PH-sensitive UCNP@Al?OH?₃/Au Nanohybrids For Fluorescence Imaging And Tumor Photothermal Therapy

A variety of commonly-applied clinical cancer treatment currently includes surgery,chemotherapy and radiotherapy etc.However,these treatments fail in downfalls among other things are intensive trauma,easy to cause toxic side effects.Photothermal Therapy?PTT?has been favored by many for its minimized trauma,lower toxicity,high specificity,wide range of application and repeatable synergistic treatment.Since most tumor are covered deep within tissues,it is difficult for common PTTs,which are mostly based on visible light for achieving tumors elimination.Upconversion nanoparticles?UCNPs?shined with their characteristics include deep tissue penetration,low cytotoxicity,stable chemical properties and none auto-fluorescence.Thusly,upconversion nanomaterials excited by near infrared light have their distinct advantages in PTT application.Firstly,using set up high-temperature solvent pyrolysis method,oil-phase UCNPs with averaged diameter at 19 nm were synthesized.Followed by surface modification with ultrathin?2-3 nm?layer of amphoteric aluminum hydroxide with exceptional biocompatibility onto the surface of UCNPs,the production of water-soluble UCNP@Al?OH?₃ nanoparticles was achieved.Moreover,medical Arlen sodium phosphate?ALS?was used as linkers,as their bisphosphate terminal preferably binds to the aluminum hydroxide,and thusly exposed the free amino group on the other terminal of the ALS.In the aqueous solution,gold nanoparticles were formed by PEI in situ reduction of chloroauric acid.The nascent gold nanoparticles then bind with the free amino terminal of ALS to form stable gold-amine bonds,and subsequently the composite of UCNP@Al?OH?₃/Au nanocomposite with exquisite water solubility.Herein,one terminal of the NHS-PEG-NHS was connected to the amino group on the surface of UCNP@Al?OH?₃/Au,while the other end was bound to the target agent cRGD polypeptide to form the UCNP@Al?OH?₃/Au-cRGD nanocomposite.Secondly,the FRET effect between UCNPs and gold nanoparticles under near infrared excitation was further investigated.In vitro heating experiment and photothermal conversion efficiency showed that when UCNP@Al?OH?₃/Au-cRGD nanocomposites were irradiated with?980 nm,1 W/cm²?light for 5 minutes,in vitro photothermal conversion efficiency of the nanocomposites could reach 24.3%when the temperature of the nanocomposites peaked at 51.5?,demonstrating a high photothermal conversion efficiency of the nanocomposite and therefore remarkable heating effect.Subsequent cytotoxicity studies showed that the survival rates of U87MG cells under irradiation by near infrared light?980 nm,0.5 W/cm²?for 1 min,3 min and 5 min were 86.90%,75.43%and 55.61%,respectively,indicated that UCNP@Al?OH?₃/Au-cRGD nanocomposites are equipped with good biocompatibility and superior photothermal therapy effect.After injection,and subsequent targeted accumulation in the tumor tissue,the thin layers of acid-sensitive aluminum hydroxide of the nanocomposites gradually dissolve in the acidic tumor microenvironment.Sizes of the nanocomposites decreased,enhanced their in vitro elimination,thus reduced their biological toxicity.FRET effect between UCNPs and gold nanoparticles were also diminished when the gold nanoparticles detached from the UCNPs during the dissolution.The exposed UCNP subsequently enhanced their fluorescence.Fluorescence intensity began to increase after 1.5 h post injection,and then peaked at 3 h,indicated that 1.5 h is the best time point for PTT.Two weeks post PTT,the U87MG?malignant glioma cells?-bearing mice showed complete tumor ablation,demonstrated that this nanocomposite is an ideal PTT with optimized fluorescence imaging effect.Organs from the treated mice were collected and performed H&E section staining.Results showed negative toxicity in any organs and that these nanocomposites are promised with good biological safety.In conclusion,this research investigated a novel nanocomposite synthesized with rare earth UCNPs and gold nanoparticles.Benefited from the in-depth penetration and minimized traumatization by near-infrared light excitation,these particular nanocomposites are enabled with excellent fluorescent imaging and PTT at the tumor site.Aluminum hydroxide intermediate layer also has promising application prospect and the potential to prepare ideal pH-sensitive nanomedicine.