Manganese Dioxide-Entrapping Dendrimers Co-Deliver Protein and Nucleotide for Magnetic Resonance Imaging-Guided Chemodynamic/Starvation/Immune Therapy of Tumors.

Development of a nanoscale drug delivery system that can simultaneously exert efficient tumor therapeutic efficacy while creating the desired antitumor immune responses is still challenging. Herein, we report the use of a manganese dioxide (MnO2)-entrapping dendrimer nanocarrier to codeliver glucose oxidase (GOx) and cyclic GMP-AMP (cGAMP), an agonist of the stimulator of interferon genes (STING) for improved tumor chemodynamic/starvation/immune therapy. Methoxy poly(ethylene glycol) (mPEG)- and phenylboronic acid (PBA)-modified generation 5 (G5) poly(amidoamine) dendrimers were first synthesized and then entrapped with MnO2 nanoparticles (NPs) to generate the hybrid MnO2@G5-mPEG-PBA (MGPP) NPs. The created MGPP NPs with an MnO2 core size of 2.8 nm display efficient glutathione depletion ability, and a favorable Mn2+ release profile under a tumor microenvironment mimetic condition to enable Fenton-like reaction and T1-weighted magnetic resonance (MR) imaging. We show that the MGPP-mediated GOx delivery facilitates enhanced chemodynamic/starvation therapy of cancer cells in vitro, and further codelivery of cGAMP can effectively trigger immunogenic cell death (ICD) to strongly promote the maturation of dendritic cells. In a bilateral mouse colorectal tumor model, the dendrimer delivery nanosystem elicits a potent antitumor performance with a strong abscopal effect, greatly improving the overall mouse survival rate. Importantly, the dendrimer-mediated codelivery not only allows the coordination of Mn2+ with GOx and cGAMP for respective chemodynamic/starvation-triggered ICD and augmented STING activation to boost systemic antitumor immune responses, but also enables T1-weighted tumor MR imaging, potentially serving as a promising nanoplatform for enhanced antitumor therapy with desired immune responses.

Phosphorus core-shell tecto dendrimers for enhanced tumor imaging: the rigidity of the backbone matters.

Nanoplatforms with amplified passive tumor targeting and enhanced protein resistance can evade unnecessary uptake by the reticuloendothelial system and achieve high tumor retention for accurate tumor theranostics. To achieve this goal, we here constructed phosphorus core-shell tecto dendrimers (CSTDs) with a rigid aromatic backbone core as a nanoplatform for enhanced fluorescence and single-photon emission computed tomography (SPECT) dual-mode imaging of tumors. In this study, the phosphorus P-G2.5/G3 CSTDs (G denotes generation) were partially conjugated with tetraazacyclododecane tetraacetic acid (DOTA), cyanine5.5 (Cy5.5) and 1,3-propane sulfonate (1,3-PS) and then labeled with 99mTc. The formed P-G2.5/G3-DOTA-Cy5.5-PS CSTDs possess good monodispersity with a particle size of 10.1 nm and desired protein resistance and cytocompatibility. Strikingly, compared to the counterpart material G3/G3-DOTA-Cy5.5-PS with both the core and shell components being soft poly(amidoamine) dendrimers, the developed P-G2.5/G3-DOTA-Cy5.5-PS complexes allow for more efficient cellular uptake and more significant penetration in 3-dimensional tumor spheroids in vitro, as well as more significant tumor retention and accumulation for enhanced dual-mode fluorescence and SPECT (after labelling with 99mTc) tumor imaging in vivo. Our studies suggest that the rigidity of the core for the constructed CSTDs matters in the amplification of the tumor enhanced permeability retention (EPR) effect for improved cancer nanomedicine development.

A Biomimetic Nanogel System Restores Macrophage Phagocytosis for Magnetic Resonance Imaging-Guided Synergistic Chemoimmunotherapy of Breast Cancer.

