Functionalized Carbon Nanomaterials in Drug Delivery: Emergent Perspectives from Application

Carbon nanotubes (CNTs) have attracted substantial research interest in biomedical sciences and bionanotechnology, rendered from its unique structure, electronic, mechanical, and optical properties. Despite the diverse potential applications, the integration of CNTs in biomedical research is one of the most challenging areas where nanotubes fall under much scrutiny. Pristine nanotubes are highly hydrophobic, and non-dispersible in most of the common aqueous and organic solvents and to render nanotubes biocompatible, functionalization is one of the key prerequisites. In this regard, covalent and noncovalent functionalization are the two widely adopted approaches for co-tethering biologically active molecules on the CNTs. Likewise, the hollow cavity of the nanotube facilitates in the endohedral encapsulation of biomolecules, peptides, DNA oligonucleotides, and proteins, thereby retaining the physiological attributes of the biological molecules. The chapter focuses on the emerging approaches to the functionalization of single-wall CNTs (SWCNTs) and the potential application of functionalized SWCNTs in tuberculosis and cancer chemotherapy using state-of-the-art density functional theory, molecular docking and molecular dynamics simulation methods

Molecular interpretation of pharmaceuticals' adsorption on carbon nanomaterials: Theory meets experiments

The ability of carbon-based nanomaterials (CNM) to interact with a variety of pharmaceutical drugs can be exploited in many applications. In particular, they have been studied both as carriers for in vivo drug delivery and as sorbents for the treatment of water polluted by pharmaceuticals. In recent years, the large number of experimental studies was also assisted by computational work as a tool to provide understanding at molecular level of structural and thermodynamic aspects of adsorption processes. Quantum mechanical methods, especially based on density functional theory (DFT) and classical molecular dynamics (MD) simulations were mainly applied to study adsorption/release of various drugs. This review aims to compare results obtained by theory and experiments, focusing on the adsorption of three classes of compounds: (i) simple organic model molecules; (ii) antimicrobials; (iii) cytostatics. Generally, a good agreement between experimental data (e.g. energies of adsorption, spectroscopic properties, adsorption isotherms, type of interactions, emerged from this review) and theoretical results can be reached, provided that a selection of the correct level of theory is performed. Computational studies are shown to be a valuable tool for investigating such systems and ultimately provide useful insights to guide CNMs materials development and design

Computational Study of Compounds with Biological Activity and their Interaction with Nano-Materials

