Nanoparticles camouflaged
by red blood cell (RBC) membranes have
attracted considerable attention owing to reservation of structure
of membrane and surface proteins, endowing prominent cell-specific
function including biocompatibility, prolonged circulation lifetime,
and reduced reticular endothelial system (RES) uptake ability. Considering
the drawbacks of carrier-free nanomedicine including the serious drug
burst release, poor stability, and lack of immune escape function,
herein we developed and fabricated a novel RBC membranes biomimetic combinational therapeutic system by
enveloping the small molecular drug coassemblies of 10-hydroxycamptothecin
(10-HCPT) and indocyanine green (ICG) in the RBC membranes for prolonged
circulation, controlled drug release, and synergistic chemo-photothermal
therapy (PTT). The self-reorganized RBCs@ICG-HCPT nanoparticles (NPs)
exhibited a diameter of ∼150 nm with core–shell structure,
high drug payload (∼92 wt %), and reduced RES uptake function.
Taking advantage of the stealth functionality of RBC membranes, RBCs@ICG-HCPT
NPs remarkably enhanced the accumulation at the tumor sites by passive
targeting followed by cellular endocytosis. Upon the stimuli of near-infrared
laser followed by acidic stimulation, RBCs@ICG-HCPT NPs showed exceptional
instability by heat-mediated membrane disruption and pH change, thereby
triggering the rapid disassembly and accelerated drug release. Consequently,
compared with individual treatment, RBCs@ICG-HCPT NPs under dual-stimuli
accomplished highly efficient apoptosis in cancer cells and remarkable
ablation of tumors by chemo-PTT. This biomimetic nanoplatform based
on carrier-free, small molecular drug coassemblies integrating imaging
capacity as a promising theranostic system provides potential for
cancer diagnosis and combinational therapy.
Low drug payload and lack of tumor-targeting for chemodynamic therapy (CDT) result in an insufficient reactive oxygen species (ROS) generation, which seriously hinders its further clinical application. Therefore, how to improve the drug payload and tumor targeting for amplification of ROS and combine it with chemotherapy has been a huge challenge in CDT. Herein, methotrexate (MTX), gadolinium (Gd), and artesunate (ASA) were used as theranostic building blocks to be coordinately assembled into tumor-specific endogenous Fe II -activated and magnetic resonance imaging (MRI)-guided self-targeting carrierfree nanoplatforms (NPs) for amplification of ROS and enhanced chemodynamic chemotherapy. The obtained ASA-MTX-Gd III NPs exhibited extremely high drug payload (∼96 wt %), excellent physiological stability, long circulating ability (half-time: ∼12 h), and outstanding tumor accumulation. Moreover, ASA-MTX-Gd III NPs could be specifically uptaken by tumor cells via folate (FA) receptors and subsequently be disassembled via lysosomal acidity-induced coordination breakage, resulting in drug burst release. Most strikingly, the produced ASA could be catalyzed by tumor-specific overexpressed endogenous Fe II ions to generate sufficient ROS for enhancing the main chemodynamic efficacy, which could exert a synergistic effect with the assistant chemotherapy of MTX. Interestingly, ASA-MTX-Gd III NPs caused a lower ROS generation and toxicity on normal cell lines that seldom expressed endogenous Fe II ions. Under MRI guidance with assistance of self-targeting, significantly superior synergistic tumor therapy was performed on FA receptor-overexpressed tumor-bearing mice with a higher ROS generation and an almost complete elimination of tumor. This work highlights ASA-MTX-Gd III NPs as an efficient chemodynamic-chemotherapeutic agent for MRI imaging and tumor theranostics.
Locating
nanomedicines at the active sites plays a pivotal role
in the nanoparticle-based cancer therapy field. Herein, a multifunctional
nanotherapeutic is designed by using graphene oxide (GO) nanosheets
with rich carboxyl groups as the supporter for hyaluronic acid (HA)–methotrexate
(MTX) prodrug modification via an adipicdihydrazide cross-linker,
achieving synergistic multistage tumor-targeting and combined chemo-photothermal
therapy. As a tumor-targeting biomaterial, HA can increase affinity
of the nanocarrier toward CD44 receptor for enhanced cellular uptake.
MTX, a chemotherapeutic agent, can also serve as a tumor-targeting
enhancer toward folate receptor based on its similar structure with
folic acid. The prepared nanosystems possess a sheet shape with a
dynamic size of approximately 200 nm and pH-responsive drug release.
Unexpectedly, the physiological stability of HA–MTX prodrug-decorated
GO nanosystems in PBS, serum, and even plasma is more excellent than
that of HA-decorated GO nanosystems, while both of them exhibit an
enhanced photothermal effect than GO nanosheets. More importantly,
because of good blood compatibility as well as reduced undesired interactions
with blood components, HA–MTX prodrug-decorated GO nanosystems
exhibited remarkably superior accumulation at the tumor sites by passive
and active targeting mechanisms, achieving highly effective synergistic
chemo-photothermal therapeutic effect upon near-infrared laser irradiation,
efficient ablation of tumors, and negligible systemic toxicity. Hence,
the HA–MTX prodrug-decorated hybrid nanosystems have a promising
potential for synergistic multistage tumor-targeting therapy.
Stimulus-responsive carrier-free MTX–MAN conjugate nanoparticles could be expected to achieve dual-receptor-mediated self-recognizing, reduced drug dosage, and enhanced synergistic chemotherapeutic effects.
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