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The design and fabrication of nanoplatforms with both nuclear medical imaging and therapeutic functions remain challenging in current precision nanomedicine. Herein, we report the design of a novel nanoplatform based on glucose-modified dendrimer-entrapped gold nanoparticles (Au DENPs) labeled with radionuclide 68Ga and incorporated with cytosine-guanine (CpG) oligonucleotide for positron emission tomography (PET)/computed tomography (CT) dual-mode imaging and immunotherapy of tumors. In this study, generation 5 poly(amidoamine) (PAMAM) dendrimers were first modified to have 8.2 DOTA and 7.3 polyethylene glycol with the other end functionalized with 2-amino-2-deoxy- D -glucose (DG) for each dendrimer, entrapped with Au NPs, and then radiolabeled with 68Ga through the DOTA chelation. The synthesized DG-Au DENPs have good cytocompatibility, targeting specificity toward cancer cells expressing glucose transporters, and the ability to be labeled by 68Ga with great labeling efficiency (≥85%) and stability (≥95%). After being loaded with CpG, the formed DG-Au DENPs/CpG polyplexes were proven to be used for tumor dual-mode PET/CT imaging and immunotherapy by effectively maturing dendritic cells to initiate a T cell-based antitumor immune response in vivo. Compared with the DG-free polyplexes, the developed DG-Au DENPs/CpG polyplexes show a much more sensitive imaging effect and better inhibition effect of tumors. These findings demonstrate a unique design of 68Ga-labeled DG-Au DENPs, a promising theranostic nanoplatform that may be extended to tackle different tumor types. [ABSTRACT FROM AUTHOR]

We report the construction of two types of core–shell tecto dendrimers (CSTDs) with different core rigidities to illustrate the impact of molecular rigidity on their gene delivery efficiency. Our study reveals that CSTDs designed with rigid cores enable promoted gene delivery, providing many possibilities for a wide range of gene delivery-associated biomedical applications. [ABSTRACT FROM AUTHOR]

Conventional cancer chemotherapy is facing difficulties in improving the bioavailability, overcoming the severe adverse side effects of chemotherapeutics and reversing the multidrug resistance of cancer cells. To address these challenges, we report a feasible strategy to realize a multistage sustained release of dual drugs using injectable short nanofibers as a carrier system. In this work, layered double hydroxide (LDH) was selected as the primary carrier to load the anticancer drug doxorubicin (DOX), and the DOX-loaded LDH was incorporated within an α-tocopheryl succinate (α-TOS)-doped poly(lactic-co-glycolic acid) (PLGA) fibrous mat. After homogenization in the presence of poly(vinyl alcohol), dual drug-loaded injectable short nanofibers (DOX@LDH/α-TOS/PLGA) with an average length of 17.4 μm and a diameter of 830.2 nm were formed to have a pH-responsive drug release profile. In an acidic tumor microenvironment, DOX@LDH/α-TOS/PLGA short nanofibers show a fast release of α-TOS due to its incorporation within the fiber matrix and a slow release of DOX due to the extended diffusion distance (first from the LDH to the fiber matrix and then from the fiber matrix to the external medium). As α-TOS can inhibit the expression of p-glycoprotein on the cell membrane, the dual drug-loaded short nanofibers can exert the therapeutic effect on multidrug-resistant cancer cells in vitro. The developed injectable short nanofiber-based drug delivery system may be extended to the treatment of different tumor types in vivo, in particular for long-term effective chemotherapy of drug-resistant tumors. [ABSTRACT FROM AUTHOR]

Development of versatile and powerful nanoplatforms for efficient therapeutic delivery represents a major topic for current nanomedicine. Herein, we present the development of core–shell tecto dendrimers (CSTDs) for co-delivery of a therapeutic gene and drug for enhanced anticancer therapy applications. In this work, CSTDs were first prepared via supramolecular recognition of β-cyclodextrin (CD)-decorated generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers as cores and adamantane (Ad)-functionalized G3 PAMAM dendrimers as shell components. The formed CSTDs with each G5 dendrimer surrounded with 4.2 G3 dendrimers were evaluated as a gene vector for delivery of plasmid DNA encoding enhanced green fluorescent protein as well as microRNA 21 inhibitor (miR 21i). We show that under an appropriate N/P ratio, the CSTDs enable effective transfection of both genetic materials to cancer cells. In particular, the transfection of miR 21i led to the inhibition of cancer cell migration, decreased miR 21 gene expression, and the effective regulation of the target genes and proteins (e.g., PTEN, PDCD4, p53, and Caspase-3). Furthermore, we revealed that the CSTDs were able to co-deliver miR 21i and an anticancer drug doxorubicin, leading to enhanced therapeutic efficacy to cancer cells in vitro. Our findings imply that the developed CSTDs could be adopted as a versatile platform for effective co-delivery of different therapeutic components for enhanced anticancer therapy applications. [ABSTRACT FROM AUTHOR]

