Polyphosphoester Based Nanocarrier For Combined Radio-Photothermal Therapy Of Breast Cancer

Objectives:Breast cancer is one of the three most common cancers worldwide.Recently,clinical researches on tumor therapy have gradually shifted from traditional monotherapy toward combined therapy as tumors are complex,diverse and heterogeneous.Combination therapy may be essential for achieving the optimized treatment efficacy of tumors through distinct tumor-inhibiting mechanisms.Photothermal therapy has attracted great interest as a new treatment for cancer.It usually uses a photothermal agent to absorb near-infrared laser energy of 700-1100nm,which is converted into heat energy to induce local moderate temperature rise to selectively kill cancer cells.However,due to the limited penetration of near infrared light,the effect of photothermal therapy is vulnerable to be limited by the depth of tissue.On the other hand,radiation therapy uses ionizing radiation to induce oxygen-centered free radicals in tumor cells,which results in DNA damage and subsequent death of tumor cells.Compared with photothermal therapy,radiotherapy is less restricted by tissue depth,but hypoxia-induced radioresistance will hinder its efficacy.Besides,it has been found that photothermal therapy can induce a certain level of temperature rise,which can promote intra-tumor blood perfusion and subsequently improve the level of oxygen in the tumor microenvironment,which can increase the sensitivity of cancer cells to radiation therapy.Therefore,the combination of PTT and RT has great potential for clinical application in the treatment of cancer.At the same time,nanocarriers are emerging as an excellent strategy for delivering both drugs simultaneously.Polyphosphoester?PPE?is a biodegradable polymer with repeating phosphoester linkages that can be easily functionalized;PPE is biocompatible and has attracted considerable attention in biomaterial researches.This work investigated the effect of combined therapy of photothermal and radiation therapy using a polyphosphoester-based nanocarrier?NPIR/Cur?.Materials and Methods:1.Firstly,the drug-loaded nanoparticles based on polyphosphate were prepared by a series of reactions and characterized by dynamic light scattering,transmission electron microscope and UV-vis absorption photometer.2.We detected the photothermal effect of IR-780 in vitro,and explored the cell uptake,photothermal effect,radiosensitization effect and the combination effect of NP_IR/Cur at the cell level.3.Finally,the animal model was used to explore the effect of combined radio-photothermal therapy,and its safety was also tested.Results:The IR-780 and curcumin coencapsulated NP_IR/Cur exhibited adequate drug loading,a significant cell killing effect at the cell level and a prolonged blood half-life,enhanced passive tumor homing,improved curcumin bioavailability,as well as combined therapeutic functions in vivo.Briefly,NP_IR/CurR/Cur could not only achieve effective thermal ablation through the conversion of near-infrared light to heat but also give rise to a significant boosted local radiation dose to trigger promoted radiation damages,thus resulting in enhanced tumor cell growth inhibition.Conclusion:In conclusion,the as-prepared NP_IR/Cur manifested excellent performance in facilitating combined photothermal and radiation therapy,thus expanding the application range of PPE-based carriers in nanomedicine,and also prompting exploration of their potential for other effective combination therapies.