Multifunctional Low-Generation Dendrimer Nanogels as an Emerging Probe for Tumor-Specific CT/MR Dual-Modal Imaging.

The development of nanoprobes that have amplified enhanced permeability and retention (EPR) effect is crucial for their precise cancer diagnosis performance. Here, we present the development of functional dendrimer-based nanogels (DNGs) with the generation three primary amine-terminated poly(amidoamine) (PAMAM) dendrimers (G3·NH2) cross-linked by N,N'-bis(acryloyl) cystamine (BAC). The DNGs were prepared through a Michael addition reaction between G3·NH2 dendrimers and BAC via an inverse microemulsion method and entrapped with gold nanoparticles (Au NPs) to form Au-DNGs. The Au-DNGs were sequentially modified with diethylenetriamine penta-acetic acid (DTPA)-gadolinium (Gd) complex, poly(ethylene glycol) (PEG)-linked arginine-glycine-aspartic (RGD) peptide, and 1,3-propanesultone (1,3-PS). The formed multifunctional RGD-Gd@Au-DNGs-PS (R-G@ADP) possessing an average diameter of 122 nm are colloidally stable and display a high X-ray attenuation coefficient, excellent r1 relaxivity (9.13 mM-1 s-1), desired protein resistance rendered by the zwitterionic modification, and cytocompatibility. With the targeting specificity mediated by RGD and the much better tumor penetration capability than the counterpart material of single dendrimer-entrapped Au NPs, the developed multifunctional R-G@ADP enable targeted and enhanced computed tomography (CT)/magnetic resonance (MR) dual-modal imaging of a pancreatic tumor model in vivo. The current work demonstrates a unique design of targeted and zwitterionic DNGs with prolonged blood circulation time as an emerging nanoprobe for specific tumor CT/MR imaging through amplified passive EPR effect.

Functional LAPONITE Nanodisks Enable Targeted Anticancer Chemotherapy in Vivo.

Development of nanoplatforms for targeted anticancer drug delivery for effective tumor therapy still remains challenging in the development of nanomedicine. Here, we present a facile method to formulate a LAPONITE (LAP) nanodisk-based nanosystem for anticancer drug doxorubicin (DOX) delivery to folic acid (FA) receptor-overexpressing tumors. In the current work, aminated LAP nanodisks were first prepared through silanization, then functionalized with polyethylene glycol-linked FA (PEG-FA) via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) chemistry, and finally employed to physically encapsulate DOX. The formed functional LAP nanodisks (for short, LM-PEG-FA) possess a high DOX loading efficiency (88.6 ± 1.2%) and present a pH-dependent release feature with a quicker DOX release under acidic pH conditions (pH 5.0) than under physiological pH conditions (pH 7.4). In vitro flow cytometry, confocal microscopic observation, and cell viability assay show that the LM-PEG-FA/DOX complexes can be specifically taken up by FAR-overexpressing human ovarian cancer cells (SK-OV-3 cells) and present a specific cancer cell therapeutic effect. Further tumor treatment results reveal that the LM-PEG-FA/DOX complexes can exert a specific therapeutic efficacy to a xenografted SK-OV-3 tumor model in vivo when compared with nontargeted LM-mPEG/DOX complexes. Therefore, the developed LM-PEG-FA nanodisks could be employed as a potential platform for targeted cancer chemotherapy.

Chemotherapy Mediated by Biomimetic Polymeric Nanoparticles Potentiates Enhanced Tumor Immunotherapy via Amplification of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction.

Construction of multifunctional nanoplatforms to elevate chemotherapeutic efficacy and induce long-term antitumor immunity still remains to be an extreme challenge. Herein, the design of an advanced redox-responsive nanomedicine formulation based on phosphorus dendrimer-copper(II) complexes (1G3 -Cu)- and toyocamycin (Toy)-loaded polymeric nanoparticles (GCT NPs) coated with cancer cell membranes (CM) are reported. The designed GCT@CM NPs with a size of 210 nm are stable under physiological conditions but are rapidly dissociated in the reductive tumor microenvironment to deplete glutathione and release drugs. The co-loading of 1G3 -Cu and Toy within the NPs causes significant tumor cell apoptosis and immunogenic cell death through 1G3 -Cu-induced mitochondrial dysfunction and Toy-mediated amplification of endoplasmic reticulum stress, respectively, thus effectively suppressing tumor growth, promoting dendritic cell maturation, and increasing tumor-infiltrating cytotoxic T lymphocytes. Likewise, the coated CM and the loaded 1G3 -Cu render the GCT@CM NPs with homotypic targeting and T1 -weighted magnetic resonance imaging of tumors, respectively. With the assistance of programmed cell death ligand 1 antibody, the GCT@CM NP-mediated chemotherapy can significantly potentiate tumor immunotherapy for effective inhibition of tumor recurrence and metastasis. The developed GCT@CM NPs hold a great potential for chemotherapy-potentiated immunotherapy of different tumor types through different mechanisms or synergies.

"Cluster Bomb" Based on Redox-Responsive Carbon Dot Nanoclusters Coated with Cell Membranes for Enhanced Tumor Theranostics.

Designing intelligent stimuli-responsive nanoplatforms that are integrated with a biological membrane system and nanomaterials to realize efficient imaging and therapy of tumors still remains to be challenging. Herein, we report a unique strategy to prepare redox-responsive yellow fluorescent carbon dot nanoclusters (y-CDCs) loaded with anticancer drug doxorubicin (DOX) and coated with the cancer cell membrane (CCM) for precision fluorescence imaging and homologous targeting chemotherapy of tumors. The y-CDs with a size of 7.2 nm were first synthesized via a hydrothermal method and crosslinked to obtain redox-responsive y-CDCs with a size of 150.0 nm. The formulated y-CDCs were physically loaded with DOX with an efficiency of up to 81.0% and coated with CCM to endow them with antifouling properties, immune escape ability to escape from macrophage uptake, and homologous targeting capability to cancer cells. Within the reductive tumor microenvironment, the y-CDCs with quenched fluorescence can dissociate to form single y-CDs with recovered fluorescence and improved tumor penetration ability and simultaneously release DOX from the "cluster bomb", thus realizing efficient targeted tumor fluorescence imaging and chemotherapy. The designed y-CDCs/DOX@CCM may represent an updated nanomedicine formulation based on CDs for improved theranostics of different types of tumors.