It remains an extreme challenge to develop multifunctional drug delivery systems with tumor specificity and a tumor microenvironment (TME) remodeling ability for achieving improved chemotherapy against malignant tumors. Herein, we report the design of diselenide-crosslinked poly( N -vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with gold (Au) nanoparticles (NPs) and methotrexate (MTX) as a multifunctional nanoplatform (for short, MTX/Au@PVCL NGs) for improved chemotherapy and computed tomography (CT) imaging of tumors. The designed MTX/Au@PVCL NGs show excellent colloidal stability under physiological conditions, while dissociating rapidly to release the incorporated Au NPs and MTX in the H 2 O 2 -abundant and slightly acidic TME. The responsive release of Au NPs and MTX effectively induces the apoptosis of cancer cells and prevents DNA replication, together contributing to the repolarization of macrophages from protumor M2-like to antitumor M1-like phenotype in vitro . The MTX/Au@PVCL NGs also enable the remodeling of tumor-associated macrophages to the M1-like phenotype in vivo in a subcutaneous mouse melanoma model, which increases the recruitment of effector T lymphocytes and reduces the content of immunosuppressive regulatory T cells to achieve synergistically enhanced antitumor efficacy when combined with MTX-mediated chemotherapy. Moreover, the MTX/Au@PVCL NGs can be used for Au-mediated CT imaging of tumors. The thus developed NG platform shows great promise as an updated nanomedicine formulation for immune modulation-enhanced tumor chemotherapy under the guidance of CT imaging.

The design and fabrication of nanoplatforms with both nuclear medical imaging and therapeutic functions remain challenging in current precision nanomedicine. Herein, we report the design of a novel nanoplatform based on glucose-modified dendrimer-entrapped gold nanoparticles (Au DENPs) labeled with radionuclide 68 Ga and incorporated with cytosine-guanine (CpG) oligonucleotide for positron emission tomography (PET)/computed tomography (CT) dual-mode imaging and immunotherapy of tumors. In this study, generation 5 poly(amidoamine) (PAMAM) dendrimers were first modified to have 8.2 DOTA and 7.3 polyethylene glycol with the other end functionalized with 2-amino-2-deoxy-D-glucose (DG) for each dendrimer, entrapped with Au NPs, and then radiolabeled with 68 Ga through the DOTA chelation. The synthesized DG-Au DENPs have good cytocompatibility, targeting specificity toward cancer cells expressing glucose transporters, and the ability to be labeled by 68 Ga with great labeling efficiency (≥85%) and stability (≥95%). After being loaded with CpG, the formed DG-Au DENPs/CpG polyplexes were proven to be used for tumor dual-mode PET/CT imaging and immunotherapy by effectively maturing dendritic cells to initiate a T cell-based antitumor immune response in vivo . Compared with the DG-free polyplexes, the developed DG-Au DENPs/CpG polyplexes show a much more sensitive imaging effect and better inhibition effect of tumors. These findings demonstrate a unique design of 68 Ga-labeled DG-Au DENPs, a promising theranostic nanoplatform that may be extended to tackle different tumor types.

Chemodynamic therapy (CDT) has received increasing attention due to its unique tumor microenvironment (TME) responsiveness and minimal adverse side effects, but the therapeutic effect of CDT alone is always limited due to the low Fenton or Fenton-like reaction efficiency at tumor sites. Herein, Fe-doped layered double hydroxide (LDH) nanosheets were synthesized to load the anticancer drug epigallocatechin-3- O -gallate (EGCG) and then conjugated with boronic acid-modified hyaluronic acid for targeted and cooperative chemo-chemodynamic therapy of tumors. The formed LDH-EGCG-HA nanoplatforms could specifically target tumor cells overexpressing CD44 receptors, quickly release iron ions and EGCG in the TME, and efficiently generate toxic hydroxyl radicals with the acceleration of Fe 3+ /Fe 2+ cycling in the Fenton reaction by EGCG. The cooperative cancer cell inhibition effect through chemotherapy and chemodynamic therapy was achieved by the significant upregulation of caspase-3 and p53 expression to induce cell apoptosis, and the deactivation of xCT and GPX-4 to inhibit GSH synthesis and reduce lipid peroxides for reinforced ferroptosis. In vivo experiments further verified that the intelligently designed LDH-EGCG-HA nanoplatforms had a superior biocompatibility with normal organs with an excellent inhibition efficacy towards tumors overexpressing CD44 receptors by targeted chemo-chemodynamic therapy.