a concentração da quitosana. Em relação ao potencial zeta todas as nanopartículas tiveram cargas positivas em pH 7,2, enquanto que, no tamanho, as partículas foram menores à medida que aumentou a quantidade de quitosana no sistema. Na microscopia eletrônica de transmissão, as partículas mostraram-se morfologicamente homogêneas e com formato esférico. Na cinética de adsorção o antígeno, contido em solução, sofreu uma adsorção de 55% nas partículas de quitosana. Com isso, observou-se que é possível criar um sistema de liberação controlada envolvendo nanopartículas de quitosana e antígeno Vi de Salmonella enterica sorotipo Typhi.