Novel strategies to facilitate tumor-specific drug delivery and restore immune attacks remain to be developed to overcome the current limitations of chemotherapy. Herein, a cancer cell membrane (CM)-camouflaged and ultrasmall iron oxide nanoparticles (USIO NPs)-loaded polyethylenimine nanogel (NG) system is reported to co-deliver docetaxel (DTX) and CD47 siRNA (siCD47). The prepared co-delivery system exhibits good colloidal stability, biocompatibility, and r1 relaxivity (1.35 mM-1 s-1 ) and enables redox-responsive release of the loaded DTX in the tumor microenvironment. The NG system realizes homologous targeting delivery of DTX and siCD47 to murine breast cancer cells (4T1 cells) for efficient chemotherapy and gene silencing; thus, inducing immunogenic cell death (ICD) and restoring macrophage phagocytic effect through downregulation of "don't eat me" signals on cancer cells. Likewise, the co-delivery system can also act on macrophages to promote their M1 polarization, which can be combined with DTX-mediated ICD and antibody-mediated immune checkpoint blockade to generate effector T cells for robust chemoimmunotherapy. Further, the USIO NPs-incorporated NG system also allows for magnetic resonance imaging of tumors. The developed biomimetic NG system acting on both cancer cells and macrophages holds a promising potential for macrophage phagocytosis-restored chemoimmunotherapy.

An Intelligent Vascular Disrupting Dendritic Nanodevice Incorporating Copper Sulfide Nanoparticles for Immune Modulation-Mediated Combination Tumor Therapy.

Development of intelligent nanoplatforms that can simultaneously target multiple factors associated with tumor growth and metastasis remains an extreme challenge. Here, an intelligent dendritic nanodevice incorporating both copper sulfide nanoparticles (CuS NPs) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a vascular disrupting agent) within the dendrimer internal cavities and surface modified with a targeting agent LyP-1 peptide is reported. The resulting generation 5 (G5) dendrimer-based nanodevice, known as G5-PEG-LyP-1-CuS-DMXAA NPs (GLCD NPs), possess good colloidal stability, pH-sensitive drug release kinetics, and high photothermal conversion efficiency (59.3%). These functional GLCD NPs exert a LyP-1-targeted killing effect on breast tumors by combining CuS-mediated photothermal therapy (PTT) and DMXAA-induced vascular disruption, while also triggering antitumor immune responses through PTT-induced immunogenic cell death and DMXAA-mediated immune regulation via M1 polarization of tumor-associated macrophages and dendritic cell maturation. In addition, with the LyP-1-mediated proapoptotic activity, the GLCD NPs can specifically kill tumor lymphatic endothelial cells. The simultaneous disruption of tumor blood vessels and lymphatic vessels cuts off the two main pathways of tumor metastasis, which plays a two-pronged role in inhibiting lung metastasis of the breast cancer model. Thus, the developed GLCD NPs represent an advanced intelligent nanoformulation for immune modulation-mediated combination tumor therapy with potential for clinical translations.

Microfluidic synthesis of fibronectin-coated polydopamine nanocomplexes for self-supplementing tumor microenvironment regulation and MR imaging-guided chemo-chemodynamic-immune therapy.

Development of nanomedicines to overcome the hindrances of tumor microenvironment (TME) for tumor theranostics with alleviated side effects remains challenging. We report here a microfluidic synthesis of artesunate (ART)-loaded polydopamine (PDA)/iron (Fe) nanocomplexes (NCs) coated with fibronectin (FN). The created multifunctional Fe-PDA@ART/FN NCs (FDRF NCs) with a mean size of 161.0 â€‹nm exhibit desired colloidal stability, monodispersity, r1 relaxivity (4.96 â€‹mM-1s-1), and biocompatibility. The co-delivery of the Fe2+ and ART enables enhanced chemodynamic therapy (CDT) through improved intracellular reactive oxygen species generation via a cycling reaction between Fe3+ and Fe2+ caused by the Fe3+-mediated glutathione oxidation and Fe2+-mediated ART reduction/Fenton reaction for self-supplementing TME regulation. Likewise, the combination of ART-mediated chemotherapy and the Fe2+/ART-regulated enhanced CDT enables noticeable immunogenic cell death, which can be collaborated with antibody-mediated immune checkpoint blockade to exert immunotherapy having significant antitumor immunity. The combined therapy improves the efficacy of primary tumor therapy and tumor metastasis inhibition by virtue of FN-mediated specific targeting of FDRF NCs to tumors with highly expressed αvß3 integrin and can be guided through the Fe(III)-rendered magnetic resonance (MR) imaging. The developed FDRF NCs may be regarded as an advanced nanomedicine formulation for chemo-chemodynamic-immune therapy of different tumor types under MR imaging guidance.

