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.

Engineered Stable Bioactive Per Se Amphiphilic Phosphorus Dendron Nanomicelles as a Highly Efficient Drug Delivery System To Take Down Breast Cancer In Vivo.

Conventional small molecular chemical drugs always have challenging limitations in cancer therapy due to their high systemic toxicity and low therapeutic efficacy. Nanotechnology has been applied in drug delivery, bringing new promising potential to realize effective cancer treatment. In this context, we develop here a new nanomicellar drug delivery platform generated by amphiphilic phosphorus dendrons (1-C17G3.HCl), which could form micelles for effective encapsulation of a hydrophobic anticancer drug doxorubicin (DOX) with a high drug loading content (42.4%) and encapsulation efficiency (96.7%). Owing to the unique dendritic rigid structure and surface hydrophilic groups, large steady void space of micelles can be created for drug encapsulation. The created DOX-loaded micelles with a mean diameter of 26.3 nm have good colloidal stability. Strikingly, we show that the drug-free micelles possess good intrinsic anticancer activity and act collectively with DOX to take down breast cancer cells in vitro and the xenografted tumor model in vivo through upregulation of Bax, PTEN, and p53 proteins for enhanced cell apoptosis. Meanwhile, the resulting 1-C17G3.HCl@DOX micelles significantly abolish the toxicity relevant to the free drug. The findings of this study demonstrate a unique nanomicelle-based drug delivery system created with the self-assembling amphiphilic phosphorus dendrons that may be adapted for chemotherapy of different cancer types.

A tumor microenvironment-responsive poly(amidoamine) dendrimer nanoplatform for hypoxia-responsive chemo/chemodynamic therapy.

BACKGROUND: Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction in the tumor microenvironment (TME) with low pH and high level of endogenous hydrogen peroxide. However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict the curative outcomes of conventional chemodynamic therapy. RESULTS: In this study, polyethylene glycol-phenylboronic acid (PEG-PBA)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were synthesized as a targeted nanocarrier to chelate Cu(II) and then encapsulate hypoxia-sensitive drug tirapazamine (TPZ) by the formation of hydrophobic Cu(II)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy. The formed G5.NHAc-PEG-PBA@Cu(II)/TPZ (GPPCT) nanoplatform has good stability and hemocompatibility, and could release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro experiments showed that the GPPCT nanoplatforms can efficiently target murine breast cancer cells (4T1) cells overexpressing sialic acid residues, and show a significantly enhanced inhibitory effect on hypoxic cells by the activation of TPZ. The excessive GSH in tumors could be depleted by the reduction of Cu(II) to Cu(I), and abundant of toxic ·OH would be generated in tumor cells by Fenton reaction for chemodynamic therapy. In vivo experiments demonstrated that the GPPCT nanoplatform could specifically accumulate at tumors, effectively inhibit the growth and metastasis of tumors by the combination of CDT and chemotherapy, and be metabolized with no systemic toxicity. CONCLUSIONS: The targeted GPPCT nanoplatform may represent an effective model for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy.

Facile Synthesis of Amphiphilic Fluorescent Phosphorus Dendron-Based Micelles as Antiproliferative Agents: First Investigations.

We designed and synthesized several families of novel amphiphilic fluorescent phosphorus dendron-based micelles showing relevant antiproliferative activities for use in the field of theranostic nanomedicine. Based on straightforward synthesis pathways, 12 amphiphilic phosphorus dendrons bearing 10 protonated cyclic amino groups (generation one), or 20 protonated amino groups (generation two), and 1 hydrophobic chain carrying 1 fluorophore moiety were created. The amphiphilic dendron micelles had the capacity to aggregate in solution using hydrophilic/hydrophobic interactions, which promoted the formation of polymeric micelles. These dendron-based micelles showed moderate to high antiproliferative activities against a panel of tumor cell lines. This paper presents for the first time the synthesis and our first investigations of new phosphorus dendron-based micelles for cancer therapy applications.

Co-delivery of Dexamethasone and a MicroRNA-155 Inhibitor Using Dendrimer-Entrapped Gold Nanoparticles for Acute Lung Injury Therapy.

