Construction Of A PH-temperature Dually Controlled Drug Release System Based On Au Nanoparticles Modified Mxene And Its Anti-breast Cancer Effect

Objective: The novel two-dimensional(2D)nanomaterial MXene has been widely studied as a nanodrug delivery platform due to its large specific surface area,abundant hydrophilic functional groups,good biohistocompatibility,and strong near infrared light(NIR)absorption ability.However,the planar structure of MXene makes it difficult to achieve high drug molecular load.It is still a challenge to modify its surface to improve its drug loading ability and photothermal conversion performance.In order to solve this problem and further improve the water-solubility of MXene in circulation and achieve controlled release of chemotherapy drugs,we constructed a new MXene@Au-PEG-DOX nanocomposite drug delivery system.Furthermore,the anti-breast cancer effect of the drug delivery system during the photothermal therapy(PTT)was explored in vivo and in vitro.Methods: In order to prepare MXene@Au-PEG-DOX nanocomposite drug delivery system,MXene was surface modified by gold nanoparticles(Au NPs).The polymeric sulfhydryl polyethylene glycol aldehyde group(SH-PEG-CHO)was introduced to improve the water solubility of the carrier,and the-CHO and-NH2 in DOX formed Schiff base bond,which was sensitive to acid and heat,to effectively load the drug.The monolayer MXene and MXene@Au nanocomposites were characterized by scanning electron microscopy(SEM),atomic force microscopy(AFM),X-ray diffraction(XRD),X-ray photoelectron spectroscopy(XPS),and energy dispersive spectroscopy(EDS).The infrared thermal imager was used to recorded temperature changes during the whole experiments.The loading and release of DOX were studied by UV-vis-NIR absorption spectra.For cell experiments,the 4T1 cell viability was detected by CCK-8 assay.The survival of 4T1 cells in each treatment group was further studied by Calcein/PI double staining kit.Balb/c female mice(4-6 weeks)were selected to establish breast cancer tumor-bearing animal models,and the metabolism and distribution of MXene@Au-PEG drug carrier in vivo were detected by inductively coupled plasma optical emission spectrometer(ICP-OES).HE staining was performed on the main organ sections of mice injected with MXene@Au-PEG solution to evaluate their biohistocompatibility.Balb/ctumor-bearing mice were divided into the following groups: control group(A),PTT group(B),DOX group(C),MXene@Au-PEG-DOX group(D),MXene@Au-PEG + PTT group(E),and MXene@Au-PEG-DOX + PTT group(F).Observed the growth of the mice and recorded the body weight and tumor volume every other day.Meanwhile,the organs of the tumor-bearing mice were stained with HE to evaluate the side effects after treatment.Results: SEM images showed that the surface of the synthesized monolayer MXene was clean.Compared with monolayer MXene,a large number of Au NPs uniformly distributed on the surface of MXene@Au nanocomposites,and the average particle size of Au NPs was between 5 nm and 30 nm.AFM images showed that the thickness of pure MXene was about 1.9 nm,and the thickness increased to 7-32 nm after loading Au NPs.The XRD results showed that the pure MXene and MXene@Au nanocomposites both had the characteristic peaks of MXene(002),while the characteristic peaks of Au NPs on MXene@Au nanocomposites were(111),(200),(220),(311),and(222).XPS results showed that MXene was mainly composed of Ti(17.51%)and C(71.28%),only a small amount of Al(0.03%)was detected.For MXene@Au nanocomposites,the main composition was Ti,C,O,and Au elements.The above experimental results all proved the successful preparation of monolayer MXene and MXene@Au nanocomposites.Infrared thermal imagers showed that MXene@Au nanocomposites exhibited better photothermal conversion performance than pure MXene,and the temperature increased gradually with the increase of MXene@Au solution concentration.Also,the MXene@Au nanocomposites exhibited excellent photothermal stability in five heating and cooling cycles.The UV-vis-NIR absorption spectrum showed that MXene had a wide absorption band in the NIR-I region.The absorbance of MXene@Au nanocomposites at 808 nm was linear with the concentration,and its extinction coefficient was 5.2 L g-1 cm-1.Compared with MXene@Au-PEG,the absorbance of MXene@Au-PEG-DOX system showed characteristic peak of DOX at 480 nm,which proved that the drug was successfully loaded on the carrier.The loading rate was 30%,and drug release was produced under the acidic microenvironment of tumor and high heat.The release rate could reach 72.26%.CCK-8 assay showed that MXene@Au-PEG nanocomposites had no obvious toxicity in vitro,and with the increase of NIR power,the cell viability gradually decreased.In six treatment groups,the MXene@Au-PEG-DOX + PTT group(F)produced significant breast cancer cell inhibiting effects.In vivo experiments showed that MXene@Au-PEGnanocomposite had good biohistocompatibility and could effectively accumulate in tumor area.After injection for 24 h,the blood content of MXene@Au-PEG nanocomposite was only 9%.At the same time,the MXene@Au-PEG-DOX + PTT group showed excellent synergistic treatment effect of PTT combined with chemotherapy,and without significant treatment side effects to breast cancer.Conclusion: In this study,a novel MXene@Au-PEG-DOX nanocomposite drug delivery system based on Au NPs modification was successfully prepared,and the p H-temperature dually controlled drug release system exhibited significant inhibitory effect on the growth of breast cancer cells(4T1)and tumor in Balb/c mice,showing excellent synergistic therapeutic effect of PTT combined with chemotherapy.It provided a new approach for future collaborative treatment of breast cancer.