Diselenide-crosslinked nanogels laden with gold nanoparticles and methotrexate for immunomodulation-enhanced chemotherapy and computed tomography imaging of tumors.

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 H2O2-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.

Core-shell tecto dendrimer-mediated cooperative chemoimmunotherapy of breast cancer.

Development of effective nanomedicines to deal with tumor immunogenicity and immunosuppression is vital to improve the immunotherapy efficacy. Herein, we developed a programmed strategy not only to activate the tumoral immune microenvironment through immunogenic cell death (ICD) effect but also to promote the maturation of dendritic cells (DCs) in lymph nodes through two modules of core-shell tecto dendrimer (CSTD)-based nanomedicines. The CSTDs with amplified tumor enhanced permeability and retention effect and improved gene delivery efficiency were formed by supramolecular self-assembly of generation 5 (G5) poly(amidoamine) dendrimers as cores and G3 dendrimers as shells. One module was employed to load doxorubicin for cancer cell chemotherapy to generate ICD, while the other module with partial surface modification of zwitterions and mannose was used for serum-enhanced YTHDF1 siRNA delivery to DCs to stimulate their maturation. These two modular CSTD-based nanomedicine formulations enable enhanced chemoimmunotherapy of an orthotopic breast tumor model through programmed treatment of cancer cells and DCs, and synergistic modulation of the maturation of DCs to activate the CD8+/CD4+ T cells for tumor killing. The developed CSTD-enabled nanomodules with improved drug/gene delivery performance may be applicable to tackle other cancer types via collaborative chemoimmunotherapy.

A tumor microenvironment-responsive core-shell tecto dendrimer nanoplatform for magnetic resonance imaging-guided and cuproptosis-promoted chemo-chemodynamic therapy.

Theranostic nanoplatforms for combination tumor therapy have gained lots of attention recently due to the optimized therapeutic efficiency and simultaneous diagnosis performance. Herein, a novel tumor microenvironment (TME)-responsive core-shell tecto dendrimer (CSTD) was assembled by phenylboronic acid- and mannose-modified poly(amidoamine) dendrimers via the phenylboronic ester bonds that are responsive to low pH and reactive oxygen species (ROS), and efficiently loaded with copper ions and chemotherapeutic drug disulfiram (DSF) for tumor-targeted magnetic resonance (MR) imaging and cuproptosis-promoted chemo-chemodynamic therapy. The formed CSTD-Cu(II)@DSF could be specifically taken up by MCF-7 breast cancer cells, accumulated to the tumor model after circulation, and released drugs in response to the weakly acidic TME with overexpressed ROS. The enriched intracellular Cu(II) ions could induce the oligomerization of lipoylated proteins and proteotoxic stress for cuproptosis, and lipid peroxidation for chemodynamic therapy as well. Moreover, the CSTD-Cu(II)@DSF could cause the dysfunction of mitochondria and arrest the cell cycle at the G2/M phase, leading to enhanced DSF-mediated cell apoptosis. As a result, CSTD-Cu(II)@DSF could effectively inhibit the growth of MCF-7 tumors by a combination therapy strategy integrating chemotherapy with cuproptosis and chemodynamic therapy. Lastly, the CSTD-Cu(II)@DSF also displays Cu(II)-associated r1 relaxivity, allowing for T1-weighted real-time MR imaging of tumors in vivo. The developed tumor-targeted and TME-responsive CSTD-based nanomedicine formulation may be developed for accurate diagnosis and synergistic treatment of other cancer types. STATEMENT OF SIGNIFICANCE: Constructing an effective nanoplatform for the combination of therapeutic effects and real-time tumor imaging remains a challenge. In this study, we reported for the first time an all-in-one tumor-targeted and tumor microenvironment (TME) responsive nanoplatform based on core-shell tecto dendrimer (CSTD) for the cuproptosis-promoted chemo-chemodynamic therapy and enhanced MR imaging. The efficient loading, selective tumor-targeting, and TME-responsive release of Cu(II) and disulfiram could enhance the intracellular accumulation of drugs, induce cuproptosis of cancer cells, and amplify the synergistic chemo-chemodynamic therapeutic effect, resulting in enhanced MR imaging and accelerated tumor eradication. This study sheds new light on the development of theranostic nanoplatforms for early accurate diagnosis and effective treatment of cancers.