Development of nanomedicines for effective therapy of acute lung injury (ALI), a common critical respiratory failure syndrome, remains to be challenging. We report here a unique design of a functional nanoplatform based on generation 5 (G5) poly(amidoamine) dendrimer-entrapped gold nanoparticles (Au DENPs) to co-deliver dexamethasone (Dex) and a microRNA-155 inhibitor (miR-155i) for combination chemotherapy and gene therapy of ALI. In this study, we synthesized Au DENPs with 10 Dex moieties attached per G5 dendrimer and an Au core diameter of 2.1 nm and used them to compress miR-155i. The generated polyplexes own a positive zeta potential (16-26 mV) and a small hydrodynamic diameter (175-230 nm) and display desired cytocompatibility and efficient miR-155i delivery to lipopolysaccharide (LPS)-activated alveolar macrophages, thus upregulating the suppressor of cytokine signaling 1 and IL-10 expression and downregulating the pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6). Likewise, as a synthetic glucocorticoid with a potent anti-inflammatory property, the attached Dex on the surface of Au DENPs could inhibit pro-inflammatory cytokine secretion by down-regulating cyclooxygenase-2 expression in the LPS-activated alveolar macrophages. The integration of Dex and miR-155i within one nanoformulation enables superior downregulation of pro-inflammatory cytokines for successful repair of damaged lung tissues in an ALI model, as demonstrated by histological examinations and pro-inflammatory cytokine downregulation in ALI lesion at the gene and protein levels. Such a combined chemotherapy and gene therapy strategy enabled by dendrimer nanotechnology may hold great promise to treat other types of inflammatory diseases.

MiR-543 regulates myoblast proliferation and differentiation of C2C12 cells by targeting KLF6.

MicroRNA-543 (miR-543) has been found to play a suppressive role in various human cancers in many studies, whereas the specific functions of miR-543 in muscle development remain poorly understood. Here, we found that the expression of miR-543 was high in skeletal muscle and increased during the differentiation of C2C12 cells. Overexpression of miR-543 repressed C2C12 cell proliferation and promoted differentiation, while knockdown of miR-543 expression produced the opposite results. During myogenesis, we predicted and verified that Krüppel-like factor 6 (KLF6), a suppressor of multiple tumor cells, was a target gene of miR-543. Then, miR-543 was found to specifically target KLF6 and repress its expression. Besides this, knockdown of KLF6 promoted the differentiation but inhibited the proliferation of C2C12 cells. Si-KLF6 can rescue the influence of miR-543 inhibitor on C2C12 cell differentiation. Our results indicate a new regulatory mechanism of miR-543 on KLF6 expression and suggest the possibility of using the miR-543/KLF6 pathway as a potential target for studying myogenesis.

Transcription Factor Sp1 Promotes the Expression of Porcine ROCK1 Gene.

Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) gene plays a crucial role in maintaining genomic stability, tumorigenesis and myogenesis. However, little is known about the regulatory elements governing the transcription of porcine ROCK1 gene. In the current study, the transcription start site (TSS) was identified by 5'-RACE, and was found to differ from the predicted one. The region in ROCK1 promoter which is critical for promoter activity was investigated via progressive deletions. Site-directed mutagenesis indicated that the region from -604 to -554 bp contains responsive elements for Sp1. Subsequent experiments showed that ROCK1 promoter activity is enhanced by Sp1 in a dose-dependent manner, whereas treatment with specific siRNA repressed ROCK1 promoter activity. Electrophoretic mobility shift assay (EMSA), DNA pull down and chromatin immunoprecipitation (ChIP) assays revealed Sp1 can bind to this region. qRT-PCR and Western blotting research followed by overexpression or inhibition of Sp1 indicate that Sp1 can affect endogenous ROCK1 expression at both mRNA and protein levels. Overexpression of Sp1 can promote the expression of myogenic differentiation 1(MyoD), myogenin (MyoG), myosin heavy chain (MyHC). Taken together, we conclude that Sp1 positively regulates ROCK1 transcription by directly binding to the ROCK1 promoter region (from -604 to -532 bp) and may affect the process of myogenesis.

