Nanoprodrugs with responsive release
properties integrate the advantages
of stimuli-responsive prodrugs and nanotechnology. They would provide
ultimate opportunity in fighting atherosclerosis. In this study, we
synthesized a redox-responsive nanoprodrug of simvastatin (TPTS) by
conjugating α-tocopherol polyethylene glycol derivative to the
pharmacophore of simvastatin with a thioketal linker. TPTS formed
nanoparticles and released parent simvastatin in the presence of hydrogen
peroxide. Moreover, by taking advantage of the self-assembly behavior
of TPTS, we developed a fibronectin-targeted delivery system (TPTS/C/T)
to codelivery simvastatin prodrug and ticagrelor. In vitro and in
vivo experiments indicated that TPTS and TPTS/C/T had good stability,
which could reduce off-target leakage of drugs. They greatly inhibited
the M1-type polarization of macrophages; reduced intracellular reactive
oxygen species level and inflammatory cytokine; and TNF-α, MCP-1,
and IL-1β were secreted by macrophage cells, thus providing
enhanced anti-inflammatory and antioxidant effects compared with free
simvastatin. TPTS/C/T realized targeted drug release to plaques and
synergistic therapeutic effects of simvastatin and ticagrelor on atherosclerosis
treatment in an ApoE–/– mouse model, resulting in excellent
atherosclerosis therapeutic efficacy and a promising biosafety profile.
Therefore, this study provides a new method for manufacturing statin
nanodrugs and a new design idea for related responsive drug release
nanosystems for atherosclerosis.
Despite the excellent progress of chemotherapy and phototherapy in tumor treatment, their effectiveness on multidrug-resistant tumors (MDR) is still unsatisfactory. One of the main obstacles is drug efflux caused by...
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