Photothermal-triggered dendrimer nanovaccines boost systemic antitumor immunity.

Tumor vaccine that can effectively activate or strengthen the body's antitumor immune response to kill and eliminate tumor cells has attracted widespread attention. Currently developed tumor vaccines have severe shortcomings such as low bioavailability and lack of dual or multiple functions, resulting in poor antitumor efficacy. Herein, we report the development of an advanced nanosystem integrated with phenylboronic acid (PBA)-functionalized poly(amidoamine) dendrimers of generation 5 (G5), copper sulfide nanoparticles, and cyclic GMP-AMP (cGAMP), an immune adjuvant (for short, G5-PBA@CuS/cGAMP) to act as a photothermal-triggered nanovaccine. We show that the prepared functional nanosystem possesses an average CuS core size of 3.6 nm, prominent near-infrared absorption feature to have an excellent photothermal conversion efficiency of 44.0%, and good protein adsorption characteristics due to the PBA modification. With these features, the developed nanosystem can be adopted for photothermal therapy of primary melanoma tumors and simultaneously absorb the whole tumor cell antigens, thus creating photothermal-triggered dendrimeric nanovaccine of G5-PBA@CuS/cGAMP/antigen in situ to induce antitumor immune response to inhibit the distal tumors as well. Meanwhile, melanoma cells treated with the G5-PBA@CuS in vitro under laser irradiation allowed the creation of G5-PBA@CuS/antigen complexes that could be further integrated with cGAMP to form preformed nanovaccine for effective primary tumor inhibition and tumor occurrence prevention. The designed photothermal-triggered dendrimeric nanovaccine may represent an advanced nanomedicine formulation to effectively inhibit the growth of primary and distal tumors, and prevent tumor occurrence through the stimulated systemic antitumor immunity.

Dendrimer-Mediated Intracellular Delivery of Fibronectin Guides Macrophage Polarization to Alleviate Acute Lung Injury.

Fibronectin (FN) is an essential glycoprotein in the extracellular matrix with favorable biological functions for potential applications in various biomedical fields including wound healing, regenerative medicine, tissue engineering, as well as diagnosis and treatment of cancer and inflammatory diseases. Herein, we aim to explore the influence of intracellular FN delivery on macrophage functions and its possible therapeutic applications. We prepared phenylboronic acid (PBA)-functionalized generation 5 (G5) poly(amidoamine) dendrimers (G5.NH2-PBA) as a nanocarrier to load FN, and reveal that the obtained dendrimers enable efficient intracellular delivery of FN at an optimized dendrimer-to-FN weight ratio of 8, which guides macrophages toward anti-inflammatory M2 phenotype polarization. Studies on action mechanisms show that the dendrimer-mediated FN intracellular delivery acts strongly on suppressing the nuclear factor-κB pathway, leading to reduced pro-inflammatory cytokine secretion and enhanced reactive oxygen species depletion in lipopolysaccharide (LPS)-activated macrophages. Further investigation in vivo using an LPS-induced mouse model of acute lung injury (ALI) shows that the dendrimer-mediated FN delivery can effectively alleviate the ALI symptoms through alleviation of lung inflammation and oxidation stress. Our work suggests a general approach to using dendrimers for mediating intracellular delivery of FN, thereby offering many opportunities to explore the biological functions of FN for different therapeutic applications toward inflammation-associated diseases.

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.

68Ga-labeled dendrimer-entrapped gold nanoparticles for PET/CT dual-modality imaging and immunotherapy of tumors.

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.

Genetic Engineering of Dendritic Cells Using Partially Zwitterionic Dendrimer-Entrapped Gold Nanoparticles Boosts Efficient Tumor Immunotherapy.