Seismic behavior and force-displacement characterization of neotype column-slab high piers.

The seismic behavior and plasticity spreading of a neotype column-slab high pier are researched in this paper. Four scale model tests of a web slab with two boundary columns are carried out under cyclic inelastic lateral displacements simulating seismic response. The test results show that the neotype column-slab high pier has strong and stable bearing capacity, good ductility, and energy dissipation capacity. The experimental values pertaining to the spread of plasticity are derived. An approach for deriving the spread of plasticity analytically is deduced and applied to the four tests. This method accurately assesses a pier's spread of plasticity for most ductility levels. At nearly all ductility levels, the mean difference between analytical assessments of the spread of plasticity and results from 4 large-scale tests is 12% with a 9% coefficient of variation.

Brain Delivery of Biomimetic Phosphorus Dendrimer/Antibody Nanocomplexes for Enhanced Glioma Immunotherapy via Immune Modulation of T Cells and Natural Killer Cells.

Fully mobilizing the activities of multiple immune cells is crucial to achieve the desired tumor immunotherapeutic efficacy yet still remains challenging. Herein, we report a nanomedicine formulation based on phosphorus dendrimer (termed AK128)/programmed cell death protein 1 antibody (aPD1) nanocomplexes (NCs) that are camouflaged with M1-type macrophage cell membranes (M1m) for enhanced immunotherapy of orthotopic glioma. The constructed AK128-aPD1@M1m NCs with a mean particle size of 160.3 nm possess good stability and cytocompatibility. By virtue of the decorated M1m having α4 and ß1 integrins, the NCs are able to penetrate the blood-brain barrier to codeliver both AK128 with intrinsic immunomodulatory activity and aPD1 to the orthotopic glioma with prolonged blood circulation time. We show that the phosphorus dendrimer AK128 can boost natural killer (NK) cell proliferation in peripheral blood mononuclear cells, while the delivered aPD1 enables immune checkpoint blockade (ICB) to restore the cytotoxic T cells and NK cells, thus promoting tumor cell apoptosis and simultaneously decreasing the tumor distribution of regulatory T cells vastly for improved glioma immunotherapy. The developed nanomedicine formulation with a simple composition achieves multiple modulations of immune cells by utilizing the immunomodulatory activity of nanocarrier and antibody-mediated ICB therapy, providing an effective strategy for cancer immunotherapy.

Bioactive Phosphorus Dendrimers as a Universal Protein Delivery System for Enhanced Anti-inflammation Therapy.

Nanocarrier-based cytoplasmic protein delivery offers opportunities to develop protein therapeutics; however, many delivery systems are positively charged, causing severe toxic effects. For enhanced therapeutics, it is also of great importance to design nanocarriers with intrinsic bioactivity that can be integrated with protein drugs due to the limited bioactivity of proteins alone for disease treatment. We report here a protein delivery system based on anionic phosphite-terminated phosphorus dendrimers with intrinsic anti-inflammatory activity. A phosphorus dendrimer termed AK-137 with optimized anti-inflammatory activity was selected to complex proteins through various physical interactions. Model proteins such as bovine serum albumin, ribonuclease A, ovalbumin, and fibronectin (FN) can be transfected into cells to exert their respective functions, including cancer cell apoptosis, dendritic cell maturation, or macrophage immunomodulation. Particularly, the constructed AK-137@FN nanocomplexes display powerful therapeutic effects in acute lung injury and acute gout arthritis models by integrating the anti-inflammatory activity of both the carrier and protein. The developed anionic phosphite-terminated phosphorus dendrimers may be employed as a universal carrier for protein delivery and particularly utilized to deliver proteins and fight different inflammatory diseases with enhanced therapeutic efficacy.

A functionalized cell membrane biomimetic nanoformulation based on layered double hydroxide for combined tumor chemotherapy and sonodynamic therapy.

