| Breast cancer is a malignant tumor with the highest prevalence rate and the sixth mortality rate among female patients,which causes great medical burden and economic pressure on society and family.Therefore,it is urgent to accelerate the progress of breast cancer research and find effective and safe treatment measures.At present,the most conventional treatment of breast cancer is still chemotherapy.Paclitaxel is one of the most commonly used chemotherapy drugs due to its good antitumor activity.However,its poor solubility and strong toxic and side effects limit its further use in clinic.For this reason,researchers have carried out many studies to improve the preparation,among which the most extensive study is paclitaxel nanoparticles(PTX NPs),hoping to improve its curative effect and solve its own problems.Although PTX NPs can improve the solubility of the drug and reduce the toxicity of the drug,there are still some problems,such as the lack of long-term intratumoral retention of the drug and poor ability to slow and control the release of the drug,which may lead to the drug cannot give full play to its therapeutic potential.Therefore,PTX NPs is combined with the temperature-sensitive hydrogel drug delivery platform.This method combines the significant advantages of temperature-sensitive hydrogel and nanoparticles into a system,which can not only load fat-soluble drugs,but also control the drug release rate and extend the local retention time of drugs by sensing changes in ambient temperature.It shows that the system has certain development value and clinical application potential.In recent years,the combination therapy model has become the main method for clinical treatment of tumors,especially the combination therapy based on photothermal therapy,which has attracted more and more attention due to its advantages of minimal invasion,short treatment time,significant therapeutic effect,and enhancing the efficacy of chemotherapy drugs.Polypyrrole(PPy)nanomaterial has good photothermal and chemical stability,and good biocompatibility,so it is widely used in many fields,especially in photothermal therapy.However,there are few studies on the treatment of breast cancer with PPy photothermal therapy combined with PTX NPs and PTX NPs Gel,and more experiments are needed to study the therapeutic effect of their combination.Based on the improvement of PTX NPs dosage form,this study hopes to further combine photothermal therapy to achieve better synergistic and toxic reduction effects.Therefore,taking PTX as anti-tumor drug and breast cancer as research model,two dosage forms of PTX NPs and PTX NPs Gel are prepared,and local injection is adopted to compare and investigate the anti-breast cancer effects of these two different dosage forms in single treatment and combined photo thermal treatment.The main research results are as follows:(i)The therapeutic effect of PTX NPs and PTX NPs Gel on breast cancer.First,PTX NPs were prepared by antisolvent precipitation combined with high pressure homogenization method,and its particle size and potential were characterized.The particle size of PTX NPs was 173.90 nm,and the Zeta potential was 15.8 ± 0.3 mV.Under transmission electron microscopy,PTX NPs showed regular rod-like structure.And stable in a variety of physiological media.Next,we dispersed 20.5%poloxamer 407(P407)and 2%poloxamer 188(P188)in PTX NPs aqueous solution to prepare PTX NPs Gel.In vitro studies showed that the IC50 values of PTX injection and PTX NPs on breast cancer cells were 1.737 μg/mL and 0.4902 μg/mL,respectively.Therefore,the cell killing capacity of PTX NPs was about 3.5 times that of PTX injection,and the toxicity of PTX NPS on 4T1 cells was stronger than that of PTX injection.In cell uptake experiments,it was also found that PTX NPs could improve the uptake rate of hydrophobic drug PTX by 4T1 cells,and 4T1 cells had a certain slow-release effect on the uptake of PTX NPs Gel.In vivo studies have shown that PTX NPs Gel can be retained at the tumor site for a long time,achieving sustained drug release and increasing the therapeutic effect of the drug.Meanwhile,the tumor inhibitory rate of PTX NPs Gel group(56.79%)was higher than that of PTX NPs group(48.64%),indicating that drugloaded temperature-sensitive hydrogel nanoparticles could increase the bioavailability of drugs and improve the therapeutic effect of breast cancer.(ii)The therapeutic effect of PTX NPs and PTX NPs Gel combined with photothermal treatment on breast cancer.In this part,the photothermal material Polypyrrole nanoparticles(PPy NPs)was first prepared and characterized.PPy NPs were prepared through a one-step polymerization method,and their particle size and potential were characterized.The particle size of PPy NPs was 229.30 nm,and the Zeta potential was 14 ±0.1 mV.Under transmission electron microscope observation,it can be seen that the regular spherical structure of PPy NPs,and can exist stably in a variety of physiological media.Then,we investigated the photothermal conversion performance of PPy NPs.It was found that 0.5 mg/mL of PPy NPs could heat up to more than 42℃ after 360 s irradiation with near infrared(NIR)laser with power of 3.5 w/cm~2 and wavelength of 808 nm,which could effectively kill tumor cells.This condition can effectively kill tumor cells.It was proved that PPy NPs had excellent photothermal conversion performance.Further in vitro studies also showed that PPy NPs had good cellular biocompatibility without NIR irradiation,and 1.1 mg/mL PPy NPs could kill more than half of tumor cells after NIR irradiation,indicating that PPy NPs could be used as an excellent photothermal conversion material for in vivo combined experiments.Cell uptake experiments showed that NIR could promote the uptake of PTX NPs by 4T1 cells,but the gel might hinder the uptake of PTX NPs by 4T1 cells under the irradiation of NIR.In vivo studies showed that within 24 h after intratumoral injection,the fluorescence signals in tumor sites of PTX+PPy NPs+ NIR and PTX+PPy NPs Gel+NIR groups had not disappeared,which indicated that intratumoral injection could maintain drugs at tumor sites well.The tumor inhibitory rate of PTX+PPy NPs Gel+NIR group(48.98%)was lower than that of PTX+PPy NPs+NIR group(91.05%).By analyzing the above experimental results,we found that the combined drug administration nanoparticle group could play the function of "1+1>2",but the presence of photoheat would affect the release of drugs from the drug-carrying gel,resulting in the anti-tumor effect of the gel group of chemotherapy combined with photoheat treatment was not ideal.However,by analyzing the changes of body weight,various organ indexes and the results of hematoxylin-eosin staining(H&E),we found that the combined administration group did not produce significant adverse effects on the body.In conclusion,in vivo efficacy experiment results showed that PTX NPs Gel had a higher inhibitory rate than PTX NPs in the absence of NIR stimulation,indicating that paclitaxel nanogel had more advantages in the treatment of breast cancer.However,after combined photothermal treatment,the tumor inhibitory rate of PTX+PPy NPs Gel+NIR group was lower than that of PTX+PPy NPs+NIR group,indicating that the presence of photothermal may affect the release of drugs in drug-carrying gel to a certain extent,leading to the unsatisfactory antitumor effect of the combined drug administration gel group.However,in the process of combined administration,it was found that the tumor inhibitory rate of PTX+PPy NPs+NIR group reached 91.05%,indicating that chemotherapy combined with photothermal treatment can improve the efficacy of PTX,reduce the dose of drugs and the adverse reactions.Therefore,the new drug delivery method of PTX+PPy NPs+NIR can provide new strategies and ideas for the treatment of breast cancer. |
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