Self-assembly of a disulfide-containing core/shell nanocomplex with intracellular environment-sensitive facilitated endo
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Self-assembly of a disulfide-containing core/shell nanocomplex with intracellular environment-sensitive facilitated endo-lysosomal escape for enhanced antitumor efficacy Lin Li1, Peng Zhang1,*
, Xiucheng Yang1, Congcong Li1, Yan Guo2, and Kaoxiang Sun1,3,*
1
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluatio, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, People’s Republic of China 2 Department of Development Planning & Discipline Construction, Yantai University, Yantai 264005, People’s Republic of China 3 State Key Laboratory of Long-Acting and Targeting Drug Delivery System, Shandong Luye Pharmaceutical Co., Ltd, Yantai 264003, People’s Republic of China
Received: 17 August 2020
ABSTRACT
Accepted: 27 October 2020
A receptor-mediated, active-targeting and glutathione (GSH) turn-on chargereversal core/shell nanocomplex HA-MEA-s-s-TGA/PAMAM@DOX was constructed to achieve increased stability, improved cellular uptake, facilitated endo-lysosomal escape and enhanced antitumor efficacy. This nanocomplex was composed of anionic hyaluronic acid (HA)-graft GSH-sensitive HA-MEA-ss-TGA as the outer shell and the cationic PAMAM@DOX core with encapsulated doxorubicin (DOX) into the hydrophobic cavities of polyamidoamine (PAMAM) dendrimers. We hypothesized that the anionic outer layer could promote cellular uptake of HA-MEA-s-s-TGA/PAMAM@DOX by HA receptormediated endocytosis. After internalization into tumor cells, the outer shell of the internalized nanocomplex was disassembled in endo-lysosomes via the destruction of disulfide linkages to re-expose PAMAM drug core. This action induced release of the encapsulated DOX and facilitated endo-lysosomal escape through the synergistic action of the proton sponge effect and cationic–anionic interaction between protonated PAMAM and endo-lysosome membranes. In vitro release profiles demonstrated the intracellular environment-responsive release behavior of DOX from this nanocomplex, with a cumulative release of 80% within 4 days in a simulated tumor intracellular microenvironment, whereas
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Springer Science+Business
Media, LLC, part of Springer Nature 2020
Handling Editor: Maude Jimenez. Lin Li and Peng Zhang have contributed equally to this work.
Address correspondence to E-mail: [email protected]; [email protected]
https://doi.org/10.1007/s10853-020-05515-4
J Mater Sci
the surface charge changed from - 18.82 mV to ? 10.95 mV. The MTT assay revealed the good biocompatibility of the negatively charged nanocomplex and efficient toxicity against HeLa cells. The designed pH/GSH dual-responsive nanocomplex could be an efficacious and safe delivery platform for cancer therapy.
GRAPHICAL ABSTRACT
Introduction According to the World Health Organization reports, cancer has become the second leading cause of death worldwide [1]. Numerous types of nanocarriers for cancer therapy have been reported [2, 3]. However,
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