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Tailored Nanomaterial Systems for Cancer Therapy

Kapri, Sutanu (2019) Tailored Nanomaterial Systems for Cancer Therapy. PhD thesis, Indian Institute of Science Education and Research Kolkata.

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    Abstract

    Nanoscience and nanotechnology represent an emerging area in the field of biomedical applications which can overcome many biological issues associated with cancer. There are two different factors such as surface area to volume ratio and quantum size effect that alter the electronic properties and increase the reactivity which are highly beneficial for applications particularly in biomedicine including cancer therapy and diagnosis. In particular, the nanoscale structures can easily interact with the biological systems. Advanced research in nanotechnology allows a smart design of the multifunctional nanomaterials for a combination of multiple therapies in a single system. Due to the limitations of monotherapy, multi-therapy has opened the collective merits of more than one treatment at a time which minimizes the side effects and improves the efficacy at lower dosages. Among the nanostructures, carbon nanomaterials offer a promising pathway and competent alternative for carrying therapeutic molecules. This could be ascribed to their allowance for both covalent and noncovalent functionalization with different functional groups. Besides carrying different moieties, carbon nanomaterials also provide enclosed payload options. They comfortably permeate the membranes of different types of cells and can enter the cells via energy-dependent endocytosis pathway depending upon the size and shape of the nanostructures. These characteristics make them excellent building blocks for targeting, imaging and multi-therapy systems. Drugs are constituted from organic molecules and get attached to carbon nanomaterials either through covalent functionalization or π-staking. Besides conventional chemotherapy there are others therapeutic precision methods such as phototherapy with an advantage of spatiotemporal selectivity. The two widely known phototherapies are photothermal therapy (PTT) and photodynamic therapy (PDT). Owing to the specific requirements of an appropriate photosensitizer, the library of photosensitizing materials remains limited. The most common PTT agents are expensive noble metal based nanostructures while commonly used PDT agents are hydrophobic organic based compounds. Therefore, our keen interest was to develop unconventional, more benign and easily tunable nanostructures for phototherapy which can potentially replace the conventional agents. In chapter 1, a general idea about cancer and its therapeutic treatments with various nanoparticles (NPs) are presented. The basic understanding of cancer and their diagnostics approach such as chemotherapy and phototherapy (photothermal therapy, PTT and photodynamic therapy, PDT) are described in detail along with the general overview of drug delivery. The interaction of photon with biological tissues and its mechanistic studies are also discussed. Along with the basic nanomaterials used in cancer therapy the biomedical applications and their related mechanistic processes driven by these nanomaterials are highlighted. Nanoporous carbon materials, cobalt based nanostructures, and heterojunction nanosheets are also elaborated in terms of their chemical and physical properties, and biomedical application. The effect of chemical functionalization of NPs with drug molecules, over a mere physical adsorption is argued. Since the biological activity depends on the size, shape and morphology of nanomaterials, nowadays a new generation of intricately designed nanomaterials is emerging where drug can be easily encapsulated and functionalized within the nanoparticle systems. It has been observed that the efficacy of chemically functionalized drug inside the cancerous cells is far better than the physically adsorbed drug. Plenty of recent works are considered which demonstrated the increase in efficacy of chemically functionalized drug by modifying the interactions of NP syetem with the drug and targeted moiety. The photochemotherapeutic properties of metal NPs such as gold nanostructures, cobalt nanostructures are also described in detail. Various nanostructures including heterojunction nanosheets utilized in PDT are analyzed in detail. Thereafter the role of heterojunction materials in PDT and their cell death mechanism are also described. After discussing the nature of NP-based delivery vehicles recently used in biomedical applications, the nanocarriers, PTT and PDT agents used in the present work are also discussed in brief. In chapter 2, synthesis methodologies of smart nanomaterials e.g. heating up, thermal decomposition, and aqueous methods are discussed. Followed by, a brief description of other physicochemical characterization techniques used in this thesis work e.g. powder X-ray diffraction (XRD), scanning electron microscope (FESEM), transmission electron microscope (TEM), high angle annular dark field scanning TEM (HAADF-STEM) coupled with energy dispersive analysis of X-rays (EDAX), atomic force microscopy (AFM), fourier transform infrared spectroscopy (FTIR), carbon, hydrogen and nitrogen (CHN) analyzer, Raman spectroscopy, surface area analysis, dynamic light scattering and zeta potential analysis, ultraviolet-visible spectroscopy (UV-Vis), photoluminescence spectroscopy (PL), fluorescence microscopy and flow cytometry are illustrated. Later, drug loading and release studies, biological assays such as MTT assay, live/dead cell assay, etc. are elaborated. In chapter 3, the synthesis and application of ~150 nm porous carbon nanosphere (PCN) towards controlled and targeted drug delivery in vitro are discussed. PCNs were synthesized from bio-waste cellulose derived from Cymbopogon flexuosus (lemon grass) by carbonization of dried grass under N₂ atmosphere. HF etching of silica renders porous carbon matrix with larger size. In this top-down approach ball milling was used in order to refine the grain size