Functional composite nanocarriers for traceable drug delivery

Abstract

Nowadays, nanoscale drug/gene delivery systems have formed great platforms for modern cancer therapy. Since many nanocarriers were employed for intracellular delivery applications, the potential cytotoxicity of these very small inorganic nanocarriers has raise worldwide considerations. In that case, the intracellular imaging and trace of nanocarriers' delivery performance became of utmost importance. Different analytical techniques have been developed for bio-imaging and tracing applications. Among them, fluorescence imaging is the widely applied one. Although the detecting and analyzing technologies of fluorescence imaging are almost mature, there still existing certain inevitable issues. The fluorescent agents have rapid photo-bleaching properties, so that the fluorescence trace is far away from nondestructive method. Moreover, the auto­ fluorescence of cells can get rise to background interruptions during detecting procedure. On the contrary, the intensities of Raman spectrum are more photo-stable and the Raman signals are easier to separate. The only disadvantage of Raman is that the low Inherent intensity. In that case, surface enhanced Raman scattering (SERS) technology is employed as a solution to that problem. That is why certain part of our research focus on SERS traceable delivery. The aim of this research project is to design and discover a serial of novel functional composite nanocarrier s based on conventional silica and emerging graphitic carbon nitride materials with favourable size, morphology, structure and surface modifications, which can be applied for Raman or Surface-enhanced Raman scattering (SERS) traceable drug/gene delivery. The works included in this thesis are listed as the following. 1) A new smart DDS with 5-10 nm gold nanoparticles aggregated on the surface of silica nanoparticles with an average patticle diameter of ca. 80-100 nm was designed through SERS-traceable nanocarriers baring carboxylic hydrazone-conjugated. This design displays a sesame-bread structure to stimulate SERS effects by the aggregation of small exposed gold seeds. It is evident that the nanocarriers have adequate biocompatibilities, while the smart DDS exhibits selective cytotoxicities between cancer and healthy cells. In here, we confirm the feasibility of SERS traceable drug delivery nanocarriers. 2) A novel stellate porous silica based delivery system was designed for SERS trace purpose. This stellate porous silica pa1ticles with an average particle size of 80-120 nm and center-radial pores of 10-30 nm were coated with in-site reduced gold nanoparticles and could materialise SERS trace after grafted SERS reporters. The trace results show high sensitivity and non-invasive features, which makes the constructed delivery system have considerable potentials to discover the dynamic delivery performances in living cells. In this work, another structured silica-gold composite nanocarrier has been constructed for SERS traceable gene delivery. We prove the SERS traceable nanocarriers could apply for gene delivery. 3) A novel ultrathin graphitic carbon nitride (g-C₃N₄) based system with small sheet size of 100-150 nm and thickness of nearly 0.6 nm was developed for small interfering RNA (siRNA) delivery. The g-C₃N₄ materials were surface modified with low molecular weight branched polyethylenimine (PEI) to obtain the capabilities of siRNA loading. The simple and label-free siRNA delivery system, which avoid possible interactions of artific ial labels, shows cytotoxicity in KHOS cancer cells and good biocompatibility in HEK.293 normal human cells. As g-C₃N₄ is Raman-active, the intracellular uptake performances of the label-free delivery system have been directly traced by Raman spech·oscopies. In th is work, we figured out a new material g-C₃N₄ that can be used for making Raman trace delivery carriers. 4) Advanced label-free g-C₃N₄ composite nanocarriers were designed for surface enhanced Raman scattering (SERS) imaging applications, and smart three-dimensional nanocaniers were constructed for fluorescence imaging applications. By the aggregations of small gold nanoparticles on ultrathin PEI-g-CC₃N₄ nanosheets, the spontaneous Raman intensity of g-C₃N₄ can be enhanced up to 5 orders of magnitude, which makes it possible for high sensitive SERS imaging. On the other hand, by using redox-sensitive non-fluorescent cross-linker to form three-dimensional smart cross-linked-g-C₃N₄ (CL-g-C₃N₄) nanocomposites, the fluorescence imaging of the designed nanocomposites can be specific and show selectivity between healthy and cancer cells. In this work, we find that advanced modified g-C₃N₄ materials have the potentials to be used for the applications of SERS and smait fluorescence traceable delivery. All in all, this project combines the branches of material chemistry, SlU'face chemistry, analytic technology, biology and nano-medicines together. The introduction of emerging SERS imaging and traceable methodology will give certain new knowledge and ideas of nanotechnology and bioengineering. The completion of this project will become the foundation of a series of novel inorganic nanocarriers for drug/gene delivery with outstanding performances like targeting, controllable stimuli-responsive release and higher therapeutic efficiency to against cancers and other human diseases threating on the human health. That is why this project will finally contribute to increase the health and welfare levels of individuals, society and the whole human beings.