Effective processing and cross-priming of tumor neoantigen by dendritic cells (DCs) to T cells for spontaneous immune response generation to effectively kill cancer cells remain challenging in cancer immunotherapy. Here, we report a general approach to genetically engineer DCs through silencing their YTHDF1 protein (an important reader protein responsible for RNA m6A methylation) expression via a dendrimeric non-viral vector to boost effective tumor immunotherapy. Poly(amidoamine) dendrimers of generation 5 were partially decorated with mannose and 1,3-propanesultone and then entrapped with gold (Au) nanoparticles. The created dendrimer nanoplatform has an Au core size of 1.8 nm; possesses desired stability, good cytocompatibility, and excellent YTHDF1 siRNA compression ability; and enables targeted gene silencing of DCs overexpressing mannose receptors to upregulate the expression of CD80 and CD86, markers of DCs maturation, potentially leading to tumor antigen cross-presentation. With these properties owned, the combination of YTHDF1 silencing of DCs with programmed cell death-ligand 1 antibody can boost the best immunotherapy of a xenografted melanoma tumor model through the created antitumor immune responses. Findings in this study demonstrate a general approach of genetic engineering of DCs via a dendrimeric non-viral vector to effectively boost antitumor immunotherapy.

Intelligent design of iron-doped LDH nanosheets for cooperative chemo-chemodynamic therapy of tumors.

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 Fe3+/Fe2+ 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.

Dendrimer-Based Nanogels for Cancer Nanomedicine Applications.

Recent advances in the field of nanotechnology bring an alternative approach to personalized medicine in cancer treatment. Nanogels (NGs) are among the nanosized superconstructs composed of amphiphilic or hydrophilic polymer networks. The design of different types of biodegradable polymer-based NGs in various biomedical applications has received extensive attention, due to their unique physicochemical properties such as highly porous structure, stimuli-responsiveness, and mimicking of some biological properties. In this review, we concisely surveyed the synthesis of dendrimer-based NGs synthesized via different methods including covalent conjugation, inverse nanoprecipitation, physical cross-linking, or self-assembly for various cancer nanomedicine applications, particularly for drug delivery, gene delivery, photothermal therapy, and combination therapy, as well as for biological imaging-guided chemotherapy. Additionally, we provide herein future perspective toward the new design of dendrimer-based NGs for different cancer nanomedicine uses.

A Dual-Responsive Platform Based on Antifouling Dendrimer-CuS Nanohybrids for Enhanced Tumor Delivery and Combination Therapy.

Design of stimuli-responsive nanomedicine with enhanced tumor delivery for combination therapy still remains a great challenge. Here, a unique design of an antifouling-dendrimer-based nanoplatform with dual pH- and redox-responsiveness is reported to meet this challenge. First, generation 5 (G5) poly(amidoamine) dendrimers are modified with targeting ligand cyclic arginine-glycine-aspartic acid (RGD) peptide through a polyethylene glycol (PEG) spacer and zwitterion of thiolated N,N-dimethyl-cysteamine-carboxybetaine (CBT) via pH-responsive benzoicimine bond to form G5.NH2 PEGRGDCBT conjugates. Then, doxorubicin (DOX) is linked to the functional G5 dendrimers through a redox-responsive disulfide bond, followed by entrapment of CuS nanoparticles within the dendrimers. The created functional dendrimer-CuS nanohybrids with a CuS core size of 3.6 nm display a good antifouling property and excellent photothermal conversion property in the second near-infrared window. In addition, the neutral surface charge of the nanohybrids is able to be switched to be positive in the tumor region with slightly acidic microenvironment due to the break of benzoicimine bond to promote their intracellular uptake, while the redox-sensitive disulfide bond affords the fast release of the conjugated DOX within tumor cells to exert its therapeutic effect. Taken together with the CuS cores, the created dendrimer-CuS nanohybrids enable enhanced combination chemotherapy and photothermal therapy of tumors.

Overcoming T Cell Exhaustion via Immune Checkpoint Modulation with a Dendrimer-Based Hybrid Nanocomplex.