of the carbonization product. FESEM and TEM analyses of PCNs confirm their spherical morphology and EDAX spectra validate the purity of PCN. The synthesized PCNs are minimally toxic to biological cells and they show high porosity, modest surface area and semi-graphitic nature, making them intelligent nanocarriers for targeted and controlled drug delivery. Minimally toxic PCNs offer encapsulation and functionalization of anticancer drug, DOX, through acid sensitive hydrazone linker which safely deliver the drug inside the targeted cells via pH sensitive cleavage of this bond. FTIR further confirms the functionalization of drug onto the surface of PCN. It is observed that chemically functionalized drug allows controlled release of drug while physically absorbed drug is randomly delivered which affects surrounding healthy cells. Furthermore, fluorescence microscopy confirms the intracellular controlled delivery of anticancer drug, doxorubicin to the targeted HeLa cells whereas non targeted HEK 293 cells are not affected. In chapter 4, the synthesis and application of porous carbon nanospheres (PNs) as controlled and targeted drug delivery vehicle obtained from ubiquitous sources are discussed. Here the size of the PNs is below 100 nm and the drug is loaded by physical adsorption, unlike chapter 3 where it is chemically functionalized. The PNs show controlled and targeted drug delivery towards HeLa cells, MDA-MB-231 cells, HEK 293 cells, RAW 264.7 and J774A.1 cells. Further the study is extended for live cell imaging using fluorescence microscope with HeLa cells. The PNs were synthesized by oxidative cutting of porous carbon matrices (PCs) obtained from carbonization of low cost precursors such as pasture grass, human hair and sucrose. The obtained PNs were characterized by TEM, FESEM and AFM which confirm their spherical morphology. The PNs obtained from pasture grass (PN-G) uniquely shows high surface area and porosity confirmed from Brunauer-Emmett-Teller (BET) surface area analysis and significantly higher graphitic fraction revealed by Raman spectroscopy. Hence, PN-G helps in significant physical loading of DOX/PI, both on the surface as well as within the mesopores by simple physisorption process to give PN-G-DOX and PN-G-PI, respectively. PN-G-DOX was coated by polyethylenimine (PEI), followed by covalently bonded folic acid (FA) to give PN-G-DOX/PEI-FA vividly studied by FTIR. It is observed that PNs are highly biocompatible towards the aforementioned cells and shows excellent drug delivery capability. Furthermore, to confirm the drug delivery into the cellular microenvironment, the cell impermeable PI dye was loaded onto the PNs. Fluorescence microscopy confirms cell permeability of the PNs which is attractive for biomedical applications. In chapter 5, polydopamine (PDA) capped cobalt phosphide nanorods (Co2P@PDA NRs) with six aspect ratios (ARs) from 1.4 to 10 were synthesized by one step thermal decomposition and micro-emulsion methods. Co₂P@PDA NRs show a cost-effective and superior option as PTT agent in comparison to noble metal nanostructures. TEM confirms the ARs of the obtained NRs and the PDA coating is studied by combining HAADF-STEM and HRTEM imaging. Intriguingly, the Co2P@PDA NRs with AR ~6.4 show a high photothermal conversion efficiency (PCE) ~ 64% among other ARs. Thereby NRs with AR 6.4 were chosen for detailed biological studies, wherein commonly used 980 nm (1 W/cm2) laser source was employed. The strategy of coating PDA not only provides excellent biocompatibility of Co2P NRs but also opens the opportunity for targeted drug delivery. Using Co₂P@PDA NRs with AR ~6.4 the temperature of the cell environment can be elevated as high as ~31oC within 10 min. Further fluorescence microscopy reveals efficient alleviation of cancer cells using Co2P@PDA NRs. Added to the advantage of Co₂P@PDA NRs towards drug delivery, DOX along with folic acid as targeting ligand was loaded onto the NRs. Fluorescence microscopy confirms the capability of excellent targeted drug delivery with Co₂P@PDA NRs. This study opens the path to design multifunctional smart materials beyond the expensive noble metal structures for cancer therapy using a synergistic effect. In chapter 6, p-n heterojunction nanosheets consisting of p-type MoS2 nanoplates integrated onto n-type nitrogen doped reduced graphene oxide (n-rGO), have been employed for PDT. MnO₂ NPs were decorated on the surface of p-n heterojunction nanosheets to overcome the hypoxia condition in cancer cells. Further the nanosheets were modified with lipoic acid functionalized poly (ethylene glycol) to provide better biocompatibility and colloidal stability in physiological solution to form p-MoS₂/n-rGO-MnO₂-PEG nanosheets. The nanosheets can easily accumulate into the cancer cells through enhanced permeable and retention (EPR) effect. Heterojunction structures are confirmed by a combined analysis of TEM and HAADF- STEM imaging. The junction characteristics are studied using mottschottky impendence spectroscopy. Under near infrared (NIR) light with 980 nm wavelength (0.4 W/cm²) irradiation, effective electron-hole separation is obtained across the heterojunction. The heterojunction promotes the migration of electrons and holes and enhances the separation of charge carriers which leads to the generation of cytotoxic reactive oxygen species (ROS) causing cell death. The seventh chapter provides the work summary and future prospects.

    Item Type: Thesis (PhD)
    Additional Information: Supervisor: Dr. Sayan Bhattacharyya
    Uncontrolled Keywords: Cancer Cell Imaging; Cancer Therapy; Cobalt Phosphide Nanorods; Enhanced Photodynamic Therapy; Live Cell Imaging; Molybdenum Sulfide; Nanomaterial Systems; Nanotoxicology; Photo-chemotherapeutic Agents; Targeted Cancer Therapy; Targeted Drug Delivery
    Subjects: Q Science > QD Chemistry
    Divisions: Department of Chemical Sciences
    Depositing User: IISER Kolkata Librarian
    Date Deposited: 27 Jun 2019 13:27
    Last Modified: 27 Jun 2019 13:27
    URI: http://eprints.iiserkol.ac.in/id/eprint/819

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