Affiliation:
1. Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Zhejiang Key Laboratory of Smart Biomaterials College of Chemical and Biological Engineering Zhejiang University Hangzhou Zhejiang 310027 China
2. Department of Chemistry Zhejiang University Hangzhou 310028 P. R. China
Abstract
AbstractThe quick diffusion of nanomedicines in the polysaccharide‐gel‐filling tumor interstitium and precise active targeting are two major obstacles that have not yet been overcome. Here, a poly(L‐glutamyl‐L‐lysine(EK) (p(EK))‐camouflaged, doxorubicin (Dox)‐conjugated nanomedicine is developed to demonstrate the underlying mechanism of zwitterionic shell in synchronous barrier‐penetration and biconditional active targeting. The zwitterionic p(EK) shell liquifies its surrounding water molecules in the polysaccharide gel of tumor interstitium, leading to five times faster diffusion than the pegylated Doxil with similar size in tumor tissue. Its doped sulfonate groups lead to more precise active tumor‐targeting than disialoganglioside (GD2) antibody by meeting the dual requirements of tumor microenvironment (TME) pH and overexpression of GD2 on tumor. Consequently, the concentrations of the nanomedicine in tumor are always higher than in life‐supported organs in whole accumulation process, reaching over ten times higher Dox in GD2‐overexpressing MCF‐7 tumors than in life‐supporting organs. Furthermore, the nanomedicine also avoids anti‐GD2‐like accumulation in GD2‐expressing kidney in a mouse model. Thus, the nanomedicine expands the therapeutic window of Doxil by more than three times and eliminates tumors with negligible myocardial and acute toxicity. This new insight paves an avenue to design nanodelivery systems for highly precise and safe chemotherapy.
Funder
National Natural Science Foundation of China
National Key Research and Development Program of China
Natural Science Foundation of Zhejiang Province
Fundamental Research Funds for the Central Universities
Subject
Mechanical Engineering,Mechanics of Materials,General Materials Science