A next generation theranostic nano-platform for sustained and enhanced inhibition of cancer stem cells

Primary tumor extermination and conventional chemotherapy are proved to be inefficient in cancer therapy in that they preferentially abolish differentiated cells whilst leaving behind treatment resistant, tumorigenic cancer stem cells (CSCs). CSCs are validated to be the root cause of therapeutic resistance, recurrence, and tumor progression. CSCs are considered to be modulated by overexpression of certain pathways, including signal transducer and activator of transcription 3 (STAT3). The aberrant activity of STAT3 has been identified in clinical inspection of > 70% of breast and prostate cancer and its inhibition by various mechanisms holds unprecedented significance in modern medicine. Niclosamide (Nic), an FDA approved anthelmintic drug, has recently been reported as potent inhibitor of STAT3 and it is seen toand triggered the activation of cancer cell apoptotic mechanism. Despite its promising cancer treatment capabilities, lack of solubility is a major bottleneck limiting its bio-availability. To circumvent the issue, we adopted a nanomedicine approach integrated with a surface decorated cucurbituril (CB[6]) host-guest chemistry using luminescent carbon nanoparticles (Nano-Carbobitaceae) for sustained and enhanced delivery of niclosamide traceable with vibrational spectroscopic methods. Carbon nanoparticles (Hydrodynamic dynamic size=55±1 nm) were obtained via the environmentally benign hydrothermal synthetic route using food grade Agave nectar as the carbohydrate source. The particles were either prefunctionalized (hHydrodynamic dynamic size= 76±13 nm) or postfunctionalized (Hydrodynamic hydrodynamic dynamic size= 93±4 nm) with CB[6] and were further loaded with STAT3 inhibitor Nic. Extensive physiochemical characterizations were subsequently carried out to confirm the binding of Nic and CB. FT-IR results indicated the a 2:3 binding complexation model. Furthermore, the 1H NMR results showed shifts in the characteristic peaks of Nic upon encapsulation in CB[6] cavity. The potential of the developed particle for the in vitro applications was evaluated. Interestingly, the hydrodynamic size of the particles was mostly preserved in various physiologically relevant media. Approximately two- fold enhancement in IIC50 values were observed for the encapsulated drug versus free drug. The IC50 value of Nic, CB[6] Nic and CB[6] CNP Nic (post functionalized) was determined to be (45±04)×10-6 M, (28±03)×10-6 M and (21±02)×10-6 M, respectively. HenceOur results indicated that, this novel nanoplatform holds promise for sustained and enhanced chemotherapeutic delivery of sparingly soluble Nic for modulation of stem cell signaling pathways

A drug-free theranostic approach for localized and systemic diseases via nanoparticles

The emergence of field of nanomedicine for addressing the biomedical challenges created a toolkit which has been evolving dynamically with the advances in the medicine itself. At the heart of nanomedicine, nanoparticles exist which are envisioned to shift the paradigm of conventional therapy by furnishing the field with their unprecedented properties. On top of the promising features, nanoparticles can also simultaneously be endowed with imageability to track the success of therapy and hence a subfield in nanomedicine called “theranostic” advened in recent years. However, the obstacles in the translation of the nanoparticles such as batch to batch variation during scale-up, the lack of control over cargo release and particle instability slowed their application in real life. An approach is proposed here where these challenges can be overcome by designing nanoparticles which are inherently therapeutic without the encapsulation of the secondary drug while they can also be imaged by various imaging modalities. These nanoparticles are based on carbon dots and hafnium oxide which can be imaged with fluorescent imaging and CT imaging as two major imaging modalities in the clinic. The surface-modified nanoparticles were utilized in this thesis to work out the localized diseases (dental biofilm, bone microdamage) and systemic diseases problems. At first, I applied strategies from materials science to modify the chemical properties of the carbon dots and worked towards the improvement of their interaction with the cells/ cellular components. I next demonstrated that the chemical properties of these nanoparticles can be tuned easily depending on the desired outcome for multiscale, multicolor imaging. Then, I geared towards the specific biomedical issues which can benefit from these nanoparticles. I presented the work on using nanoparticles of hafnium for the detection of the dental plaque by typical dental X-ray device based on a molecularly targeted approach toward carious bacteria. The therapeutic antibiofilm properties of these nanoparticles were established as well by comprehensive in vitro and in vivo studies. The inherently therapeutic nanoparticles of carbon which target the pH of the biofilm were investigated in the follow-up study without changing the diversity of the oral microbiota. The nanoparticles developed in the previous chapters were aptly surface functionalized and were used to target the bone microdamage in the following chapter. The distinct X-ray characteristic of the hafnium oxide nanoparticles made the detection of the damage viable in vivo using advanced CT technologies. Moreover, we showed that the nanobeacons of carbon dot can be used in the fluorescent microscopic evaluation of the bone damages ex vivo. Finally, the nanoparticle of inherently therapeutic carbon dots derived from certain algae was suggested to be used as activatable agents for the UV therapy of the cancerous skin cells. Together, these studies present the promise of the ‘inherently theranostic’ nanoparticles for the health-related issues. Therefore, the conveyed message which is built throughout this thesis is the unlimited opportunities for these agents which can be extended to the realm of the medicine itself

