Stimuli-responsive PEGylated prodrugs for targeted doxorubicin delivery.
In recent years, stimuli-sensitive prodrugs have been extensively studied for the rapid "burst" release of antitumor drugs to enhance chemotherapeutic efficiency. In this study, a novel stimuli-sensitive prodrug containing galactosamine as a targeting moiety, poly(ethylene glycol)-doxorubicin (PEG-DOX) conjugate, was developed for targeting HepG2 human liver cancer cells. To obtain the PEG-DOX conjugate, both galactosamine-decorated poly(ethylene glycol) aldehyde (Gal-PEG-CHO) and methoxy poly(ethylene glycol) aldehyde (mPEG-CHO) were firstly synthesized and functionalized with dithiodipropionate dihydrazide (TPH) through direct reductive amination via Schiff's base formation, and then DOX molecules were chemically conjugated to the hydrazide end groups of TPH-functionalized Gal-/m-PEG chains via pH-sensitive hydrazone linkages. The chemical structures of TPH-functionalized PEG and PEG-DOX prodrug were confirmed by (1)H NMR analysis. The PEG-DOX conjugate could self-assemble into spherical nanomicelles with a mean diameter of 140 nm, as indicated by transmission electron microscopy and dynamic light scattering. The drug loading content and loading efficiency in the prodrug nanomicelles were as high as 20 wt.% and 75 wt.%, respectively. In vitro drug release studies showed that DOX was released rapidly from the prodrug nanomicelles at the intracellular levels of pH and reducing agent. Cellular uptake and MTT experiments demonstrated that the galactosamine-decorated prodrug nanomicelles were more efficiently internalized into HepG2 cells via a receptor-mediated endocytosis process and exhibited a higher toxicity, compared with pristine prodrug nanomicelles. These results suggest that the novel Gal-PEG-DOX prodrug nanomicelles have tremendous potential for targeted liver cancer therapy.
State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
Minghui
M
Xu
State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: jmqian@mail.xjtu.edu.cn.
Junmin
J
Qian
State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
Xuefeng
X
Liu
State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
Ting
T
Liu
State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
Hongjie
H
Wang
D016923:Cell Death / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005453:Fluorescence; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D011355:Prodrugs / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy
D008823:Micelles; D011355:Prodrugs; D011092:Polyethylene Glycols; D004317:Doxorubicin; C028210:monomethoxypolyethylene glycol
Doxorubicin; Liver cancer; Poly(ethylene glycol); Reduction/pH dual-sensitivity; Targeted prodrug