The Construction Of Phototherapeutic Agents Based Diketopyrrolopyrrole Derivatives And The Study For Anti-tumor Properties

Currently,cancer has become a major killer of human health.The traditional tumor treatment methods of surgery combined with chemotherapy and radiotherapy are ineffective due to their side effects and non-selective nature,while causing great pain to patients.Therefore,the safer and more effective tumor treatments are urgently needed.With the development of nanotechnology,tumor phototherapy has received wide attention because of its light controllable,non-invasive and high select,and a series of studies have been conducted in preclinical and actual clinical treatment.Phototherapy includes photothermal therapy(PTT)and photodynamic therapy(PDT).Among them,PTT is the conversion of light energy from near-infrared light to heat energy by photothermal agents at the tumor site,thus causing tumor cells die via overheat.PDT is a photosensitized energy transfer process involving oxygen molecules,which eventually produces cytotoxic reactive oxygen species and kills tumor cells.However,traditional phototherapeutic agents often have disadvantages such as poor biocompatibility,low photostability,weak light absorption and complex structural modifications.And traditional single phototherapeutic means also have defects such as tumor cell thermal tolerance resistance,solid tumor hypoxia and limited light penetration depth,which make it difficult to completely cure tumors by phototherapy.Herein,this dissertation designs and synthesizes two novel diketopyrrolopyrrole(DPP)derivatives and self-assembles them with two drugs to prepare multifunctional nanomedicines,respectively,realizing a multimodal synergistic tumor treatment strategy.The main research includes the following two aspects:1.In order to realize the triple synergistic tumor treatment strategy of phototherapy/chemotherapy/anti-angiogenic therapy,nano-self-assembly of chemotherapy and anti-angiogenic agent protocatechuic acid with a synthetic nearinfrared phototherapeutic agent(DPP-BPA)to obtain a nanotherapeutic platform with multiple functions.Meanwhile,to increase drug accumulation at tumor sites,homotypic cancer cell membranes were encapsulated on the surface of BPP NPs,which were prepared to evade immune cell phagocytosis to increase drug accumulation,and mimetic cancer cell membrane-encapsulated nanodrugs(m BPP NPs)with both homologous targeting and immune evasion functions were prepared.Both cellular experiments and in vivo experiments in tumor-bearing nude mice demonstrated the biocompatibility,excellent phototoxicity and strong anti-angiogenic ability of m BPP NPs,which can trigger a large number of cancer cells to apoptosis and present good anti-tumor effects.2.In order to overcome the existence of inflammatory response and thermal tolerance resistance to phototherapy,the natural product quercetin was self-assembled with synthetic NIR phototherapeutic agent DPP-RD nano to prepare RD/Qu NPs with high photothermal conversion efficiency(50%)and high photostability,which realized the efficient multimodal synergistic therapy of photothermal/photodynamic/chemotherapy.Cellular experiments demonstrated that RD/Qu NPs have excellent biosafety,ideal low-dose phototoxicity,and good synergistic effects;in vivo experiments in tumorbearing nude mice demonstrated that RD/Qu NPs can be enriched in a large number of fast tumor sites and exert synergistic ablation of tumors under laser irradiation.RD/Qu NPs may become a versatile platform for future tumor treatment.