In the last few decades, computer simulation became a potent tool to study experimental systems such as chemical reactions and adsorption mechanisms in more detail. Every day, developments in computers and computational software are made to increase the computational power to study more complex systems. In this thesis, computational methods were used to study the reactivity of two classes of compounds and their interaction with carbon-based materials; the two classes are platinum-based antitumor drugs and fluoroquinolones antimicrobials compounds. The hydrolysis reaction of cis-[Pt(PMe3)2(etga)], cis-[Pt(PMe3)2(3-Hfl)]+ containing ethyl gallate (etga) and 3-Hydroxyflavone(3-HFl), designed to try to limit the side effects of cisplatin, studied by means of density functional theory (DFT) calculations. The calculations showed that the activation energies are significantly lower than those calculated for cisplatin, with consequent high hydrolysis reaction rate that might make such complexes subject to fast degradation, causing potentially poor pharmacological activity; indeed, the complexes present lower cytotoxic activity compared to cisplatin. The complete mechanism of action (hydrolysis reaction, reaction with DNA bases and reaction with cysteine) of phenanthriplatin, a monofunctional platinum complex, was studied by means of DFT calculations. Moreover, a comparison between phenanthriplatin and cisplatin was made with the aim of understanding why phenanthriplatin presents a higher cytotoxicity activity compared to cisplatin. The hydrolysis reaction showed that phenanthriplatin\u2019s activation energy barrier is close to the energy barriers obtained for the first hydrolysis of cisplatin. The reaction with guanine is kinetically favoured in phenanthriplatin in respect to cisplatin. Finally, the reaction between phenanthriplatin and cysteine showed that such reaction is disadvantageous, both kinetically and thermodynamically, in phenanthriplatin in respect to cisplatin. This can explain why phenanthriplatin is more cytotoxic than cisplatin. The non-covalent interaction between graphene prototypes, new candidates as drugs delivery systems, and cisplatin were investigated through MP2 and DFT calculation. Different orientations of cisplatin in respect to the circumcoronene, one parallel and three perpendicular, were taken into account. The parallel orientation presents the highest value of interaction energy in vacuum. Finally, the introduction of the solvent does not drastically change the interaction energy profiles between cisplatin and circumcoronene. Thus, a favourable adsorption of cisplatin on graphene can be predicted. As regards the fluoroquinolones (FQ) antimicrobials compounds, the relative stability and photochemical behaviour of the different protonation states of CFX in gas phase and in water was studied by means of molecular dynamics simulations and DFT calculations. This work confirm the predominance of the zwitterionic form in water in respect to the neutral form. Finally, the protonation sequence was confirmed through the comparison with the crystalline structures found in the literature, through the calculation of the relative stability for such species and the calculated absorption UV-Vis spectra. Finally, the adsorption of both neutral and zwitterionic forms of CFX to the inner and outer surface of carbon nano-tubes (CNT) in vacuum and in water was studied through molecular dynamics simulations. The simulation results showed that CFX remains adsorbed to the surface of CNT both in vacuum and in water thanks to p-p interactions. Finally, the adsorption Gibbs free energy were carried out for the adsorbed zCFX and nCFX, finding out that adsorption is thermodynamically favoured. In conclusion, the use of computational chemistry can help to rationalize the experimental data and to investigate various mechanicistic hypothesis

