Preparation Of Acidic-Microenvironment-Gelatable Poly(amino Acid)s-Coated Nanoparticles And Application Of Combined Tumor Diagnosis And Treatment

Cancer is one of the major diseases which can threaten human health seriously.Thermal ablation technology is a new type of treatment developed in recent years,which has many advantages such as high efficiency,low side effects,and no damage to normal tissues.The paper systematically reviewed the research status of different types of thermal ablation therapy and related materials.On this basis,in view of the characteristics of transcatheter arterial embolization,such as minimally invasion,high efficiency,and easy to be combined with other treatment methods,in order to solve the problems about certain inherent risks,side effects and thermal ablation of traditional embolization treatment,the combination of hyperthermia and embolization was used,which makes tumor treatment simpler,more efficient and safer.Inspired by the tumor microenvironment responsive drug delivery system,the paper proposes to develop a series of pH-responsiveness composite materials which can be used as a non-invasive embolization material for hyperthermia,embolization,diagnosis and treatment integration.The composite materials were composed of responsive triblock poly?amino acid?s?PGTTC?coated inorganic nanoparticles?Au,Fe₃O₄,Fe₃O₄@Au?,with a view to achieving efficient and non-invasive combined diagnosis and treatment of tumors that cannot be surgically removed.In this paper,a series of pH-responsive composite materials of triblock poly??L-glutamic acid-L-tyrosine?-L-threonine-?L-glutamic acid-L-tyrosine?-L-cysteine?)?PGTTC?with an adjustable pH value was synthesized by the ring-opening polymerization of N-carboxycyclic anhydrides?NCAs?,and then compounded with Au nanoparticles.The polymer structures,average molecular weight,degradabilities,the response performances,photothermal effects,and biocompatibilities of the composite materials were tested,and the results showed that the polymer structures were in line with forecast,whose pH response pH value in the range of 4.0-6.6 could varyied with the adjusting of the ratio of L-glutamicglutamic acid to and L-tyrosinetyrosine in the polymer.The composite materials are also with excellent biocompatibilities and photothermal effects.In order to verify its tumor diagnosis and treatment effects,H22 tumor-bearing mice and VX2 tumor-bearing rabbits were used as experimental models,respectively,and saline solutions of the composite materials were injected through the tail veins or the ear veins.Then SPECT-CT,Magnetic resonance imaging?MRI?,small animal in vivo fluorescence imaging,computed tomography?CT?,digital subtraction angiography?DSA?and other systems were used to evaluate the tumor targeting acumlation abilities,vascular embolization treatments,and photothermal effects of the composite materials.The results showed that the composite materials can be fully acumlated in the tumor site and vascular embolism occurred after 24 h after injection,then the tumor tissues disappeared after the 30 days.Compared with simple embolization therapies,laser photothermal therapy has significant thermal effects,and the ablation and necrosis of tumors in the photothermal-embolization treatment groups were significantly accelerated,and the tumor tissues completely disappeared within 20 days.Since the photothermal therapis is only applicable to the treatment of superficial epidermal tumors,in order to implement thermal ablation-embolization combined diagnosis and treatment for deep-body tumors such as liver tumors,PGTTC coated Fe₃O₄ were used in this paper to obtain Fe₃O₄@PGTTCs,which showed excellent magnetocaloric effects under the Alternating Magnetic Field?AMF?,and its temperature can reach 50?after 5min in vitro,and the temperature inside the tumor can reach 62.8?.Compared with the embolization therapy alone,the combined magnetocaloric therapy can effectively accelerate the necrosis of tumor tissue.H&E pathological sections showed that the tumor cells almost disappeared,and no recurred.Ki-67 pathological section staining showed that the apoptosis level of tumor tissues increased,and the number of dividing cells decreased sharply.The MRI results showed that the materials can be used as an effective negative MRI contrast agent to achieve the integration of combination therapy and multi-modality imaging.In order to give the materials more functionality,Au loaded Fe₃O₄nanoparticles were prepared and Fe₃O₄@Au@PGTTCs composite material was prepared to realize photo-magnetocaloric and CT-MR integrated embolization-thermal ablation diagnosis and treatment.The results showed that Fe₃O₄@Au@PGTTCs had favourable CT and MR contrast effects and photothermal-magneto-thermoembolization combined treatments.Animal experiments showed that the tumors were necrotic and ablated within 15 days after treatment,and there was no recurrence.,Indicating that the composite materials have not only excellent multimodal contrast effects,but also excellent combined therapeutic effects.