Construction Of Acid-activated Porphyrin Nanoparticles And Its Application In Tumor Diagnosis And Theranostics

Cancer has become the number one killer threatening human health,and the development of safe and efficient multifunctional nanomedical platforms can provide important tools for accurate diagnosis and effective treatment of tumors.Porphyrins have been widely applied in the fields of bioimaging and optical therapy because of their unique molecular structure and excellent optical properties.However,traditional porphyrin nanoparticles lack tumor targeting,and the activation state of“always on”is not conducive to the acquisition of pathological diagnostic information and inevitably causes non-specific damage to normal tissues.In view of the above problems,this thesis aims to construct multifunctional activated porphyrin nanoparticles,which can activate imaging and therapy functions in tumor cells,thus improving the accuracy of imaging and therapy.The main research content of this thesis is as follows:（1）Development of acid-activated porphyrin iron oxide nanoparticles for tumor photodynamic therapy（PDT）.We designed and synthesized a new p H-responsive porphyrin organic molecule（TFPP-PH）based on tetra（pentafluorophenyl）porphyrin（TFPP）,and self-assembled with Fe₃O₄ and tamoxifen（TAM）to construct acid-activated porphyrin iron oxide nanoplatforms（TFNP and TFNP-TAM）.The nanoparticles have p H-responsive fluorescence imaging,magnetic resonance imaging（MRI）properties and photodynamic effects.Compared with TFNP,TFNP-TAM exhibits better p H-responsive performance in solution with stronger fluorescence emission,higher reactive oxygen species（ROS）production（12-fold）,and more pronounced T₁-MRI contrast effects.Based on these properties,we applied TFNP-TAM to a mouse tumor model to achieve sensitive and accurate specific fluorescence/MRI dual-mode imaging and efficient PDT/chemotherapy combination therapy within the tumor.（2）Development of acid-activated manganese porphyrin nanoparticles for tumor chemodynamic therapy.We further introduced Mn²⁺with T₁-weighted imaging ability into the system to synthesize p H-responsive manganese porphyrin（Mn-TFPP-PH）,and self-assembled with TAM to construct acid-activated manganese porphyrin nanoparticles（Mn-TFNP-and Mn-TFNP-TAM）.The nanoparticles have p H-responsive MRI properties and catalytic activity.Under acidic condition,their longitudinal relaxation rate（r₁）increases,showing brighter T₁-MRI contrast.At the same time,as Fenton-like reagents,they can catalyze H₂O₂ to produce hydroxyl radical（·OH）.Compared with Mn-TFNP,Mn-TFNP-TAM showed better catalytic activity in solution.Both in vivo and in vitro experiments demonstrated that the manganese porphyrin nanoparticles have acid-activated MRI ability and TAM synergistic CDT/chemotherapy effect.（3）Development of H₂S-and ALP-stimulated responsive porphyrin nanoparticles.We further synthesized carboxylated metalloporphyrins and constructed H₂S-activated bimetallic nanoparticles Zn-Cu and Gd-Cu.Meanwhile,ALP or p H dual-activated Adenosine triphosphate（ATP）-porphyrin nanoparticles were constructed with protonated TFPP-PH.Upon stimulus triggering,the nanoparticles dissociate and release porphyrins,resulting in enhanced fluorescence emission and increased ROS production of porphyrins,exerting better imaging and photosensitive properties.