Computational Study of Compounds with Biological Activity and their Interaction with Nano-Materials

In the last few decades, computer simulation became a potent tool to study experimental systems such as chemical reactions and adsorption mechanisms in more detail. Every day, developments in computers and computational software are made to increase the computational power to study more complex systems. In this thesis, computational methods were used to study the reactivity of two classes of compounds and their interaction with carbon-based materials; the two classes are platinum-based antitumor drugs and fluoroquinolones antimicrobials compounds. The hydrolysis reaction of cis-[Pt(PMe3)2(etga)], cis-[Pt(PMe3)2(3-Hfl)]+ containing ethyl gallate (etga) and 3-Hydroxyflavone(3-HFl), designed to try to limit the side effects of cisplatin, studied by means of density functional theory (DFT) calculations. The calculations showed that the activation energies are significantly lower than those calculated for cisplatin, with consequent high hydrolysis reaction rate that might make such complexes subject to fast degradation, causing potentially poor pharmacological activity; indeed, the complexes present lower cytotoxic activity compared to cisplatin. The complete mechanism of action (hydrolysis reaction, reaction with DNA bases and reaction with cysteine) of phenanthriplatin, a monofunctional platinum complex, was studied by means of DFT calculations. Moreover, a comparison between phenanthriplatin and cisplatin was made with the aim of understanding why phenanthriplatin presents a higher cytotoxicity activity compared to cisplatin. The hydrolysis reaction showed that phenanthriplatin\u2019s activation energy barrier is close to the energy barriers obtained for the first hydrolysis of cisplatin. The reaction with guanine is kinetically favoured in phenanthriplatin in respect to cisplatin. Finally, the reaction between phenanthriplatin and cysteine showed that such reaction is disadvantageous, both kinetically and thermodynamically, in phenanthriplatin in respect to cisplatin. This can explain why phenanthriplatin is more cytotoxic than cisplatin. The non-covalent interaction between graphene prototypes, new candidates as drugs delivery systems, and cisplatin were investigated through MP2 and DFT calculation. Different orientations of cisplatin in respect to the circumcoronene, one parallel and three perpendicular, were taken into account. The parallel orientation presents the highest value of interaction energy in vacuum. Finally, the introduction of the solvent does not drastically change the interaction energy profiles between cisplatin and circumcoronene. Thus, a favourable adsorption of cisplatin on graphene can be predicted. As regards the fluoroquinolones (FQ) antimicrobials compounds, the relative stability and photochemical behaviour of the different protonation states of CFX in gas phase and in water was studied by means of molecular dynamics simulations and DFT calculations. This work confirm the predominance of the zwitterionic form in water in respect to the neutral form. Finally, the protonation sequence was confirmed through the comparison with the crystalline structures found in the literature, through the calculation of the relative stability for such species and the calculated absorption UV-Vis spectra. Finally, the adsorption of both neutral and zwitterionic forms of CFX to the inner and outer surface of carbon nano-tubes (CNT) in vacuum and in water was studied through molecular dynamics simulations. The simulation results showed that CFX remains adsorbed to the surface of CNT both in vacuum and in water thanks to p-p interactions. Finally, the adsorption Gibbs free energy were carried out for the adsorbed zCFX and nCFX, finding out that adsorption is thermodynamically favoured. In conclusion, the use of computational chemistry can help to rationalize the experimental data and to investigate various mechanicistic hypothesis

