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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Modulation of Macrophages Using Nanoformulations with Curcumin to Treat Inflammatory Diseases: A Concise Review.

Curcumin (Cur), a traditional Chinese medicine extracted from natural plant rhizomes, has become a candidate drug for the treatment of diseases due to its anti-inflammatory, anticancer, antioxidant, and antibacterial activities. However, the poor water solubility and low bioavailability of Cur limit its therapeutic effects for clinical applications. A variety of nanocarriers have been successfully developed to improve the water solubility, in vivo distribution, and pharmacokinetics of Cur, as well as to enhance the ability of Cur to polarize macrophages and relieve macrophage oxidative stress or anti-apoptosis, thus accelerating the therapeutic effects of Cur on inflammatory diseases. Herein, we review the design and development of diverse Cur nanoformulations in recent years and introduce the biomedical applications and potential therapeutic mechanisms of Cur nanoformulations in common inflammatory diseases, such as arthritis, neurodegenerative diseases, respiratory diseases, and ulcerative colitis, by regulating macrophage behaviors. Finally, the perspectives of the design and preparation of future nanocarriers aimed at efficiently exerting the biological activity of Cur are briefly discussed.

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.

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.

Phosphorus dendron nanomicelles as a platform for combination anti-inflammatory and antioxidative therapy of acute lung injury.

Rationale: Development of novel nanomedicines to inhibit pro-inflammatory cytokine expression and reactive oxygen species (ROS) generation for anti-inflammatory therapy of acute lung injury (ALI) remains challenging. Here, we present a new nanomedicine platform based on tyramine-bearing two dimethylphosphonate sodium salt (TBP)-modified amphiphilic phosphorus dendron (C11G3) nanomicelles encapsulated with antioxidant drug curcumin (Cur). Methods: C11G3-TBP dendrons were synthesized via divergent synthesis and self-assembled to generate nanomicelles in a water environment to load hydrophobic drug Cur. The created C11G3-TBP@Cur nanomicelles were well characterized and systematically examined in their cytotoxicity, cellular uptake, intracellular ROS elimination, pro-inflammatory cytokine inhibition and alveolar macrophages M2 type repolarization in vitro, and evaluated to assay their anti-inflammatory and antioxidative therapy effects of ALI mice model through pro-inflammatory cytokine expression level in bronchoalveolar lavage fluid and lung tissue, histological analysis and micro-CT imaging detection of lung tissue injury in vivo. Results: The nanomicelles with rigid phosphorous dendron structure enable high-capacity and stable Cur loading. Very strikingly, the drug-free C11G3-TBP micelles exhibit excellent cytocompatibility and intrinsic anti-inflammatory activity through inhibition of nuclear transcription factor-kappa B, thus causing repolarization of alveolar macrophages from M1 type to anti-inflammatory M2 type. Taken together with the strong ROS scavenging property of the encapsulated Cur, the developed nanomicelles enable effective therapy of inflammatory alveolar macrophages in vitro and an ALI mouse model in vivo after atomization administration. Conclusion: The created phosphorus dendron nanomicelles can be developed as a general nanomedicine platform for combination anti-inflammatory and antioxidative therapy of inflammatory diseases.

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.

Fibronectin-Coated Metal-Phenolic Networks for Cooperative Tumor Chemo-/Chemodynamic/Immune Therapy via Enhanced Ferroptosis-Mediated Immunogenic Cell Death.

The development of nanomedicine formulations to overcome the disadvantages of traditional chemotherapeutic drugs and integrate cooperative theranostic modes still remains challenging. Herein, we report the facile construction of a multifunctional theranostic nanoplatform based on doxorubicin (DOX)-loaded tannic acid (TA)-iron (Fe) networks (for short, TAF) coated with fibronectin (FN) for combination tumor chemo-/chemodynamic/immune therapy under the guidance of magnetic resonance (MR) imaging. We show that the DOX-TAF@FN nanocomplexes created through in situ coordination of TA and Fe(III) and physical coating with FN have a mean particle size of 45.0 nm, are stable, and can release both DOX and Fe in a pH-dependent manner. Due to the coexistence of the TAF network and DOX, significant immunogenic cell death can be caused through enhanced ferroptosis of cancer cells via cooperative Fe-based chemodynamic therapy and DOX chemotherapy. Through further treatment with programmed cell death ligand 1 antibody for an immune checkpoint blockade, the tumor treatment efficacy and the associated immune response can be further enhanced. Meanwhile, with FN-mediated targeting, the DOX-TAF@FN platform can specifically target tumor cells with high expression of αvß3 integrin. Finally, the TAF network also enables the DOX-TAF@FN to have an r1 relaxivity of 6.1 mM-1 s-1 for T1-weighted MR imaging of tumors. The developed DOX-TAF@FN nanocomplexes may represent an updated multifunctional nanosystem with simple compositions for cooperative MR imaging-guided targeted chemo-/chemodynamic/immune therapy of tumors.

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.