The development of nanoformulations with simple compositions that can exert targeted combination therapy still remains a great challenge in the area of precision cancer nanomedicine. Herein, we report the design of a multifunctional nanoplatform based on methotrexate (MTX)-loaded layered double hydroxide (LDH) coated with chlorin e6 (Ce6)-modified MCF-7 cell membranes (CMM) for combined chemo/sonodynamic therapy of breast cancer. LDH nanoparticles were in situ loaded with MTX via coprecipitation, and coated with CMM that were finally functionalized with phospholipid-modified Ce6. The created nanoformulation of LDH-MTX@CMM-Ce6 displays good colloidal stability under physiological conditions and can release MTX in a pH-dependent manner. We show that the formulation can homologously target breast cancer cells, and induce their significant apoptosis through arresting the cell cycle via cooperative MTX-based chemotherapy and ultrasound (US)-activated sonodynamic therapy. The assistance of US can not only trigger sonosensitizer Ce6 to produce reactive oxygen species, but also enhance the cellular uptake of LDH-MTX@CMM-Ce6 via an acoustic cavitation effect. Upon intravenous injection and US irradiation, LDH-MTX@CMM-Ce6 displays an admirable antitumor performance towards a xenografted breast tumor mouse model. Furthermore, the modification of Ce6 on the CMM endows the LDH-based nanoplatform with fluorescence imaging capability. The developed LDH-based nanoformulation here provides a general intelligent cancer nanomedicine platform with simple composition and homologous targeting specificity for combined chemo/sonodynamic therapy and fluorescence imaging of tumors.

Nanoparticle-Mediated Multiple Modulation of Bone Microenvironment To Tackle Osteoarthritis.

Development of nanomedicines that can collaboratively scavenge reactive oxygen species (ROS) and inhibit inflammatory cytokines, along with osteogenesis promotion, is essential for efficient osteoarthritis (OA) treatment. Herein, we report the design of a ROS-responsive nanomedicine formulation based on fibronectin (FN)-coated polymer nanoparticles (NPs) loaded with azabisdimethylphoaphonate-terminated phosphorus dendrimers (G4-TBP). The constructed G4-TBP NPs-FN with a size of 268 nm are stable under physiological conditions, can be specifically taken up by macrophages through the FN-mediated targeting, and can be dissociated in the oxidative inflammatory microenvironment. The G4-TBP NPs-FN loaded with G4-TBP dendrimer having intrinsic anti-inflammatory property and FN having both anti-inflammatory and antioxidative properties display integrated functions of ROS scavenging, hypoxia attenuation, and macrophage M2 polarization, thus protecting macrophages from apoptosis and creating designed bone immune microenvironment for stem cell osteogenic differentiation. These characteristics of the G4-TBP NPs-FN lead to their effective treatment of an OA model in vivo to reduce pathological changes of joints including synovitis inhibition and cartilage matrix degradation and simultaneously promote osteogenic differentiation for bone repair. The developed nanomedicine formulation combining the advantages of both bioactive phosphorus dendrimers and FN to treat OA may be developed for immunomodulatory therapy of different inflammatory diseases.

Brain delivery of fibronectin through bioactive phosphorous dendrimers for Parkinson's disease treatment via cooperative modulation of microglia.

Effective treatment of Parkinson's disease (PD), a prevalent central neurodegenerative disorder particularly affecting the elderly population, still remains a huge challenge. We present here a novel nanomedicine formulation based on bioactive hydroxyl-terminated phosphorous dendrimers (termed as AK123) complexed with fibronectin (FN) with anti-inflammatory and antioxidative activities. The created optimized AK123/FN nanocomplexes (NCs) with a size of 223 nm display good colloidal stability in aqueous solution and can be specifically taken up by microglia through FN-mediated targeting. We show that the AK123/FN NCs are able to consume excessive reactive oxygen species, promote microglia M2 polarization and inhibit the nuclear factor-kappa B signaling pathway to downregulate inflammatory factors. With the abundant dendrimer surface hydroxyl terminal groups, the developed NCs are able to cross blood-brain barrier (BBB) to exert targeted therapy of a PD mouse model through the AK123-mediated anti-inflammation for M2 polarization of microglia and FN-mediated antioxidant and anti-inflammatory effects, thus reducing the aggregation of α-synuclein and restoring the contents of dopamine and tyrosine hydroxylase to normal levels in vivo. The developed dendrimer/FN NCs combine the advantages of BBB-crossing hydroxyl-terminated bioactive per se phosphorus dendrimers and FN, which is expected to be extended for the treatment of different neurodegenerative diseases.