Molecular modeling of drug delivery systems based on carbon nanostructures: structure, function, and potential applications for anticancer complexes of Pt(II)

The medication with Pt(II) drugs (cisplatin, carboplatin, and oxaliplatin) has been an effective alternative for treating cancers due to their notable inhibition of cancer cells growth and the prevention of metastasis. Nevertheless, the low selectivity of these metallodrugs for malignant cells produces severe side effects, which limit this chemotherapy. In this context, carbon nanohorns (CNHs) have been considered potential nanovectors for drugs, since they present low toxicity, drug-loading capacity, biodegradation routes, and biocompatibility when oxidized. However, there is still a lack of studies regarding the molecular behavior of these nanocarriers on cell membranes. The present work aims to characterize the interactions between inclusion complexes drug@CNH, which are formed by platinum drugs encapsulated in CNHs, and plasma membranes by using molecular dynamics simulations. The results demonstrated that the van der Waals contribution played a primary role (∼74%) for the complex stability, which explain the confined dynamics of drugs inside the CNHs. The free energy profiles revealed an endergonic character of the drug release processes from CNHs, in which the energy barrier for oxaliplatin release (~24 kcal mol–1 ) was ~30% larger than those for carboplatin and cisplatin (~18 kcal mol-1 ). The simulations also showed four stages of the interaction mechanism CNH--membrane: approach, insertion, permeation, and internalization. Despite the low structural disturbance of the membranes, the free energy barrier of ∼55 kcal mol-1 for the CNHs translocation indicated that this transport is kinetically unfavorable by passive process. The in silico experiments evidenced that the most likely mechanism of cisplatin delivery from CNHs involve the approach and insertion stages, where the nanovector adheres on the surface of cancer cells, as reported in in vitro studies. After this retention, the drug load may be slowly released in the tumor site. Finally, simulations of the cellular uptake of Pt(II) drugs also pointed out significant energy barriers (~30 kcal mol-1 ) for this process, which reflects their low permeability in membranes as discussed in experimental studies. In addition to reinforcing the potential of CNH as nanovector of Pt(II) drugs, the results presented in this thesis may assist and drive new experimental studies with CNHs, focusing on the development of less aggressive formulations for cancer treatments.A medicação com fármacos a base de Pt(II) (cisplatina, carboplatina e oxaliplatina) tem sido uma alternativa efetiva para tratar cânceres devido à sua notável inibição do crescimento de células cancerosas e a prevenção de metástases. No entanto, a baixa seletividade dessas metalodrogas por células cancerosas gera severos efeitos colaterais. Nesse contexto, nanohorns de carbono (CNHs) têm sido considerados potenciais nanovetores de fármacos, devido a baixa toxicidade, capacidade de carreamento de fármacos, rotas de biodegradação, e biocompatibilidade quando oxidados. Porém, existe uma carência de estudos tratando o comportamento desses nanocarreadores em biomembranas. Esse trabalho tem como objetivo caracterizar as interações entre complexos de inclusão fármaco@CNH, formados por fármacos de Pt(II) encapsulados em CNHs, e membranas usando simulações por dinâmica molecular. Os resultados demonstraram que a contribuição de van der Waals teve um papel primário (∼74%) na estabilidade dos complexos, o que explica a dinâmica confinada dos fármacos dentro dos CNHs. Os perfis de energia livre revelaram o caráter endergônico da liberação dos fármacos a partir de CNHs, nos quais a barreira de energia para a liberação da oxaliplatina (~24 kcal mol– 1 ) é ~30% maior do que aquelas para carboplatina e cisplatina. As simulações mostraram quatro estágios do mecanismo de interação CNH-membrana: aproximação, inserção, permeação e internalização. Apesar do baixo distúrbio estrutural das membranas, a barreira de energia livre de ∼55 kcal mol-1 para a translocação de CNHs indicou que esse transporte é desfavorável cineticamente via o processo passivo. Os experimentos in silico evidenciam que o mecanismo mais provável de entrega de cisplatina a partir de CNHs envolve a aproximação e inserção, onde o nanovetor adere na superfície de células cancerosas, como reportado em estudos in vitro. Após essa retenção, a carga de fármaco deve ser ligeiramente liberada no tumor. As simulações de captação celular de fármacos de Pt(II) também apontaram barreiras de energia significativas (∼30 kcal mol-1 ) para esse processo, o que reflete a baixa permeabilidade deles em membranas como discutido em estudos experimentais. Além de reforçar o potencial de CNHs como nanovetores de fármacos de Pt(II), os resultados apresentados nessa tese podem auxiliar e impulsionar novos estudos com CNHs, focando no desenvolvimento de formulações menos agressivas para tratamentos de câncer.FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerai

