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.
Lack
of tumor targeting and low drug payload severely impedes various
nanoagents further employed in small-cell lung cancer (SCLC). Therefore,
how to develop a new targeting ligand and enhance drug payload has
been an urgent need for SCLC therapy. Herein, we first sift and verify
that capreomycin (Cm) has a high affinity toward CD56 receptors overexpressed
on SCLC cells. Motivated by the concept of self-targeted drug delivery,
Cm is selected as the specific targeting ligand toward CD56 receptors
and chemodrug doxorubicin (Dox) is adopted to be covalently linked via the redox-responsive disulfide linkage. The synthesized
self-distinguishing prodrug (Dox-ss-Cm) and FDA-approved photosensitizer
indocyanine green (ICG) as structural motifs can be self-assembled
into theranostic nanoagents (ICG@Dox-ss-Cm NPs) within an aqueous
solution. Such carrier-free nanoagents with high drug payload can
exert targeted on-demand drug release under multiple stimuli of intracellular
lysosomal acidity, glutathione (GSH), and an external near-infrared
(NIR) laser. Besides, our nanoagents can be specifically self-targeted
to SCLC sites in vivo and self-distinguishing via SCLC cells in vitro; thus, they decrease
the undesirable effects on normal tissues and organs. Further in vitro and in vivo studies uniformly
confirm that such nanoagents show highly synergistic effects for SCLC
chemo-photothermal therapy (PTT) under the precise guidance of NIR
fluorescence (NIRF)/photoacoustic (PA) imaging. Taken together, our
work can provide a novel and promising strategy for the targeted treatment
of SCLC.
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