Study On The Preparation Of Protoporphyrin-based Nanoplatform And Application In Theranostic For Tumor Therapy

Constructing one nanoplatform combined imaging and therapy,which can reduce time-cost during diagnosis and treatment,has become a hotspot with rapid development in nanomedicine.Photodynamic therapy(PDT)is one tested treatment in clinical anti-tumor trails.Compared to chemotherapy and radiotherapy,PDT is disease site-specific,minimally invasive,less systemic toxicity and side-effect.However,the unusual metabolism in malignant tumor make it hypoxia,which is against the oxygen-consuming therapy.How to solve this dilemma become a spot to improve therapeutic efficiency in PDT.In addition,it is of significance to make the whole therapy visible.Not only can it provide guidance prior to treatment and prognosis evaluation but save cost of operations.The aim of this thesis is to construct“smart”nanoplatform based on protoporphyrin.Integrate diagnosis and therapy in one to improve therapeutic efficiency and explored the application in bioimaging and anti-cancer effect.First,consider to realize synergetic therapy,in the second chapter,we construct GNRs@BPP-Gd nanoparticle which was gold nanorods(GNRs)coated by protoporphyrin-protein complex.The hyperthermia induced by photothermal effect stemming from GNRs can improve blood circulation to boost oxygen content at tumor site,thereby to achieve synergetic therapy.The obtained GNRs@BPP-Gd had a uniform morphology,good thermal and solution stability.CCK-8 assay showed that under dark condition,GNRs@BPP-Gd had little toxicity to4T1 cell.When treated by illumination,the cell viability was lower in synergetic treatment compared with single treatment.The relaxivity of GNRs@BPP-Gd was 9.522 m M^-1s^-1,which was three times higher than Magnevist?.GNRs@BPP-Gd can accumulate effectively on 4T1tumor and provided magnetic resonance imaging(MRI)in high quality.4T1 tumors were inhibited in two weeks indicated GNRs@BPP-Gd could serve as MR imaging-guided photothermal and photodynamic synergetic therapy agent.Additionally,based on the unique microenvironment in tumor,in the third chapter,we chose?-ALA,a precursor of Pp IX in the biosynthesis pathway in mitochondria,as our photodynamic therapeutic agent.A mitochondria-targeted ligand was modified with?-ALA to increase the endogenous synthetic yield of Pp IX.In order to realize stimuli-response at tumor region,manganese dioxide was synthesized by biomineralization to obtained“smart”Tar A@b M nanoparticle.Meanwhile,manganese dioxide could react with the high concentration of hydrogen peroxide in tumor site to release oxygen to relieve hypoxia.Under illumination condition,the overproduced reactive oxygen species(ROS)can attact mitochondria to promote apoptosis.The obtained Tar A@b M nanoparticle was in uniform size and good stability.The stimulated stimuli-responsive assay identified that?-ALA can be controlled release under GSH,p H and enzyme condition.The mitochondria-target assay demonstrated that Tar A@b M possessed good mitochondria targeted ability,and had a high level of Pp IX in endogenous synthetic.MRI test demonstrated that the relaxivity of Tar A@b M was5.410 m M^-1s^-1under acid condition which can be used as a guided prior to treatment.The fluorescent(FL)imaging result demonstrated that in situ FL can ensure the successful endogenous synthesis of Pp IX as well as make the whole treatment visible.In animal experiment,Tar A@b M treated group showed excellent anti-tumor effect on 4T1 tumor and had little influence on normal tissues based on relevant assay.All the results showed that Tar A@b M could serve as MR/FL imaging guided photodynamic therapy agent.