T cell exhaustion, in which dysfunctional T cells are limited in cytokine release and constrained in immune response, leads to immune escape of cancer cells and decreased efficiency of cancer immunotherapy. Direct regulation or blocking of programmed death 1 (PD-1) represents a promising strategy to overcome T cell exhaustion for reinvigorating anticancer immunity. Here, the construction of a 1,3-propanesultone (1,3-PS)-grafted zwitterionic dendrimer-entrapped gold nanoparticle platform chelated with Gd(III) (Gd-Au DENP-PS) for immune checkpoint modulation is reported. The developed Gd-Au DENP-PS possesses good stability, antifouling property, biocompatibility, and dual-mode computed tomography (CT)/magnetic resonance (MR) imaging functions, and allows for efficient packaging and serum-enhanced delivery of PD-1 siRNA to mediate PD-1 gene silencing in T cells in vitro, and also in vivo in a melanoma-bearing mouse model and in healthy aging mice. The dendrimer nanocomplexes or T cell-laden nanocomplexes enable suppression of tumor growth through the generation of significant effector CD8+ and CD4+ T cells, and the tumor immunotherapeutic potency can be further improved by combination with an indoleamine 2,3-dioxygenase inhibitor. This study identifies a new possibility with a functional dendrimer-based nanohybrid platform for dual-mode CT/MR imaging-guided cancer immunotherapy via the regulation of T cell exhaustion.

Impact of molecular rigidity on the gene delivery efficiency of core-shell tecto dendrimers.

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.

Dendrimer-based nanohybrids in cancer photomedicine.

Cancer phototherapy with non-invasiveness and high therapeutical efficiency has emerged as a hot spot research in cancer management. Various nanomaterials have been involved in the development of novel photoactive agents to overcome the current limitations in cancer phototherapy. Dendrimers, as an excellent nanocarrier with unique physicochemical properties, have received extensive attention and much effort has been made in the development of dendrimer-based hybrid platforms for photomedicine applications. Dendrimers can be entrapped with photosensitive agents within their internal cavities and be surface modified with reactive molecules, constructing multifunctional nanoplatforms for cancer treatment. In this review, we concisely survey the design of several different kinds of dendrimer-based nanohybrids for cancer photomedicine applications, and provide an overview of their recent applications in molecular imaging, single-modality photothermal therapy or photodynamic therapy, combination therapy, and theranostics of cancer. In addition, we also briefly discuss the future perspectives in the area of dendrimer-based nanohybrids for cancer photomedicine.

Core-Shell Tecto Dendrimers Enable Enhanced Tumor MR Imaging through an Amplified EPR Effect.

Development of nanoplatforms that can amplify the passive tumor targeting effect based on enhanced permeability and retention (EPR) effect is crucial for precision cancer nanomedicine applications. Herein, we present the development of core-shell tecto dendrimers (CSTDs) as a platform for enhanced tumor magnetic resonance (MR) imaging through an amplified EPR effect. In this work, poly(amidoamine) (PAMAM) dendrimers of generation 5 (G5) were decorated with ß-cyclodextrin (CD) and then assembled with G3 PAMAM dendrimers premodified with adamantane (Ad) via supramolecular recognition of CD and Ad. The formed G5-CD/Ad-G3 CSTDs were conjugated with tetraazacyclododecane tetraacetic acid (DOTA)-Gd(III) chelators and further acetylated to neutralize the remaining CSTD periphery amines. We reveal that the formed CSTD.NHAc-DOTA(Gd) (CSTD-D-Gd) complexes have a narrow size distribution and satisfactory colloidal stability, and are cytocompatible within the concentration range studied. Compared to the single dendrimer counterpart of G5.NHAc-DOTA(Gd) (G5-D-Gd) complexes, the CSTD-D-Gd complexes with a higher molecular weight and volume possess a longer rotation correlation time, hence having a longitudinal relaxivity (r1) of 7.34 mM-1 s-1, which is 1.5 times larger than that of G5-D-Gd complexes (4.92 mM-1 s-1). More importantly, the CSTD-D-Gd complexes display better permeability in the three-dimensional (3D) cell spheroids in vitro through fluorescence imaging and a more significant EPR effect for improved tumor MR imaging in vivo than the G5-DOTA-Gd complexes. The generated CSTD-D-Gd complexes may be adopted for enhanced tumor MR imaging through an amplified passive EPR effect and also be further extended for different cancer theranostic applications.