A Micelle System Based On Molecular Economy Principle For Breast Cancer Treatment

Objectives: Multidrug resistance(MDR)and metastasis of breast cancer contribute to the failure of clinical breast cancer therapy.There are some issues existed in traditional chemotherapeutic treatment,including obvious side effects and poor accumulation of nanomedicine at tumor sites.This work intends to construct a micelle system based on molecular economy principle,which will provide a train of thought for nanomedicine design.In addition,it will take full advantage of each component to achieve the goal of promoting drug accumulation at tumor sites,overcoming MDR and inhibiting metastasis of breast cancer.Methods: DOX-ADD@TPGS-NO micelles were prepared by thin-film hydration method,with nitric oxide donor(TPGS-NO)derivated from D-?-tocopheryl polyethylene glycol 1000 succinate(TPGS)acting as the drug carrier for doxorubicin-adjudin conjugate(DOX-ADD).The pH and redox dual-sensitive drug release characteristics of DOX-ADD and TPGS-NO were studied by high performance liquid chromatography(HPLC)and microplate reader.Drug-sensitive(MCF7)and drug-resistant(MCF7/ADR)human breast cancer cells were chosen for the models for MDR investigation.Two different methods including confocal laser scanning microscope and flow cytometer were applied for intercellular uptake studies.The cytotoxicity of DOX-ADD@TPGS-NO micelles was detected by MTT assay.Furthermore,the synergistic mechanism study of overcoming MDR was explored.The effects of TPGS-NO on drug delivery and accumulation at tumor sites in vivo and ex vivo were studied via a noninvasive optical imaging system(IVIS).4T1 tumor model serving as both subcutaneous and metastatic models was established to explore the antitumor growth and metastasis inhibition on breast cancer of DOX-ADD@TPGS-NO micelles.Results: DOX-ADD@TPGS-NO micelles were quite facile to be fabricated,with small particle size and good dispersibility.The drug encapsulation efficiency of DOX-ADD in the micelle system was as high as 90.3 ± 3.2%.The micelle system showed obvious pH and redox dual-sensitive drug release behaviors.DOX-ADD@TPGS-NO micelles could enhance in vitro cellular uptake both in drug sensitive and resistant tumor cells,and showed great potential in overcoming MDR.The synergistic mechanism of overcoming MDR was attributed to mitochondria dysfunction caused by TPGS and ADD.In the biodistribution experiment,TPGS-NO exhibited significantly enhanced micelles accumulation at tumor sites and even maintained high drug concentration for a long period of time.DOX-ADD@TPGS-NO micelles could reduce the surface and inner metastasis at lung tissues of breast cancer,indicating potent metastasis inhibition efficacy.Conclusions: The construction of DOX-ADD@TPGS-NO micelles was based on ‘molecular economy' principle,which was supposed to describe the fact that,(1)the fabrication of micelles was quite facile which saved time and energy,(2)the micelles exhibited high drug encapsulation efficiency which meant less consumption of drugs or excipients,(3)and more importantly,each of the pH and redox dual-sensitive released agents was supposed to exhibit one or more active function.TPGS-NO could significantly promote drug delivery and accumulation at tumor sites.The micelles demonstrated great potential in overcoming MDR and inhibiting metastasis.Altogether,the establishment of the micelle system greatly enriched and expanded the application of NO donor,as well as providing an attractive strategy for nanomedicine design and clinical application in cancer treatment.