Breast Cancer Treatment Based On Multifunctional Polymer Nanomaterials

Objective:Malignant tumors have gradually become a major threat for human life and health.Breast cancer has a high incidence among women around the world,and has become the most common cancer in women.The development of breast cancer treatments is important and urgent.At present,the clinical therapeutic strategies for breast cancer mainly include surgery,radiotherapy and chemotherapy.However,these methods have serious limitations,such as invasiveness,toxic side effects,and incomplete treatment.These shortcomings reduce the quality of life of breast cancer patients with a risk of recurrence and metastasis.Phototherapy is an emerging non-invasive treatment method,mainly including photodynamic therapy and photothermal therapy.Photodynamic therapy(PDT)refers to a treatment method in which photosensitizers convert oxygen inside the tumor into cytotoxic reactive oxygen species(ROS)under the stimulation of an external light source,thereby killing tumor cells.Photothermal therapy(PTT)refers to a treatment method in which photothermal agents convert light energy into heat energy to generate high temperature to kill tumor cells.Compared with traditional treatment methods,phototherapy has the advantages of strong specificity,non-invasiveness and reproducible treatment.Polymer dots(Pdots)have good light absorption ability,photostability,anti-photobleaching ability,excellent drug loading performance and good biocompatibility,which is an excellent candidate for light-responsive therapeutic nanomedicines.The purpose of this study is to construct a related breast cancer tumor treatment nanoplatform based on polymer nanomaterials,which can be used for phototherapy or combined with radiotherapy to inhibit the development of breast cancer.Methods:The nuclear localization signal peptide-modified polymer nanomaterials(Pdots-NLS)and tantalum oxide-encapsulated composite polymer nanomaterials(PP@m Ta O_x)were synthesized by nanoprecipitation method.The morphology and structure of Pdots-NLS and PP@m Ta O_xwere characterized by electron microscopy,and their hydrated particle size and surface potential changes were measured using dynamic light scattering.The light absorption properties of these two materials were detected by absorption spectroscopy,and the CT imaging capability of PP@m Ta O_xwas investigated by micro-computed tomography.The photoresponse effect of these two materials was measured by electron thermometer,the reactive oxygen generation of Pdots-NLS was studied by absorption spectroscopy under NIR light,and the X-ray responsiveness of PP@mTaO_xwas measured by fluorescence spectroscopy.MTT and CCK-8 assays were used to detect the cytotoxicity and stimuli-responsive toxicity of these two materials.Biological transmission electron microscopy was used to study the uptake of PP@m Ta O_xby cells,and fluorescence imaging microscopy was used to study the ability of cells to uptake these two materials.Calcein-AM/PI staining was used to detect the level of live/dead cells after treatment with these two materials,and fluorescence microscopy imaging was used to detect the production of ROS at the cellular level.The cellular stress resistance-related proteins Hsp90 and Hsp47 were detected by q RT-PCR and western blotting.A subcutaneous tumorigenesis model in nude mice was established,and the intratumoral injection was followed by external stimulation nanotherapy,and hematoxylin-eosin(H&E)staining was used to study the in vivo biosafety of these two materials.Results:The characterization results show that Pdots-NLS has stable properties,obvious light-responsive ROS generation ability and photothermal effects.MTT and CCK-8 experiments confirmed that Pdots-NLS had no obvious cytotoxicity,and had good cytotoxicity in response to NIR light stimulation.Fluorescence microscopy imaging technology proved that Pdots-NLS can be well taken up by cells,and confirmed that the surface modification of Pdots with NLS peptides can increase the cellular internalization ability of Pdots,and verified that Pdots-NLS has a good response to NIR light at the cellular level ROS production.Pdots-NLS has obvious tumor inhibitory effect on tumor-bearing mice,and has good biological safety.The characterization results show that PP@mTaO_xis uniformly dispersed,and the photothermal conversion,photodynamic and radiotherapy sensitization effects of PP@m Ta O_xare obvious.PP@m Ta O_xhas no obvious cytotoxicity,and fluorescence microscopy imaging and biological electron microscopy confirmed that PP@m Ta O_xcan be well taken up by cells.PP@m Ta O_xexhibited good ROS generation in response to applied near-infrared light as well as X-ray stimuli.Live/dead cell staining experiments confirmed that PP@m Ta O_xcan produce significant tumor cell killing effects under NIR light and X-ray stimulation.PP@m Ta O_xhas obvious tumor suppressing effect on tumor-bearing mice under the stimulation of near-infrared light and X-ray,and each treatment group did not produce obvious biological system toxicity.Conclusion:In this paper,the nuclear localization signal peptide-modified polymer nanomaterial Pdots-NLS was synthesized,which successfully achieved significantly stronger tumor cell targeting than the non-peptide modified control group Pdots,and achieved the purpose of high aggregation in tumor cells and tumor killing.In this paper,a composite nanomaterial platform PP@m Ta O_x,which is radiosensitized and synergized with PDT and PTT,was successfully designed to realize multimodal synergistic treatment of breast cancer.PP@m Ta O_xachieved good tumor inhibition under the dual response conditions of NIR and radiation.As a result,the growth rate of tumor volume was significantly inhibited.Based on the functional design of polymer nanomaterials,this paper provides alternative therapeutic options and theoretical strategies for the future clinical treatment of tumors.