ENCAPSULATION OF PLATINUM-BASED DERIVATIVES WITHIN CARBON NANOTUBES: INVESTIGATIONS ON CONTROLLED RELEASE AND IN VIVO BIODISTRIBUTION

Ph.DDOCTOR OF PHILOSOPH

Poster Session

Posters presented by: P01: Adam S. Abbott, University of Georgia P02: Yasmeen Abdo, University of Mississippi P03: Vibin Abraham, Virginia Tech P04: Asim Alenaizan, Georgia Institute of Technology P05: Isuru R. Ariyanthna, Auburn University P06: Brandon W. Bakr, Georgia Institute of Technology P07: [Matthew Bassett, Georgia Southern University] P08: Alexandre P. Bazanté, University of Florida P09: Andrea N. Becker, University of Tennessee P10: Randi Beil, University of Tennessee P11: Andrea N. Bootsma, University of Georgia/Texas A&M University P12: Adam Bruner, Louisiana State University P13: Lori A. Burns, Georgia Institute of Technology P14: Chanxi Cai, Emory University P15: Katherine A. Charbonnet, University of Memphis P16: Marjory C. Clement, Virginia Tech P17: Wallace D. Derricotte, Emory University P18: Harkiran Dhah, University of Tennessee P19: Manuel Díaz-Tinoco, Auburn University P20: Vivek Dixit: Mississippi State University P21: Eric Van Dornshuld, Mississippi State University P22: Katelyn M. Dreux, University of Mississippi P23: Narendra Nath Dutta, Auburn University P24: William Earwood, University of Mississippi P25: Thomas L. Ellington, University of Mississippi P26: Marissa L. Estep, University of Georgia P27: Yanfei Guan, Texas A&M University P28: Andrew M. James, Virginia Tech P29: Yifan Jin, University of Florida P30: Dwayne John, Middle Tennessee State University P31: Sarah N. Johnson, University of Mississippi P32: Noor Md Shahriar Khan, Auburn University P33: Monika Kodrycka, Auburn University P34: Ashutosh Kumar, Virginia Tech P35: Elliot Lakner, University of Alabama P36: Robert W. Lamb, Mississippi State University P37: S. Paul Lee, University of Mississippi P38: Zachary Lee, University of Alabama P39: Conrad D. Lewis, Middle Tennessee State University P40: Guangchao Liang, Mississippi State University P41: Chenyang Li, Emory University P42: Hannah C. Lozano, University of Memphis P43: SharathChandra Mallojjala, University of Georgia/Texas A&M University P44: Zheng Ma, Duke University P45: Elvis Maradzike, Florida State University P46: Ashley S. McNeill, University of Alabama P47: Stephen R. Miller, University of Georgia P48: W. J. Morgan, University of Georgia P49: Apurba Nandi, Emory University P50: Daniel R. Nascimento, Florida State University P51: Brooke N. Nash, Mississippi College P52: Carlie M. Novak, Georgia Southern University P53: Young Choon Park, University of Florida P54: Kirk C. Pearce, Virginia Tech P55: Rudradatt (Randy) Persaud, University of Alabama P56: Karl Pierce, Virginia Tech P57: Kimberley N. Poland, University of Mississippi P58: Chen Qu, Emory University P59: Duminda S. Ranasinghe, University of Florida P60: Hailey B. Reed, University of Mississippi P61: Matthew Schieber, Georgia Institute of Technology P62: Jeffrey B. Schriber, Emory University P63: Thomas Sexton, University of Mississippi P64: Holden T. Smith, Louisiana State University P65: Aubrey Smyly, Mississippi College P66: B. T. Soto, University of Georgia P67: Trent H. Stein, University of Alabama P68: Cody J. Stephan, Georgia Southern University P69: Thomas Summers, University of Memphis P70: Zhi Sun, University of Georgia P71: Monica Vasiliu, University of Alabama P72: Jonathan M. Waldrop, Auburn University P73: Tommy Walls, Southern Louisiana University P74: Qingfeng (Kee) Wang, Emory University P75: Constance E. Warden, Georgia Institute of Technology P76: Jared D. Weidman, University of Georgia P77: Melody Williams, University of Memphis P78: Donna Xia, University of Alabama P79: Qi Yu, Emory University P80: Boyi Zhang, University of Georgia P81: Tianyuan Zhang, Emory University P82: Michael Zott, Georgia Institute of Technolog

Cancer Nanomedicine

This special issue brings together cutting edge research and insightful commentary on the currentl state of the Cancer Nanomedicine field

Nanocellulose from the Appalachian Hardwood Forest and Its Potential Applications

Nanofibrillated cellulose (NFCs) are nanoscale fibers of high aspect ratio that can be isolated from a wide variety of cellulosic sources, including wood and bacterial cellulose. With high strength despite of their low density, NFCs are a promising renewable building block for the preparation of nanostructured materials and composites. To fabricate NFC-based materials with improved mechanical and chemical properties and additional new functionalities for different applications, it is essential to tailor the surface properties of individual NFCs. The surface structures control the interactions between NFCs and ultimately dictate the structure and macroscale properties of the bulk material. This research was focused on determining the feasibility of using hardwood residues from the Appalachian Hardwood Forest for the production of nanofibrillated cellulose (NFC). In addition, some modifications during the NFC production process were performed to evaluate their improvement to incorporate more antimicrobial copper in the cellulosic backbone. This thesis has been divided in the following main chapters: 1) Literature review regarding to nanocellulosic materials and their production processes, 2) Nanocellulose current and potential applications, 3) Nanofibrillated cellulose from the Appalachian Hardwood logging residues, 4) Modified nanofibrillated from the Appalachian Hardwood logging residues, 5) Preparation of nanocellulose using ionic liquids -- A review, 6) Nanocellulose-based drug delivery system -- A review, 7) Safety aspects on the utilization of lignocellulosic based materials - A review