Affiliation:
1. Key Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
2. State Key Laboratory of Southwestern Chinese Medicine Resources School of Pharmacy Chengdu University of Traditional Chinese Medicine Chengdu 611137 China
Abstract
AbstractThe complex tumor immune pathology requires a precise spatial‐control release of the combination drugs, but most multi‐drug loaded nanoparticles release all drugs simultaneously in the tumor microenvironment (TME), making them difficult to reach the exact action site. To address the spatial specific release of drugs, a carrier‐free self‐assembled multi‐responsive nanodrug delivery system is designed, in which p‐phthalaldehyde (p‐APA) and dithiodipropionic acid are used to connect metformin (MET) and 7‐ethyl‐10‐hydroxycamptothecin (SN38) through a matrix metalloproteinase‐2 (MMP‐2) responsive peptide, and dipyridamole (DIP) is further loaded (MA‐GPLGVRGDK‐SS‐SN38@DIP, MR NPs). The MR NPs first target tumor by enhanced permeability and retention effect, then the highly expressed MMP‐2 at tumor site cleaves GPLGVRGDK, breaking the nanoparticle into three parts—DIP, MA‐GPLG, and VRGDK‐SS‐SN38. DIP automatically binds with platelets in TME, inhibiting their function and restraining tumor metastasis. MA‐GPLG releases MET in response to the acidic TME to reverse the immunosuppressive networks through PD‐L1 downregulation and M2‐like macrophages repolarization. Moreover, VRGDK‐SS‐SN38 binds to the overexpressed integrin αvβ3 receptor to achieve tumor cells specific delivery and precise killing. Overall, this study offers an intelligent spatial‐specific multi‐responsive carrier‐free drug delivery system in breast cancer, which releases drug spatial specifically, therefore reverses the tumor immunosuppressive microenvironment and inhibits metastasis.
Funder
National Natural Science Foundation of China
Fundamental Research Funds for Central Universities of the Central South University
Subject
Electrochemistry,Condensed Matter Physics,Biomaterials,Electronic, Optical and Magnetic Materials