Recent drug delivery nanosystems for cancer treatment
still suffer
from the poor tumor accumulation and low therapeutic efficacy due
to the complex in vivo biological barriers. To resolve
these problems, in this work, a novel gradient redox-responsive and
two-stage rocket-mimetic drug nanocarrier is designed and constructed
for improved tumor accumulation and safe chemotherapy. The nanocarrier
is constructed on the basis of the disulfide-doped organosilica-micellar
hybrid nanoparticles and the following dual-functional modification
with disulfide-bonded polyethylene glycol (PEG) and amido-bonded polyethylenimine
(PEI). First, prolonged circulation duration in the bloodstream is
guaranteed due to the shielding of the outer PEG chains. Once the
nanocarrier accumulates at the tumoral extracellular microenvironment
with low glutathione (GSH) concentrations, the first-stage redox-responsive
behavior with the separation of PEG and the exposure of PEI is triggered,
leading to the improved tumor accumulation and cellular internalization.
Furthermore, with their endocytosis by tumor cells, a high concentration
of GSH induces the second-stage redox-responsiveness with the degradation
of silsesquioxane framework and the release of the encapsulated drugs.
As a result, the rocket-mimetic drug carrier displays longer circulation
duration in the bloodstream, higher tumor accumulation capability,
and improved antitumor efficacy (which is 2.5 times higher than that
with inseparable PEG). It is envisioned that the rocket-mimetic strategy
can provide new solutions for improving tumor accumulation and safety
of nanocarriers in further cancer chemotherapy.
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