Construction Of PH And Photothermy Induced Thermo-sensitive Dual Controlled Release Polydopamine Nanocomposite Drug Loading System

The incidence and the mortality of cancer in China rank the first in the world,among which cervical cancer is one of the most.Therefore,it is extremely urgent to find effective treatment methods to cervical cancer.Traditional treatment of cervical cancer includes chemotherapy,radiotherapy and surgery,but these treatment methods have many disadvantages.Nnano-drug delivery system based on stimuli-responsive release in targeting multi-mode combination therapy is expected to be a new strategy for curing cancer.In this paper,we designed a kind of nanoparticle based on polydopamine modified with nucleic acid aptamer AS1411.After further linking withβ-CD,DOX and Ce6 could be loaded at the same time and we called this system as DOX@PDA-β-CD/Ce6-AS1411.On the basis of physicochemical characterization of DOX@PDA-β-CD/Ce6-AS1411,its anti-tumor effects in vitro and in vivo were further systematically studied.The drug loading system is expected to be a new strategy for cervical cancer treatment.Firstly,PDA was synthesized by the method of oxidation polymerization.After modified with HS-β-CD and NH₂-AS1411 on the surface of PDA,DOX and Ce6 were loaded on the system and DOX@PDA-β-CD/Ce6-AS1411 was constructed finally.TEM,particle size and Zeta potential test results showed that DOX@PDA-β-CD/Ce6-AS1411was nearly spherical and uniformly dispersed with an average particle size of 207.8±1.47 nm.The surface Zeta potential of this system was-17.8±1.6 m V.EDAX energy spectra and IR spectra resulats verified the successful modification of HS-β-CD and NH₂-AS1411 on the PDA surface.Under the irradiation of 808 nm laser（2 W/cm²）,the temperature of DOX@PDA-β-CD/Ce6-AS1411 aqueous solution increased gradually with the extension of exposure time,and reached the highest value of 65.8℃in 8 min,which showed that the system exhibit good photothermal properties and can be used for PTT.DOX@PDA-β-CD/Ce6-AS1411 showed good photodynamic properties and produced high level of ROS under the irradiation of 660 nm laser（50 m W/cm²）,which could be used in photodynamic therapy（PDT）.In DOX@PDA-β-CD/Ce6-AS1411 system,ER%and DL%of DOX were77.7%and 38.8%respectively,and the ER%and DL%of Ce6 were 53.8%and 5.4%respectively.Under the conditions of p H 5.0 and 808 nm laser irradiation（2 W/cm²）,the release rate of DOX and Ce6 reached 81.5%and 81.6%respectively.Photodynamic performance test showed that the drug release in this system was responsive controlled by p H and photothermal.Cell uptake test indicated that DOX@PDA-β-CD/Ce6-AS1411 accumulate in He La cells effectively,and reactive oxygen species（ROS）detection showed that this system release high level of ROS after exposure 660 nm laser irradiation（50 m W/cm²）.CCK-8 test manifested that DOX@PDA-β-CD/Ce6-AS1411 significantly inhibite the proliferation of He La cells after 1 min of 808 nm laser irradiation（2 W/cm²）and 660 nm laser irradiation respectively（50 m W/cm²）.After U14 cervical cancer bearing mice models being established and irradiated by 808 nm laser（2 W/cm²）,the tumor tissues exhibited ideal photothermal imaging performance.In vivo experiment results further showed that the antitumor effect of DOX@PDA-β-CD/Ce6-AS1411 was significantly improved after 5minutes of irradiation with 808 nm laser（2 W/cm²）and 660 nm laser（50 m W/cm²）respectively on tumor site in mice,and the tumor inhibition rate reached 89.3%.Pathological section results showed that the drug loading system induce flaky apoptosis and necrosis in tumor tissues,immunohistochemistry result showed that this system inhibit Ki67expression significantly in tumor tissues,which indicated that DOX@PDA-β-CD/Ce6-AS1411 possess an ideal anti-tumor effect,and its mechanism of proliferation inhibition effect was correlated with its ability of inducing apoptosis and necrosis.Pathological section of liver and kisney tissues and serum liver and kidney function indicator assay results manifested that the drug delivery system had ideal biological safety and no hepatorenal toxicity.In conclusion,DOX@PDA-β-CD/Ce6-AS1411 can not only control the release of drugs accurately,but also achieve three modes of chemotherapy,PTT,PDT combination therapy,which provides a theoretical basis for the application of responsive multi-mode combination therapy nano drug delivery system in anti-tumor research.