Design And Preparation Of Functional Nanocarriers Based On Porphyrin Core And Their Application Study In Dual Mechanism Combined Antitumor

Chemotherapy is one of the most important currently used treatment approaches for cancer,but chemotherapy drugs generally have shortcomings such as short half-life,severe side effects,and poor drug resistance.To a certain extent,nano drug delivery system(NDDS)can overcome the shortcomings of clinical chemotherapydrugs,which can solubilize chemotherapeutic drugs,increase the circulation time of drugs in the blood,and target drug delivery.However,the treatment effect of monomodal chemotherapy is not as excellent as expected,therefore,researchers have begun to explore new treatment methods,such as immunotherapy,photothermal therapy,gene therapy,and photodynamic therapy etc..People have found that the therapeutic effect of combined treatment with chemotherapy and new treatment method is better than that of chemotherapy or new treatment method.Photodynamic therapy(PDT)is a treatment method that the photosensitizer can generate reactive oxygen species(ROS)after being excited by laser irradiation with a specific wavelength,and which can induce necrosis or apoptosis of cancer cells.The treatment method plays a role in diagnosing and treating tumors.Due to the high ROS yield from chlorin(Ce6),indocyanine green(ICG),porphyrin,etc.,they are usually used as photosensitizers.Since most photosensitizers are hardly soluble in water,they must be modified by water-soluble or functional molecules and self-assemble into nanocarriers before biological applications.Therefore,the rational designing of the carrier material is the key to the ideal therapeutic effect of PDT.However,the designing of carrier materials usually has a series of problems such as difficulty in the synthesis of the materials and high cost.More importantly,the introduction of complex compounds in the carrier materials makes them having a large potential metabolic toxicity.Therefore,in recent years,in order to avoid side effects caused by the carrier materials or its degradation products,excipients approved by the FDA and EMA have attracted increasing attention from researchers.In this work,we tried the carrier-free transport of photosensitizers.In the system,we focus on the carrier-free transport of photosensitizers by designing functional molecules to self-assemble into nanomicelles,so as to achieve the purpose of photosensitizers transporting chemotherapy drugs while self-transporting.The main content of the paper is as follows:1.Preparation of mPEG-modified porphyrin core functional nanomicelles and their application in synergistic antitumor.In this chapter,the FDA-approved polyethylene glycol derivative(mPEG)was coupled to the porphyrin(TAPP)through amidation reaction to form a functional amphiphilic polymer TAPP-4mPEG with a photodynamic effect.The amphiphilic polymer self-assembles in an aqueous solution to form a nanomicelle,which particle size is about 18 nm.The reactive oxygen probe 1,3-diphenylisobenzofuran(DPBF)is used to detect reactive oxygen species(ROS)generated by laser irradiation.The test results showed that ROS generated,which proved that they could be used in photodynamic therapy.The anti-tumor drug(paclitaxel,PTX)was loaded into the porphyrin core nanomicelles to achieve the combined treatment of chemotherapy and photodynamic therapy.The results of in vivo and in vitro experiments show that the combined treatment of chemotherapy and PDT can significantly inhibit tumor growth,prolong the survival time of tumor-bearing mice,and dose not have significant damage to the normal organs.2.Preparation of TPGS-modified porphyrin core functional nanomicelles and their application in synergistic antitumor.D-alpha-Tocopheryl polyethylene glycol succinate(TPGS)is an FDA-approved PEGylated derivative of vitamin E,in addition to the properties of polyethylene glycol,it can also improve cell uptake improve cellular uptake and the solubility of various drugs,can inhibit tumor cell proliferation,promote apoptosis,regulate the cell cycle,inhibit tumor cell migration,and assist drugs to treat cancer.First,TPGS is carboxylated,and then carboxylated TPGS(C-TPGS)and hydrophobic porphyrin(TAPP)are connected through an amidation reaction to synthesize a functional amphiphilic polymer TAPP-TPGS with photodynamic effect and assist anti-tumor effect.The amphiphilic polymer self-assembled into stable nanomicelles in aqueous solution,which particle size is about 20 nm.TAPP-4TPGS has similar properties to TAPP-4mPEG,but its tumor suppressing effect is higher than TAPP-4mPEG.Cytotoxicity experiments show that TPGS has an inhibitory effect on tumor cells,and at the same time,it does not show obvious toxic side effects on normal cells within a certain concentration range,that is to say introducing TPGS can further improve the tumor suppressive effect of nano-medicine,and will not cause obvious damage to normal tissues.