Experimental Research On Nuclei-targeting Radiotherapy For Malignant Tumors Based On Nuclear-nanomedicine

BackgroundThe study combining radionuclides with nanomaterials to improve tumor treatment is an integration of cross-disciplinary fields,which has unique significance for scientific research and potential prospect for clinical application.However,most of the existed studies about this combination merely utilize nanomaterials as a carrier of radionuclides in a almost mechanical manner,which generates a pure plus of the biological effect of each of the two components.To find a method that can tactfully combine their separate properties to exert certain mutual reaction,can not only benefit the effective utilization and simplify the design of materials,but also contribute to a highly-efficient tumor treatment via a synergistic effect.This thesis was focused on above scientific ideas,and supported by our long-term partner,the biochemistry of rare-earth and medical functional materials team from Shanghai Institute of Ceramics,Chinese Academy of Sciences,who has advanced techniques in synthesizing nanomaterials.We skillfully combined the clinically common used radionuclides with specific properties,with nanomaterials that have mature synthesis technology,and constructed two types of nuclide-nanocomposites based on their complementary advantages.Confirmed by a series of biological examinations,both the two designed structures in this research have realized a synergistically enhanced and highly-efficient tumor treatment.Detailedly,it contains two aspects of contents:Research contents and results1.¹³¹I-AuNPs-TAT-based Nuclei-targeting Internal Radio-immunity Therapy for TumorUtilizing a modified nonpolar reduction method,Aunanoparticles（AuNPs）with a uniformly ultra small size（diameter,8.36 nm）were successfully fabricated,which have favourable dispersity and stability.Further,the cell penetrating peptide（TAT）was conjuncted onto the surface of AuNPs,and the produced AuNPs-TAT displayed a superior performance for nuclei targeting under the observation of confocal microscopy and biological-transmission electron microscope（bio-TEM）.Finally,a classical Iodogen-catalyzed method was used for ¹³¹I labeling,and the final product(¹³¹I-AuNPs-TAT)was obtained with an initially high labeling rate and good stability in vitro.In this nuclear-nanocomposite,TAT peptide targetedly delivered ¹³¹I into the cell nuclei for a direct damage to DNA.Meanwhile,AuNPs induced the conversion ofβ-rays emitted from ¹³¹I to form X-rays,which can not only enlarge the radiation coverage,but also initiate an immunity-enhancement effect.According to the experimental results in vitro and in vivo,this composite material can obviously suppress the growth of colon tumor,thus synergistically enhancing the efficacy of ¹³¹I-induced IRT.Herein,we proposed a novel method named internal radio-immunity therapy（IRIT）,and the synthetic process and functional mechanism of ¹³¹I-AuNPs-TAT were summarized as the following schematic diagram:2.¹²⁵I-TiO₂-TAT/HA2-based Lysosomes-escaping and Nuclei-targeting Catalytic Internal Radiotherapy for TumorWith a typical solvothermal method,the highly-active single crystal TiO₂nanoparticles（TiO₂NPs）with anatase（101）crystal face were successfully synthesized.The TiO₂NPs were in a good uniformity with rhombus-shaped morphology,and the average particle diameter was 11.78±2.23 nm in length and 3.91±0.56 nm in width.Further,the fusion peptide TAT/HA2,with dual function of escaping from lysosome and targeting into cell nuclei,was conjuncted on the surface of TiO₂NPs to form TiO₂-TAT/HA2 and subsequently observed under bio-TEM to confirm its function.At last,the radionuclide ¹²⁵I was labeled on TiO₂-TAT/HA2 via the Iodogen-catalyzed method,and the production ¹²⁵I-TiO₂-TAT/HA2 displayed a good stability in vitro.In this structure,TAT/HA2 mediated the targeted killing of ¹²⁵I to the nuclei DNA.Simultaneously,the reaction between auger electrons（AEs）of ¹²⁵I and TiO₂will catalyze the activation of water molecules,which further facilitating the generation ofγ-rays-induced cytotoxic·OH.Demonstrated by the in vitro and in vivo experiments,¹²⁵I-TiO₂-TAT/HA2 can significantly control the progression of pancreatic tumor,and obviously improve the ¹²⁵I-induced tumor IRT.The most attractive innovation of this work lies in that,it effectively utilizing ¹²⁵I as an electron donar for the catalytic excitation of TiO₂NPs and activation of water molecules,which further facilitated the process ofγ-rays-induced water radiolysis,thus generating a larger amount of·OH and finally realizing a highly-efficient tumor treatment.This innovative strategy was named as catalytic internal radiotherapy（CIRT）,and the functional mechanism was summarized as follows:DiscussionRadiotherapy plays an important role in the regular treatments of malignant tumors,among which the internal radiation therapy（IRT）attracts much attention for its special advantage of low side effects for normal tissue compared to the external radiation therapy.In IRT,radionuclides take the anti-tumor function via decaying various rays.However,the drawback of certain types of radiation rays,e.g.insufficient energy and deficient penetration depth,limits the therapeutic efficiency and clinical application of radionuclides.In recent years,there has been a fast development of nanomaterials in medical application,while related research in IRT has a quite limited number and research content,which indicates a broad space of study and development.Thus,in this thesis,we make an initial exploration with the aim of finding new ideas and approaches for tumor treatment.With the aim of improving the treatment efficacy of tumor and promoting people’s health,our group makes an in-depth research of new strategies for improving cancer treatment.Upon analyzing the decaying rays of clinical common radionuclides(¹³¹I,¹²⁵I),we fabricated two specific nanomaterials（AuNPs,TiO₂NPs）with special properties,and utilized tactful synthesizing technics to combine radionuclides with nanomaterials,which can exert the complementary advantages through certain physical and chemical reactions.A series of experimental detections have demonstrated the superior effects of both two composites for tumor treatment,and we further conducted a deep exploration and rigorous verification for the related mechanism.In summary,this research combines the feature of the decay product of radionuclides with the superior property of nanomaterials via ingenious design,and realized two types of highly-efficient tumor therapies named“IRIT”and“CIRT”,respectively.These designs are not only promising in broadening the clinical application of nuclear-nanomedicines,but has also provided new ideas and new strategies for the scientific study of tumor treatment.