| Cancer has been one of the biggest risks to human health since 21 st century. Various methods for cancer diagnosis and therapy have been emerged with the development of nanotechnology. Furthermore, novel theranostic nanomedicine capable of precise cancer diagnosis and highly efficient therapy have attracted more attention from researchers. Recently, albumin has been developed as drug nanocarriers for cancer theranostics application due to its superior biocompatibility. In this study, Gd2O3@albumin nanoparticles with tunable particle size were synthesized using albumins as nanoreactors. With surface modification of a photosensitizer(PS) chlorin e6(Ce6) via amidation, a theranostic nanoparticle(SM-NPs) was achieved for successful magnetic resonance imaging(MRI) guided photothermal/photodynamic therapy of tumors.These investigations are shown as follows:Chapter 1. This chapter is an overall introduction of Gd2O3 MRI agents, photothermal/photodynamic therapy of tumors, theranostic nanomedicine and protein-based nanocarriars.The basis and main contents of this dissertation are listed.Chapter 2. Gd2O3 nanocrystals were synthesized using bovine serum albumin( BSA) as nanoreactors, with tunable particle sizeswell regulated through reaction time(4.7±0.5 nm for 4 h,5.1±0.4 nm for 8 h,10.1±1.2 nm for 12 h, respectively). A typical PS Ce6 was further conjugated to the protein corona of the nanoreactor through facile chemical coupling, resulting in the theranostic SM-NPs. SM-NPs showed a typical core-shell nanostructure with a single layer protein for the shell and Gd2O3 nanocrystals for the core.Chapter 3. Further characterization of SM-NPs was carried out, showing concentration-dependent photothermal effect and abundant ROS productivity of SM-NPs upon a 660 nm irradiation. Furthermore, compared with free Ce6, SM-NPs can effectively improve the photostability and chemical stability of Ce6. And SM-NPs with relatively suitable size hold a higher r1 value than that of clinical MR agent Gd-DTPA.Chapter 4. In vitro cell studies including cellular uptake, intracellular ROS, photo-cytotoxicity, as well as lysosomal disruption were investigated. Firstly, the cellular uptake amount of SM-NPs, which is also time-dependent, was much higher than that of free Ce6. Upon irradiation, SM-NPs can effectively generate intracellular ROS at an even low concentration, followed by severe lysosomal disruption. For the evaluation of photo-cytotoxicity, SM-NPs primarily possessed photodynamic cytotoxicity at relatively low doses of Ce6 under irradiation, while higher doses could cause remarkable photothermal damage, indicating that SM-NPs can effectively generate severe photo-cytotoxicity, owing to enhanced cellular uptake of Ce6 and effective singlet oxygen and photothermal effect.Chapter 5. In vivo evaluation showed that SM-NPs can distribute into tumors at 24 h post-injection via EPR effect by analysis of Ce6 fluorescence signals as well as Gd concentration. With enhanced tumor accumulation, SM-NPs exhibited stronger MR signals in tumor site during 24 h post-injection. When exposed to the 660 nm irradiation, SM-NPs resulted in the temperature elevation of 13oC at tumor site indicating a potent hyperthermia owing to their remarkable photothermal effect. With a single dose of SM-NPs(5 mg kg-1), tumor-bearing-mice were irradiated with single wavelength laser. As a result, SM-NPs showed more significant photo-damage against the tumors as compared to free Ce6, probably owing to their enhanced tumor accumulation, and preferable photo-induced cytotoxicity.In summary, we fabricated albumin composite theranostic nanoparticles through hollow albumin as the nanoreactor, and explored their applications in MR imaging and phototherapy. The albumin composite theranostic nanoparticles would have promising potentials in the field of cancer theranostics. |
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