Construction And Characteristic Evaluation Of A Photothermally Responsive Polydopamine Nanometer Drug Delivery System

In this study,polydopamine（PDA）-coated poly（lactic-co-glycolic acid）（PLGA）nanoparticles were prepared by emulsification-solvent evaporation method and co-incubation method,and were grafted with targeting ligand folic acid（FA）and long-cycle polymers.Polyethylene glycol（PEG）was used to construct a new nanocarrier system DOX-PLGA@PDA-DOX/PEG/FA with tumor targeting and photothermal response.The drug loading system utilizes the tumor targeting of folic acid ligand and the long-cycle effect of PEG to improve the anti-tumor effect of DOX and combines the photothermal effect of polydopamine to provide diverse options for chemotherapy and photothermal treatment of tumors.Orthogonal experiments were used to optimize the preparation process of DOX-PLGA nanoparticles.When the drug loading ratio was 1:5,the oil-water ratio was 1:10,and 300 W was sonicated for 5 minutes,the amount of triethylamine was 10μl,the PVA concentration was 1%,and acetone was used as the solvent At the time,DOX-PLGA nanoparticles had the best encapsulation efficiency of 86.55%and drug loading capacity of 16.98%.DOX-PLGA@PDA-DOX/PEG/FA nanoparticles coated with PDA and ligands were prepared by co-incubation.The orthogonal experiment results showed that when the incubation ratio（DOX-PLGA:DA）was 1:5,incubation When the time is 10h,the incubation pH is 8.0,and the dosage of DOX is 0.5mg,DOX-PLGA@PDA-DOX/PEG/FA has the best encapsulation efficiency and drug loading.The DOX-PLGA@PDA-DOX/PEG/FA nanoparticles were characterized by infrared spectroscopy（FT-IR）,X-ray diffraction（XRD）,and ultraviolet spectrophotometry（UV）.The particle size and particle size distribution,surface potential,and transmission electron microscopy（TEM）were used to characterize the morphology of different DOX nano preparations.The stability of the nanoparticles and the hemolysis experiment were also investigated.In vitro dissolution experiments were used to examine the in vitro release behavior and response characteristics of different DOX nano-formulations.FT-IR,XRD and UV results showed that dopamine could polymerize and successfully incubate the surface of PLGA nanoparticles.TEM results showed that the DOX-PLGA@PDA-DOX/PEG/FA nanoparticles were spherical particles with an average particle size of 130.4 nm and a negatively charged surface（-15.11 mv）.Nanoparticles have good stability,and the drug leakage rate is less than 10%after high-speed centrifugation.No significant change in the particle size,PDI,and potential of the nanoparticles was observed after refrigerated at 4°C for 35 days.The near-infrared laser irradiation experiments show that the DOX-PLGA@PDA-DOX/PEG/FA nanoparticles have good photothermal effect,and the temperature increase amplitude is time-dependent.In vitro release experiments show that the nanoparticles have multiple response characteristics in acidic,oxidizing（hydrogen peroxide,H₂O₂）and reducing（glutathione,GSH）media,and can promote rapid drug release.In vivo pharmacokinetic results in rats showed that AUC_0→t→t of the DOX-PLGA@PDA-DOX/PEG/FA nanoparticle group was 17.29μg·h/ml,MRT_0→t→t was 14.87h,C_maxax was 11.81μg/ml,t_1/2/2 is 18.93h,which is 15.86 times,8.4 times,8.2 times,8.88 times of the DOX group,respectively.The tissue distribution results showed that DOX-PLGA@PDA-DOX/PEG/FA nanoparticles increased the distribution of the drug in the liver,spleen and kidney,and maintained a high concentration level after 12 hours.MTT results show that DOX-PLGA@PDA-DOX/PEG/FA nanoparticles have the strongest growth inhibition effect on HepG2 cells with IC₅₀0 of 0.756μg/ml.When nanoparticles are combined with near-infrared laser irradiation,IC₅₀0 further decreases to 0.288μg/ml.Folic acid inhibition experiments show that DOX-PLGA@PDA-DOX/PEG/FA nanoparticles can be taken up by HepG2 cells through the specific binding of ligand receptors.In addition,the uptake process is also mediated by clathrin and caveolin-mediated endocytosis Regulation.Apoptosis test results show that nanoparticles mainly act in the S phase（DNA replication phase）in Hep G2 cell cycle.DOX-PLGA@PDA-DOX/PEG/FA nano-irradiation with near-infrared laser can significantly increase the active oxygen level of HepG2 cells and increase the sensitivity of the cells to chemotherapeutic drugs.A H22 liver cancer model of BALB/c mice was established,and the in vivo efficacy of different DOX nano preparations was evaluated.The results showed that the DOX-PLGA@PDA-DOX/PEG/FA experimental group showed the best antitumor effect.Compared with other DOX preparation experimental groups,the nanomedicine can improve the levels of inflammatory factors IL-6 and TNF-α,reduce the toxic and side effects related to DOX,and is consistent with the results of HE staining.At the same time,it can effectively target tumor tissues and The temperature is rapidly increased under the stimulation of near-infrared laser to improve the tumor treatment effect of chemotherapy drugs.In summary,DOX-PLGA@PDA-DOX/PEG/FA nanoparticles have a stable preparation process and good safety,which can extend the circulation time of the drug in the body,reduce toxicity,and increase the enrichment in tumor tissues.The combination of light and heat therapy provides a reference for multi-modality combined therapy of tumors.