| The rapid progress in nanoscience and nanotechnology has greatly promoted the application of nanomaterials in biomedical field. It is the key to explore the efficient and fast method for surface functionalization of nanomaterials to promote the extensive applications of nanotechnology in biomedical field. It is significant to develop high efficiency, stable, biocompatible and functional nanomaterials for cancer therapy in the nanomedicine field. For cancer treatment, building intelligent stimuli-responsive drug delivery systems and advanced functional nanoparticles can not only provide new perspective for the improvement of anticancer drug delivery system, but also provide guidelines for the development of cancer theranostics.To further improve the biosafety of mesoporous silica nanoparticles(MSNs), gold nanorods(Au NRs), molybdenum disulfide(Mo S2) and other fascinating materials, enhance the accuracy of the drug controlled release behavior, promote the bioavailability of agents, enrich nanomaterials modified methods and strengthen the therapeutic effects against cancer cells, a series of research work were carried out in this dissertation. In this dissertation, we employed the synthesis of inorganic nanoparticles with tunable size and morphology as the starting point, the design of organic-inorganic functional nanoparticles as the main line, the good biocompatibility as the benchmark, and the construction of powerful anticancer nanodevices as the target. The research content and main assignment of this dissertation involve two aspects:(1) Mesoporous silica nanoparticle(MSNs) based nanocarriers are further designed and developed for p H-responsive drug delivery;(2) Novel photothermal agent and multifunctional theranostic agent are respectively fabricated based on Mo S2 and Au NRs. The main contents were detailed as follows:(1) Based on the design concept of “p H-responsive”, polyelectrolyte multilayers(PEM) composed of poly(allylamine hydrochloride)(PAH) and poly(styrene sulfonate)(PSS) were coated onto the MSN surface via a layer-by-layer(Lb L) self-assembly technique, and doxorubicin hydrochloride(DOX) was loaded into the prepared PEM-MSNs, thus constructing potential p H-responsive carrier systems. It is the first time to evaluate their biocompatibility and efficiency, emphasizing the influences of the layer numbers on the release profiles, cytotoxicity and hemocompatibility. It is demonstrated that PEM layer thickness has an exponential relationship with the number of coated layers. PEM-MSNs exhibited a very low and layer thickness-dependent cytotoxicity against macrophage cells. They did not induce obvious hemolysis or cause significant platelet aggregation, but also did not activate any coagulation pathways. DOX release profiles of nanoparticles was p H-dependent. The cellular uptake of DOX-loaded PEM-MSNs in cancer cells was remarkably larger than that in normal cells. The cellular uptake of DOX-loaded PEM-MSNs in cancer cells was remarkably larger than that in normal cells, thus resulting in a desirable growth-inhibiting effect on cancer cells. DOX-loaded PEM-MSNs exhibited a slower and prolonged DOX accumulation in the nucleus than free DOX. In vivo biodistribution indicated that they induced a sustained drug concentration in blood plasma but lower drug accumulation in the major organs, especially in the heart, compared to free DOX.(2) No obvious histopathological abnormalities or lesions were observed in major organs after intravenous administration with DOX@(PAH/PSS)4-MSNs for 2 and 24 h, but a low level of hemorrhage or congestion was observed in the lung and spleen, which may be caused by nanoparticle accumulation in these organs. The particle aggregation could influence the long term biosafety. For practical drug delivery applications, the carrier materials should be biocompatible and biodegradable to minimize harmful side effects. Chitosan(CHI) and alginate(ALG) are biodegradable, biocompatible, and natural marine based polysaccharides. Herein, we present a facile strategy for the synthesis of functionalized MSN-based nanocarriers with p H-responsive delivery behaviors and improved biosafety features. For this purpose, MSNs were synthesized and then Lb L assembled with alginate/chitosan multilayers to act as p H-sensitive gatekeepers and biocompatible shell layers. MSNs were synthesized, modified and served as cores around which the two bilayers of ALG/CHI were alternatively assembled. The nanoparticles exhibited good dispersity in aqueous solution, and the measured hydronamic size was 167 nm. The release of DOX from nanocarriers was p H-dependent, and the release rate increased with the decrease of p H value. The in vitro evaluation on He La cells showed that the DOX-loaded nanocarriers provided a sustained intracellular DOX release and a prolonged DOX accumulation in the nucleus, thus resulting in a prolonged therapeutic efficacy. In addition, the pharmacokinetic and biodistribution studies in healthy rats showed that DOX-loaded nanocarriers had longer systemic circulation time and slower plasma elimination rate than free DOX, giving a half-time(t1/2) of 262.5 h, which were 4.1 times longer and than free DOX. The histological results also revealed that the nanocarriers had good tissue compatibility. Due to the chemical versatility, both ALG and CHI in shell layers can be further reacted with multifunctional molecules such as thermoresponsive polymers and/or targeting ligands, thus allowing construction of multiresponsive nanocarriers.(3) Most of the previous reports were based on the chemically exfoliated Mo S2 nanosheets, which required complex fabrication process and is difficult to control the size and thickness of nanosheets. Based on the design concept of “efficient photothermal agent”, flower-like Mo S2-PEG nanoflakes were first synthesized via a facile hydrothermal method and then modified with lipoic acid-terminated polyethylene glycol(LA-PEG), endowing the obtained nanoflakes with high colloidal stability and very low cytotoxicity. The photothermal conversion efficiency of the synthesized Mo S2-PEG nanoflakes was calculated to be 27.6%. Our results also demonstrated that the photothermal treatment of cancer cells could damage the integrity of lysosomal membrane and cell skeleton and therefore efficiently kill cancer cells, which would be promising materials for future photothermal therapy applications.(4) Based on the design concept of “multifunctional and efficient photothermal agent”, a triple-functional theranostic agent based on the co-integration of gold nanorods(Au NRs) and superparamagnetic iron oxide(Fe3O4) into polypyrrole(PPY) was developed. A NIR-absorbing conjugated polymer, PPY, was first used to encapsulate Au NRs and obtain Au/PPY nanoparticles by iron cation-mediated oxidation polymerization. After this process, a large number of ferric(Fe3+) and ferrous ions(Fe2+) remained in the obtained Au/PPY nanoparticles. These residual Fe ions subsequently served as precursors to form Fe3O4 crystals in situ on the surface of presynthesized Au/PPY nanoparticles and thus obtain a theranostic agent. Such a theranostic agent(referred to as Au/PPY@Fe3O4) not only exhibits strong magnetic property and high near-infrared(NIR) optical absorbance, but also produces high contrast for magnetic resonance(MR) and X-ray computed tomography(CT) imaging. Importantly, under the irradiation of NIR 808-nm laser at the power density of 2 W/cm2 for 10 min, the temperature of the solution containing Au/PPY@Fe3O4(1.4 mg/m L) increased by about 35 oC. Cell viability assay showed that these nanocomposites had low cytotoxicity. Furthermore, in vitro photothermal treatment test demonstrates that the cancer cells can be efficiently killed by the photothermal effects of the Au/PPY@Fe3O4 nanocomposites. This study demonstrated that the highly versatile multifunctional Au/PPY@Fe3O4 nanocomposites have great potential in simultaneous multimodal imaging-guided cancer theranostic applications.In conclusion, we hope the above results greatly promote the application of MSNs, Au NRs, Mo S2, PPY and Cu S-based nanomaterials in nanomedicine, as well as provide new impetus to the future explorations of functional nanomaterials in cancer therapy. |
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