Kinetics for the hydrolysis of Ti(OC<inf>3</inf>H<inf>7</inf>)<inf>4</inf>: A molecular dynamics simulation study

Using molecular dynamics (MD) simulations in conjunction with a reactive force field method, the chemical kinetics of the hydrolysis of titanium tetraisopropoxide (Ti(OC3H7)4, TTIP) at high-temperature conditions is investigated. The MD simulations allow for presenting the complete dynamic process of the TTIP conversion at the atomic level. The rate constant of TTIP hydrolysis at 1 atm is estimated to be k=1.23×1014×exp(-11,323/T(K))mol-1cm3s-1 using a second-order reaction model. On the basis of Ti-containing intermediate species profiles, the evolutions of the main decomposition products during the TTIP hydrolysis are identified and key reaction pathways are elucidated. The results show that the clusters are formed before TiO2 molecules are observed. During the decomposition, Ti-containing species with one or two C-O bonds and carbon-free species with more than two Ti-O bonds are formed and undergo two separate pathways. One is the combination via the formation of Ti-O-Ti bridges, forming early clusters that serve as precursors for large TiO2 nanoparticles. The other is the further decomposition to smaller molecules such as TiO2 that participate in the subsequent cluster formation. Interactions between Ti and O atoms in the cluster stabilize the large structure through the abstraction of water and -CxHy groups

Optimum light weight concrete mix design against high temperature

The fire phenomenon can cause the loss of structural materials resistance which may end to damage or even structural total collapse. Physical and chemical changes in concrete due to firing also make serious structural defects in concrete structures. Therefore, prevention of reduction of concrete resistance is attended in this research. The primary idea is based on decreasing concrete thermal conductivity to increase chemical and physical resistance. Because of low density and porosity light weight aggregate concrete has low thermal conductivity which can postpone the resistant loss due to high temperature. A set of tests performed to achieve an optimum light weight aggregate concrete mix design in room normal temperature by changing the amount of sensitive mix components and controlling compressive strength and density. In next step some effective additives were implemented to make the optimum mix design against high temperature. For this purpose, 9 different mix designs obtained from the Taguchi method were prepared. For each mix design, 9 test specimens were made. At each, ambient temperature, 400 ͦC and 800 ͦC, three samples of each design are tested. The experiments conducted in this research include testing of compressive strength, ultrasonic pulse, and weight loss and heat effect on the appearance of lightweight concrete. It was seen that the effect of temperature above 400 ͦC is more significant on concrete compressive strength and in temperatures below 400 ͦC density loss is more considerable. The results of tests indicate that reducing the water to cement ratio and using super plasticizer has a desirable effect on the physical and mechanical properties of lightweight concrete at higher temperatures. However, test results showed that the presence of silica fume up to 15 percent of weight of cement can’t improve the strength of lightweight concrete neither in ambient nor in elevated temperature. Optimum mix design lost about 49 percent of compressive strength in 800 ͦC. Also it was observed that loss of density and compressive strength due to elevated temperature are in direct relation

Do nickel and iron catalyst nanoparticles affect the mechanical strength of carbon nanotubes?

The growth of carbon nanotubes (CNTs) is strongly mediated by the interaction between Carbon atoms and catalyst nanoparticles, in particular in processes like chemical vapor deposition or floating method. However, the effects these nanoparticles on the mechanical strength of the grown CNTs have remained elusive. Using molecular dynamics dynamic simulations via ReaxFF force fields, the interactions between defect-free single wall CNTs and a series of Nickel (Ni) and Iron (Fe) nanoparticles (NPs) are studied. Pure metal NPs significantly reduce the strength of the CNTs whereas oxidized NPs have more limited detrimental effects. For the same Oxygen content, we also observe that the Fe oxide NPs weaken C-C bonds, i.e. CNTs grown in the presence of Ni particles have higher mechanical strength comparing to those obtained from Fe-based nanoparticles. An analysis of the formation and dissociation of chemical bonds between the C, O, Ni and Fe atoms together with the stress analysis during tensile tests also enable us to elucidate the role of the NPs on the failure mechanisms. The C-C bonds interacting directly with Ni atoms are weakened and therefore control the failure of the CNTs. Surprisingly, the failure of the same CNTs in contact with Fe nanoparticles is driven by the weakening of C-C bonds not directly bonded to Fe atoms.status: publishe