Hyaluronic Acid–Methotrexate Conjugates Coated Magnetic Polydopamine Nanoparticles for Multimodal Imaging-Guided Multistage Targeted Chemo-Photothermal Therapy

Combination cancer therapy with various kinds of therapeutic approaches could improve the effectiveness of treatment while reducing side effects. Herein, we elaborately developed a theranostics nanoplatform based on magnetic polydopamine (MPDA) coated with hyaluronic acid–methotrexate conjugates (MPDA@HA–MTX) for chemo-photothermal treatment (PTT). In this nanoplatform, Fe₃O₄ served as the core was applied as contrast agent for T₂-weighted magnetic resonance imaging (MRI) and early phase magnet targeting. Meanwhile, PDA was used as a versatile shell for effective loading of chemotherapeutic doxorubicin (DOX) to achieve controlled release and PTT simultaneously. Moreover, HA–MTX conjugates could offer later-phase specific cellular dual-targeting ability during the therapy. Both <i>in vitro</i> and <i>in vivo</i> studies demonstrated that DOX-loaded MPDA@HA–MTX (MPDA/DOX@HA–MTX) exhibited the preferential tumor accumulation, enhanced specificity to target tumor cells, pH-/laser-responsive release, and high tumor cell-killing efficiency. By combined chemo-PTT under the guidance of fluorescence/MR imaging, the tumors in mice were completely eliminated after treatment, indicating that MPDA@HA–MTX nanoparticles have great potential as a novel drug-loading platform for imaging-guided multistage targeted chemo-photothermal combination therapy

Methotrexate–Camptothecin Prodrug Nanoassemblies as a Versatile Nanoplatform for Biomodal Imaging-Guided Self-Active Targeted and Synergistic Chemotherapy

“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 <i>in vivo</i> NIR fluorescence (NIRF) and photoacoustic (PA) dual-modal imaging. Both <i>in vitro</i> and <i>in vivo</i> 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