Programming Injectable DNA Hydrogels Yields Tumor Microenvironment-Activatable and Immune-Instructive Depots for Augmented Chemo-Immunotherapy.

Injectable hydrogels have attracted increasing attention for promoting systemic antitumor immune response through the co-delivery of chemotherapeutics and immunomodulators. However, the biosafety and bioactivity of conventional hydrogel depots are often impaired by insufficient possibilities for post-gelling injection and means for biofunction integration. Here, an unprecedented injectable stimuli-responsive immunomodulatory depot through programming a super-soft DNA hydrogel adjuvant is reported. This hydrogel system encoded with adenosine triphosphate aptamers can be intratumorally injected in a gel formulation and then undergoes significant molecular conformation change to stimulate the distinct release kinetics of co-encapsulated therapeutics. In this scenario, doxorubicin is first released to induce immunogenic cell death that intimately works together with the polymerized cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) in gel scaffold for effectively recruiting and activating dendritic cells. The polymerized CpG ODN not only enhances tumor immunogenicity but minimizes free CpG-induced splenomegaly. Furthermore, the subsequently released anti-programmed cell death protein ligand 1 (aPDL1) blocks the corresponding immune inhibitory checkpoint molecule on tumor cells to sensitize antitumor T-cell immunity. This work thus contributes to the first proof-of-concept demonstration of a programmable super-soft DNA hydrogel system that perfectly matches the synergistic therapeutic modalities based on chemotherapeutic toxicity, in situ vaccination, and immune checkpoint blockade.

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.

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.

Cationic phosphorus dendron nanomicelles deliver microRNA mimics and microRNA inhibitors for enhanced anti-inflammatory therapy of acute lung injury.

The development of efficient nanomedicines to repress the repolarization of M1 phenotype macrophages and therefore inhibit pro-inflammatory cytokine overexpression for anti-inflammatory therapy is still a challenging task. We report here an original gene delivery nanoplatform based on pyrrolidinium-modified amphiphilic generation 1 phosphorus dendron (C12G1) nanomicelles with a rigid phosphorous dendron structure. The nanomicelles display higher gene delivery efficiency than the counterpart materials of pyrrolidinium-modified G1 phosphorus dendrimers, and meanwhile exhibit excellent cytocompatibility. The C12G1 nanomicelles can be employed to co-deliver the miRNA-146a mimic (miR-146a mimic) and miRNA-429 inhibitor (miR-429i) to inhibit the Toll-like receptor-4 signaling pathway and p38 mitogen-activated protein kinase signaling pathway, respectively, thus causing repression of M1 phenotype alveolar macrophage polarization. The developed C12G1/miR-mixture polyplexes enable efficient therapy of lipopolysaccharide-activated alveolar macrophages in vitro and an acute lung injury mouse model in vivo. The generated cationic phosphorus dendron nanomicelles may hold promising potential for anti-inflammatory gene therapy of other inflammatory diseases.

Amphiphilic phosphorous dendron micelles co-deliver microRNA inhibitor and doxorubicin for augmented triple negative breast cancer therapy.

