"All-in-one" carrier-free-based nano-multi-drug self-delivery system could combine triple advantages of small molecules, nanoscale characteristics, and synergistic combination therapy together. Researches have showed that dual-acting small-molecular methotrexate (MTX) could target and kill the folate-receptor-overexpressing cancer cells. Inspired by this mechanism, a novel collaborative early-phase tumor-selective targeting and late-phase synergistic anticancer approach was developed for the self-assembly of chemotherapeutic drug-drug conjugate, which showed various advantages of more simplicity, efficiency, and flexibility over the conventional approach based only on single or combination cancer chemotherapy. MTX and 10-hydroxyl camptothecin (CPT) were chosen to conjugate through ester linkage. Because of the amphiphilicity and ionicity, MTX-CPT conjugates as molecular building blocks could self-assemble into MTX-CPT nanoparticles (MTX-CPT NPs) in aqueous solution, thus notably improving the aqueous solubility of CPT and the membrane permeability of MTX. The MTX-CPT NPs with a precise drug-to-drug ratio showed pH-/esterase-responsive drug release, sequential function "Targeting-Anticancer" switch, and real-time monitoring fluorescence "Off-On" switch. By doping with a lipophilic near-infrared (NIR) cyanine dye (e.g., 1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide, DiR), the prepared DiR-loaded MTX-CPT NPs acted as an effective probe for in vivo NIR fluorescence (NIRF) and photoacoustic (PA) dual-modal imaging. Both in vitro and in vivo studies demonstrated that MTX-CPT NPs could specifically codeliver multidrug to different sites of action with distinct anticancer mechanisms to kill folate-receptor-overexpressing tumor cells in a synergistic way. This novel, simple, and highly convergent self-targeting nanomulti-drug codelivery system exhibited great potential in cancer therapy.
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.
Retinoic acid (RA) induces rapid differentiation of embryonic stem cells (ESCs), partly by activating expression of the transcription factor Hoxa1, which regulates downstream target genes that promote ESCs differentiation. However, mechanisms of RA-induced Hoxa1 expression and ESCs early differentiation remain largely unknown. Here, we identify a distal enhancer interacting with the Hoxa1 locus through a long-range chromatin loop. Enhancer deletion significantly inhibited expression of RA-induced Hoxa1 and endoderm master control genes such as Gata4 and Gata6. Transcriptome analysis revealed that RA-induced early ESCs differentiation was blocked in Hoxa1 enhancer knockout cells, suggesting a requirement for the enhancer. Restoration of Hoxa1 expression partly rescued expression levels of ∼40% of genes whose expression changed following enhancer deletion, and ∼18% of promoters of those rescued genes were directly bound by Hoxa1. Our data show that a distal enhancer maintains Hoxa1 expression through long-range chromatin loop and that Hoxa1 directly regulates downstream target genes expression and then orchestrates RA-induced early differentiation of ESCs. This discovery reveals mechanisms of a novel enhancer regulating RA-induced Hoxa genes expression and early ESCs differentiation.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.