A Self-Targeting, Dual ROS/pH-Responsive Apoferritin Nanocage for Spatiotemporally Controlled Drug Delivery to Breast Cancer.

In this study, an intelligent pH and ROS dual-responsive drug delivery system based on an apoferritin (AFt) nanocage was prepared. This therapeutic system can specifically self-target 4T1 breast cancer cells by exploiting L-apoferritin receptor SCARA 5, avoiding the nonspecific binding or aggregation of nanoparticles due to the chemical functionalization for targeting. The characteristics of AFt were utilized for the simultaneous delivery of anticancer drug doxorubicin (DOX) and photosensitizer rose bengal (RB). RB exhibited efficient reactive oxygen species (ROS) generation, which can be applied to photodynamic therapy. Meanwhile, the AFt nanocage was prone to undergoing peptide backbone cleavage when oxidized by ROS. Therefore, by combining the intrinsic pH-responsive property of AFt, the dual ROS/pH-responsive system was developed. The time and location of drug release can be controlled by the combination of internal and external stimulus, which avoids the incomplete drug release under single stimulus response. The drug release rate increased significantly (from 26.1% to 92.0%) under low-pH condition (pH 5.0) and laser irradiation. More DOX from AFt entered the nucleus and killed the tumor cells, and the cell inhibition rate was up to ∼83% (DOX concentration: 5 µg/mL) after 48 h incubation. In addition, the biodistribution and the in vivo antitumor efficacy (within 14 d treatment) of the nanosystem were investigated in 4T1 breast cancer BALB/c mice. The results indicated that the system is a promising therapeutic agent involving ROS/pH dual response, self-targeting, and chemo-photodynamic therapy.

A Smart Responsive Dual Aptamers-Targeted Bubble-Generating Nanosystem for Cancer Triplex Therapy and Ultrasound Imaging.

The absence of targeted, single treatment methods produces low therapeutic value for treating cancers. To increase the accumulation of drugs in tumors and improve the treatment effectiveness, near-infrared 808 nm photothermal responsive dual aptamers-targeted docetaxel (DTX)-containing nanoparticles is proposed. In this system, DTX and NH4 HCO3 are loaded in thermosensitive liposomes. The surface of liposomes is coated with gold nanoshells and connected with sulfydryl (SH) modified AS1411 and S2.2 aptamers. The nanosystem has good biocompatibility and uniform size (diameter about 200 nm). The drug is rapidly released, reaching a maximum amount (84%) at 4 h under 808 nm laser irradiation. The experiments conducted in vitro and in vivo demonstrate the nanosystem can synergistically inhibit tumor growth by combination of chemotherapy, photothermal therapy, and biological therapy. Dual ligand functionalization significantly increases cellular uptake on breast cancer cell line (MCF-7) cells and achieves ultrasound imaging (USI) at tumor site. The results indicate that this drug delivery system is a promising theranostic agent involving light-thermal response at tumor sites, dual ligand targeted triplex therapy, and USI.

CuS as a gatekeeper of mesoporous upconversion nanoparticles-based drug controlled release system for tumor-targeted multimodal imaging and synergetic chemo-thermotherapy.

In this work, a tumor-targeted multifunctional mesoporous upconversion nanoparticle-based drug controlled release system was developed for UCL/MRI/PAT guided synergetic chemo-thermotherapy. Herein, the core-shell mesoporous upconversion nanoparticles served as drug carrier exhibiting higher upconversion luminescence emission intensity, with CuS as a gatekeeper through a cleavable disulfide bond under the influence of glutathione. CuS could not only prevent drug from early release during the delivery but also improve the delivery system function with the ability of photothermal therapy and photoacoustic tomography. Hyaluronic acid grafted on the surface of mesoporous upconversion nanoparticles could interact with CD44 receptors over-expressed in tumor cells, facilitating the drug delivery system to accumulate in tumor tissues. The synergy between chemotherapy and photothermal therapy was studied in vitro and in vivo, showing powerful anti-tumor effect. In cooperation with the multi-mode imaging, the size, site and morphology of tumor were clearly observed throughout the disease's progression.

Multimodal imaging-guided, dual-targeted photothermal therapy for cancer.

The ability to selectively destroy cancer cells while sparing normal tissue is highly desirable during cancer therapy. Herein, dual-targeted photothermal therapy was achieved by the integration of upconversion nanoparticles, Fe3O4 nanoparticles (IONPs), Prussian blue nanoparticles (PBNPs) and hyaluronic acid (HA). PBNPs converted near-infrared (NIR) light into heat and HA/Fe3O4 NPs served as dual-targeting moieties. The as-obtained nanocomposites could also be applied as a multimodal probe for upconversion luminescence (UCL) imaging, enhanced T2-weighted magnetic resonance (MR) imaging and photoacoustic tomography (PAT) imaging. This multifunctional nanoparticle (MFNP) system prepared by a layer-by-layer (LBL) assembly method exhibited excellent dispersivity and low toxicity in vitro and in vivo. Furthermore, the research provided effective results for dual-targeted photothermal ablation of cancer with ∼4 fold higher tumor accumulation than that in the absence of HA/magnetic field. The photothermal therapeutic efficacy has been greatly improved in the S180 tumor model. We present a strategy for multimodal imaging-guided, dual-targeted physical cancer therapy and highlight the promise of using multifunctional nanostructures for cancer theranostics.