Combined chemo/gene therapy of cancer through different action mechanisms has been emerging to enhance the therapeutic efficacy towards cancer, and still remains a challenging task due to the lack of highly effective and biocompatible nanocarriers. In this work, we report a new nanosystem based on amphiphilic phosphorus dendron (1-C12G1) micelles to co-deliver microRNA-21 inhibitor (miR-21i) and doxorubicin (DOX) for combination therapy of triple negative breast cancer. The amphiphilic phosphorus dendron bearing a long linear alkyl chain and ten protonated pyrrolidine surface groups was prepared and was demonstrated to form micelles in water solution and have a hydrodynamic size of 103.2 nm. The micelles are shown to be stable, enable encapsulation of an anticancer drug DOX with optimal loading content (80%) and encapsulation efficiency (98%), and can compress miR-21i to form polyplexes to render it with good stability against degradation. The co-delivery system of 1-C12G1@DOX/miR-21i polyplexes has a pH-dependent DOX release profile, and can be readily phagocytosed by cancer cells to inhibit them due to the different anticancer mechanisms, which was further validated after intravenous injection to treat an orthotopic triple-negative breast tumor model in vivo. With the proven biocompatibility under the studied doses, the developed amphiphilic phosphorus dendron micelles could be developed as an effective nanomedicine formulation for synergistic cancer therapy.

Phosphorous Dendron Micelles as a Nanomedicine Platform for Cooperative Tumor Chemoimmunotherapy via Synergistic Modulation of Immune Cells.

Design of effective nanomedicines to modulate multiple immune cells to overcome the immune-suppressive tumor microenvironment is desirable to improve the overall poor clinical outcomes of immunotherapy. Herein, a nanomedicine platform is reported based on chemotherapeutic drug doxorubicin (DOX)-loaded phosphorus dendron micelles (M-G1-TBPNa@DOX, TBP, tyramine bearing two dimethylphosphonate) with inherent immunomodulatory activity for synergistic tumor chemoimmunotherapy. The M-G1-TBPNa@DOX micelles with good stability and a mean particle size of 86.4 nm can deliver DOX to solid tumors to induce significant tumor cell apoptosis and immunogenic cell death (ICD). With the demonstrated intrinsic activity of M-G1-TBPNa that can promote the proliferation of natural killer (NK) cells, the ICD-resulted maturation of dendritic cells of the DOX-loaded micelles, and the combination of anti-PD-L1 antibody, the synergistic modulation of multiple immune cells through NK cell proliferation, recruitment of tumor-infiltrating NK cells and cytotoxic T cells, and decrease of regulatory T cells for effective tumor chemoimmunotherapy with strong antitumor immunity and immune memory effect for effective prevention of lung metastasis are demonstrated. The developed phosphorous dendron micelles may hold great promise to be used as an advanced nanomedicine formulation for synergistic modulation of multiple immune cells through NK cell proliferation for effective chemoimmunotherapy of different tumor types.

Redox-Responsive Dendrimer Nanogels Enable Ultrasound-Enhanced Chemoimmunotherapy of Pancreatic Cancer via Endoplasmic Reticulum Stress Amplification and Macrophage Polarization.

Developing a multifunctional nanoplatform to achieve efficient theranostics of tumors through multi-pronged strategies remains to be challenging. Here, the design of the intelligent redox-responsive generation 3 (G3) poly(amidoamine) dendrimer nanogels (NGs) loaded with gold nanoparticles (Au NPs) and chemotherapeutic drug toyocamycin (Au/Toy@G3 NGs) for ultrasound-enhanced cancer theranostics is showcased. The constructed hybrid NGs with a size of 193 nm possess good colloidal stability under physiological conditions, and can be dissociated to release Au NPs and Toy in the reductive glutathione-rich tumor microenvironment (TME). The released Toy can promote the apoptosis of cancer cells through endoplasmic reticulum stress amplification and cause immunogenic cell death to maturate dendritic cells. The loaded Au NPs can induce the conversion of tumor-associated macrophages from M2-type to antitumor M1-type to remodulate the immunosuppressive TME. Combined with antibody-mediated immune checkpoint blockade, effective chemoimmunotherapy of a pancreatic tumor mouse model can be realized, and the chemoimmunotherapy effect can be further ultrasound enhanced due to the sonoporation-improved tumor permeability of NGs. The developed Au/Toy@G3 NGs also enable Au-mediated computed tomography imaging of tumors. The constructed responsive dendrimeric NGs tackle tumors through a multi-pronged chemoimmunotherapy strategy targeting both cancer cells and immune cells, which hold a promising potential for clinical translations.