Preparation of Porphyrin-based Nanomaterials and Antitumor Study

Author:Wang Kui

Supervisor:tian hua yu


Degree Year:2019





Cancer seriously threatens the health of humans,and the traditional therapy methods are poor effect,which can not meet people’s need for health.The emergence of nanomaterials will bring about crucial changes for humans health.Due to its unique structure and phototherapy function,porphyrins have received widespread attention in the field of tumor therapy.Molecular porphyrin have poor water solubility,which can cause porphyrin molecule aggregation influence tumor therapy effect.Porphyrin molecule can rapid metabolism in vivo,which are not benefit for blood circulation and tumor accumulation of porphyrin.Therefore,preparation of porphyrin nanomaterials can overcome above issue.In this paper,we choose porphyrin molecule as the monomer,and adopt the strategy of covalent bonding or non-covalent self-assembly to prepare nanoparticles of porphyrin.Thereforoe,in vivo blood circulation,tumor accmulation ability,and anti-tumor therapy effect of porphyrin are improved.Firstly,photodynamic therapy(PDT)still faces a key challenge associated with its oxygen-dependent property,which limits its therapeutic efficiency against hypoxic tumor.To address the problem,porphyrin based covalent organic nanosheets(CONs)are prepared with molecular heterostructure.The molecular heterostructure of CONs can afford highly efficient charge carrier separation,a long lifetime of electrons and holes can be obtained,the electrons can reduce O2 to form O2·-,and at the same time,the holes can oxidize water to produce·OH.Therefore,type Ⅰ PDT can be obtained.On the other hand,the recombination of electrons and holes can result in an important non-radiative attenuation,and thus the energy is emitted as the heat.A combination of type Ⅰ PDT and photothermal therapy(PTT)serve as an effective way to get around the difficulties of hypoxia in type Ⅱ PDT.Intravenous injection of CONs in nude mice followed by the combination of type Ⅰ PDT and PTT under single wavelength irradiation achieve significant tumor ablation.We have further developed porphyrin-based covalent organic framework(COFs)nanocomposites to expand the biomedical applications of porphyrin-based nanomaterials.The low dispersibility and aqueous stability of COFs are intractable issue retarding the biomedical applications.To address the issue,water-dispersible nanocomposites(COF@IR783)through the assembly of cyanines and COFs are firstly proposed and prepared.Therefore,a strategy "killing three birds with one stone" is developed.Firstly,the dispersibility and aqueous stability of nanocomposites are improved compared to COFs.The nanocomposites have nano-sized morphology and negative charges,which are beneficial in realizing the long circulation properties and enhanced permeability and retention(EPR)mediated tumor targeted delivery for in vivo application.Secondly,the nanocomposites have enhanced PTT ability at near-infrared region compared to cyanines.The nanocomposites also have photoacoustic(PA)imaging ability,which can guide the antitumor therapy in vivo.Lastly,the nanocomposites can be further used as drug-delivery carriers for loading anticancer cis-aconityl-doxorubicin(CAD)prodrug becoming COF@IR783@CAD.In comparison with individual PTT or chemotherapy,the combinational PTT and chemotherapy of COF@IR783@CAD achieve significant tumor ablation.Immunotherapy has become a promising therapy method for cancer,but it is only effective in a small number of patients.However,phototherapy can cause immunogenic death of tumor cells,which can improve the immunotherapy of cancer.We have developed porphyrin-based nanomaterials by multi-component self-assembly,which can achieve photodynamic/photothermal therapy guided by photoacoustic imaging and release tumor-associated antigens.In vivo experiments have demonstrated its good tumor accumulation ability and anti-tumor therapeutic effect.When phototherapy is combined with anti-programmed death ligand 1(a-PD-L1),the results of 4T1 bilateral tumors in vivo indicate that the combination of phototherapy and immunotherapy can not only inhibit the growth of the original tumor,but also significantly inhibition of the growth of distant tumor.Mechanism studies have shown that phototherapy performed by nanomaterials of porphyrin can significantly enhance the infiltration of killer T cells in the tumor sites.Therefore,we have addressed the solubility and aggregation problem of porphyrins by establishing three nanomaterial methods mentioned above,and extended the application of porphyrin in tumor therapy.