Synthesis Of Multifunctional PLGA Nanotheranostics And Its Application In The Tumor Visible Chemo-Photothermal Therapy

Background:Malignant tumor is one of the biggest killers of human health today.Therefore,the early diagnosis and non-toxic treatment of cancer has become the biggest challenge of the current cancer diagnosis and treatment.Photothermal therapy?PTT?is a minimally invasive treatment of cancer developed in recent years.The light-absorbing materials?photothermal therapy agent?can convert light energy into heat under the external light source to kill tumor cells.The systemic toxicity can be greatly reduced by the tumor targeting and selective exposure to the tumor site.The ideal photothermal therapeutic should have strong absorption in the near infrared light region?650-950 nm?and biosafety.In addition,the successful PTT also need to rely on the appropriate imaging technology to determine the location of the tumor,the size,in vivo distribution and enrichment in tumor tissue.We should monitor the changes of the temperature of tumor and surrounding healthy tissue during PTT and evaluate the therapeutic effect at the same time.Therefore,it has become a hot topic recently to endow the photothermal therapy agents with the proper imaging function to improve the effiency and accuracy of PTT.In order to achieve this goal,the design and preparation of nanotheranostics,which integrate diagnosis and photothermal therapy,has become one of the most ideal strategies.Poly?lactic-co-glycolic acid??PLGA?is a macromolecular organic compound synthesized by random polymerization of two monomers,lactic acid?LA?and glycolic acid?GA?,which show good biocompatibility,biodegradability,mechanical strength and plasticity.PLGA passed the FDA certification,officially listed as a pharmaceutical excipient into the United States Pharmacopoeia.As reported,by endowing the PLGA system with the specific function,the structural modification of the PLGA system could be realized.Thus,PLGA-based system not only can be used as a clinical molecular imaging probe to diagnose diseases,but also can effectively load and deliver drugs for disease treatment.This paper studied two kinds of PLGA nanotheranostics which could be used for the tumor visible chemo/photothermal synergistic therapy,and we evaluated the structures and properties of the PLGA nanotheranostics in detail.Purpose:Nanocarriers based deliver system,which can implement high performances of multi-functions,are of great interest,especially for improving cancer therapy.At the same time,imaging-guided diagnosis and therapy has been highlighted in the area of nanomedicines.However,integrating multiple functions with high performance in one theranostic?'all-in-one'?still presents considerable challenges.Herein,we reported a new approach to construct Mn²⁺-coordinated doxorubicin?DOX?-loaded poly?lactic-co-glycolic acid??PLGA?nanoparticles,combined with the performance of magnetic resonance imaging.Mn²⁺-PDA@DOX/PLGA nanoparticles could be used as a platform for synergistic chemo-photothermal tumor therapy.And then,for further promote the construct of 'all-in-one'nanoparticles,we prepared a hybrid nanoparticles with drug-loading capacity,catalase-mimetic activity,photoacoustic?PA?imaging ability and photothermal properties by decorating Au nanoparticles on a doxorubicin?DOX?-loaded poly?lactic-co-glycolic acid??PLGA?vehicle.Method:Chapter 1 Mn²⁺-coordinated PDA@DOX/PLGA nanoparticles as a theranostic agent for synergistic chemo-photothermal tumor therapyDOX-loaded PLGA?DOX/PLGA?nanoparticles were first synthesized through a double emulsion-solvent evaporation method,and then modified with polydopamine?PDA?through self-polymerization of dopamine,leading to the formation of PDA@DOX/PLGA nanoparticles.Mn²⁺ ions were then coordinated on the surfaces of PDA@DOX/PLGA to obtain Mn²⁺-PDA@DOX/PLGA nanoparticles.The physical and chemical characteristics of the nanotheranostics were analyzed by means of various detection methods,including size distribution,structural characteristics,optical properties,drug loading and release properties.We construct the subcutaneous xenograft tumor model of CT26 tumor cells in mice and explored the effect of magnetic resonance imaging in vivo and in vitro.Then we evaluated the biological safety of the nanoparticles,including cytotoxicity test,tumor cell uptake experiment,biocompatibility and in vivo distribution analysis.Last,the therapeutic effects of the synergistic drug and the photothermal agent on the tumor-bearing mice were investigated.Chapter 2 Au-PLGA hybrid nanoparticles for PA imaging-guided cancer synergistic chemo-photothermal tumor therapyPLGA/DOX@PDA NPs were prepared according to our previous work,and then HAuCl4·3H2O was added to the PLGA/DOX@PDA NP suspension.The obtained PLGA/DOX@PDA-Au NPs suspension was mixed with PEG-NH2,and PEG-modified PLGA/DOX@PDA-Au NPs?PLGA/DOX@PDA-Au-PEG NPs?were finally synthesized.The morphology and structural characteristics of nanoparticles were discussed.Meanwhile,in vitro performances of Au nanoparticles were investigated,including stability,photoacoustic imaging,biocompatibility and photothermal properties,catalase-mimicking activity,the release of DOX and the uptake of cells.The model of 4T1 tumor-bearing mice was constructed to evaluate the in vivo effects of nanoparticles,including the distribution of the nanotheranostics,PA imaging,the synergistic anticancer activity and the biocompatibility.Results:Chapter 1:The synthesized Mn²⁺-PDA@DOX/PLGA nanoparticles were spherical,with a diameter of about 200 nm,and were uniformly dispersed.Meanwhile,Mn²⁺ was successfully attached to the surface of PDA@DOX/PLGA nanoparticles.In our system,Mn²⁺-PDA@DOX/PLGA nanoparticles could destroy tumors in a mouse model directly,by thermal energy deposition,and could also simulate the chemotherapy by thermal-responsive delivery of DOX to enhance tumor therapy.Furthermore,the coordination of Mn²⁺ could afford the high magnetic resonance?MR?imaging capability with sensitivity to temperature and pH.The results demonstrated that Mn²⁺-PDA@DOX/PLGA nanoparticles had a great potential as a theranostic agent due to their imaging and tumor-growth-inhibition properties.Chapter 2:The synthesized Au-PLGA hybrid nanoparticles were spherical,with a diameter of about 200 nm.Au was uniformly distributed on the surface of the nanoparticles.Meanwhile,the connection of PEG greatly enhanced the water solubility and stability of the nanoparticles.The results revealed that the as-prepared Au-PLGA hybrid nanoparticles possessed high photothermal conversion efficiency of up to approximately 69.0%,meanwhile their strong acoustic generation endowed them with efficient PA signal sensing for cancer diagnosis.On an 808 nm laser irradiation,the O2 generation,DOX release profile and reactive oxygen species?ROS?level were all improved,which were beneficial to relieving tumor hypoxia and enhanced the cancer chemo/PTT combined therapy.Overall,the multifunctional Au-PLGA hybrid nanoparticles with these combined advantages can potentially be utilized for PA imaging-guided disease diagnosis and synergistic tumor ablation.