Surface Modification Of Black Phosphorus Nanosheets For Photothermal Therapy

Nowadays,cancer has become the first threat to human life and health.However,conventional methods such as chemotherapy,radiotherapy and surgical treatment are not very effective for cancer treatment and bring great pain to patients.How to diagnose and treat cancer effectively has become one of the major challenges to hunan-being.Targeting nano medicine is a new type of tumor treatment,which can reduce the toxic and side effects of chemotherapy drugs and enhance selectivity.With the continuous development of optical technology and the deep intersection of nanotechnology,biotechnology and medical technology,new methods of laser-mediated antitumor therapy,such as photothermal therapy and photodynamic therapy,provide a new idea for tumor treatment.These methods are safe and controllable,with little damage to normal tissues and strong killing effect on tumors.They can treat a variety of cancers without drug resistance.Photothermal therapy is a non-invasive anti-tumor method by means of photonic nanomedicine.Relying on photothermal reagents with high photothermal conversion efficiency,the treatment is carried out by generating photothermal effect under the near-infrared light irradiation at the wavelength of 808 nm.Combination of photothermal therapy and targeted nano medicine will help to develop a new laser-controlled drug release system,and realize multimodality therapy of tumor and improve the anti-tumor effect.Black phosphorus(BP)is a new two-dimensional photoelectric material.With excellent photoelectric characteristics,ultra-high photothermal conversion efficiency,good biocompatibility and degradability,it has shown great potential in the fields of photoelectricity and nanobiophotonics.However,black phosphorus is easy to be degraded and lose its crystalinity when exposed in light,oxygen and water,which greatly limits its applications.Therefore,surface modification is in urgent needed to increase its stability and expand its application range.Polydopamine(PDA)is a kind of adhesion biopolymer with high photothermal properties.It can adhere to a variety of material surfaces through the oxidative self-polymerization of dopamine under mild conditions.The surface modification of black phosphorous with polydopamine can form a synerstic photothermal effect and increase the thermal stability.In this paper,polydopamine-coating was used to surface modification of the black phosphorus nanosheets,and further design two kinds of multi-functional and efficient photonic nanomedicine.It can be used for photothermal therapy and photothermal-chemo synergistic therapy of cervical cancer or breast cancer with satisfactory therapeutic effect.This paper mainly did the following four aspects of research:(1)We prepared the BP nanosheets using a simple liquid exfoliation of bulk BP sample,then coated the BP nanosheets with polydopamine(PDA),modified with targeting polymer mercapto group-poly(ethylene glycol)-folic acid(HS-PEG-FA),and successly prepared a novel photonic nanomedicine BP@PDA-PEG-FA.The nanocapsule was loaded with doxorubicin(DOX)as a model drug for photothermal-chemo synergistic therapy of cervical cancer.The drug loading content of DOX showed that BP nanosheets had a large loading capacity of 300% for chemotherapy drugs DOX.Raman spectroscopy verified that the coating of polydopamine film can enhance the stability of black phosphorus nanosheets in the liquid environment.A near infrared laser(NIR)with a wavelength of 808 nm and a infrared imaging devices were used to explore the photothermal effect of the photonic nanomedicine,and the photothermal conversion efficiency was calculated.It was found that the photothermal conversion efficiency increased from 21.4% to 26% after the surface modification of black phosphorus by polydopamine,with excellent photothermal effect and photothermal stability.Furthermore,DOX was rapidly released from the DOX-loaded BP NSs in a tumor microenvironment at low pH under NIR laser irradiation,demonstrating the effects of pH-photothermal responsive drug release behavior and higher antitumous effect.(2)Fluorescence microscopy was used to track the uptake of drug molecules in living cells,and the results showed that the cell uptake of the system was enhanced in vivo.Biocompatibility evaluation showed that the drug release system with good biocompatibility.In vitro experiments showed that BP-DOX@PDA-PEG-FA could be used as a photothermal reagent for the photothermal treatment(PTT)of tumor,and achieved chemo-photothermal synergistic effect.In vivo experiments proved the photonic nanomedicine based on BP nanosheets can actively identify the overexpressed receptors on tumor cell membrane by folate,therefore specifically identify tumor cells.It exhibited enhanced stability,significantly high photothermal efficiency,lower side effects and targeting ability for cancer cells.The NIR laser mediated photothermal-chemo synergistic therapy has good biocompatibility,outstanding anti-tumor efficacy and potential clinical application value for tumor treatment.(3)Based on the above research,we further prepared a multi-functional dual drug co-delivery photonic nanomedicine BP-DOX@PDA-PEOz-BTZ for combined photothermal-chemo therapy of breast cancer.The photonic nanomedicine is loaded with doxorubicin(DOX)and bortezomib(BTZ).Polydopamine coating can improve the biostability and photothermal stability of black phosphorus nanosheets.As a substitute of polyethylene glycol(PEG),poly(2-ethyl-2-oxazoline)(PEOz)ligand has been connected to the nanocapsule in order to achieve longer in vivo circulation,increase the cell uptake and reduce the accelerated blood clearance(ABC)phenomenon.With the second drug bortezomib connected onto the polydopamine(PDA)through pH-responsive covalent bonds,we avoided the non-specific binding of bortezomib to various proteins and achieved the pH-responsive drug release,and successfully applied bortezomib to the treatment of solid tumors which previously used only for lymphoma.The surface charge of the nanocapsule was reversed from negative to positive at the tumor extracellular pH(~6.8),ionizing the tertiary amide groups along the PEOz chain,thus facilitating the cell internalization of the nanocarrier.Photothermal effects tests proved that the dual drug co-delivery photonic nanomedicine had high photothermal efficiency and good photothermal stability.The NIR-controled drug release experiments confirmed that the dual-drug co-delivery system also has pH-photothermally responsive drug release behavior.(4)Fluorescence microscopy was used to track the uptake of drug molecules in living cells.The results validated that the charge reversal induced by the tertiary amides groups inonization along PEOz chain is the key to the pH sensitivity of the nanocarrier,which is beneficial to the uptake of the photonic nanomedicine by tumor cells.Both in vitro and in vivo experiments proved that the dual drug co-delivery photonic nanomedicine of BP-DOX@PDA-PEOz-BTZ had good biological compatibility,strong cellular uptake and cytotoxicity,excellent pH sensitivity and photothermal effect,as well as NIR laser mediated photothermal-chemo combined anti-tumor effect.We proved that the NIR laser mediated synergistic effect can increase the tumor-killing effect and reduce the side effects,which can be very promising to photothermal-chemo synergistic cancer therapy.To sum up,this study intersected optics with biomedicine,chemistry and materials science,expanded the application range of the new two-dimensional photoelectric material black phosphorus from photoelectricity to nanobiophotonics domain.The surface modification of polydopamine on black phosphorus nanosheets enhanced the stability of black phosphorus in liquid environment,improved the photothermal effect and photo-stability.It realized the NIR-controllable degradation of black phosphorus in vivo,and further achieved NIR-controlled release of anti-tumor drugs.In this paper,the photonic nanomedicine for the combined photothermal-chemo synergistic therapy of cervical cancer or breast cancer were successfully prepared,and have achieved good therapeutic effect.It provides a good research basis for the design of other NIR laser mediated anti-tumor drugs and clinical applications of photothermal-chemo synergistic therapy for cancer.