Photoresponsive PAMAM Dendrimer Loaded With Chloroquine For Breast Cancer Treatment

Polyamide amine(PAMAM)dendrimer has been widely used in drug delivery,gene therapy,biological imaging and other medical fields due to its small size,easy surface modification and hydrophobic inside.Howerver,PAMAM has certain cytotoxicity,hemolysis,and is easy to be removed in the process of blood circulation,which limit its application in biomedical field.In addition,PAMAM has biological effects beyond drug delivery and could induce autophagy in different cell lines.Due to the dual relationship between autophagy and tumor,this provides two different ideas for tumor treatment: inhibiting autophagy could increase the efficiency of cancer therapy,or activating autophagy may induce autophagic programmed cell death.Therefore,manipulating autophagic processes has become a new method to improve the efficacy for nanomaterial-involved cancer treatment.Based on the above,we mainly discussed the application of PAMAM in antitumor therapy.The specific research contents were as follows:1.The photoresponsive nanocarrier(PAMAM-DEACM/HA,abbreviated as PD/HA)was constructed.The physicochemical properties of the system were characterized by dynamic light scattering(DLS),transmission electron microscopy,ultraviolet absorption spectroscopy,etc.,which showed that PD/HA had high stability and good photoresponsiveness.The anti-tumor effect of PD/HA on breast cancer cells(MDA-MB-231)was investigated through experiments such as cell uptake and cytotoxicity,which indicated PD/HA had good dark toxicity and phototoxicity.The effect of PD/HA on autophagy was further studied by fluorescence microscopy,western blotting and flow cytometry.The results showed that PD/HA induced protective autophagy through Akt-m TOR pathway upon light irradiation.2.The photoresponsive nanocomposites loaded with chloroquine(CQ@PAMAMDEACM/HA)were constructed.At the animal level,the MDA-MB-231 breast cancer orthotopic xenograft model was established in nude mice to investigate the tumor enrichment,biosafety and antitumor effect.The results showed nanoparticles could be enriched into tumors in a short time by small animal imaging technology.In vivo experiments,it was verified that PD/HA had a certain antitumor effect.In addition,CQ further increased the sensitivity of caner cells and significantly inhibited the growth of tumor.This study uses the drug carrier and biological toxicity of PAMAM to enhance the antitumor efficacy by optically controlling drug release and regulating autophagy level,which provides a new idea for cancer therapy.