Activatable Semiconducting Polymer Nanoinducers Amplify Oxidative Damage via Sono-Ferroptosis for Synergistic Therapy of Bone Metastasis.

Bone metastases are secondary malignant tumors that commonly occur after the spread of advanced cancer cells. We herein report the activatable semiconducting polymer nanoinducers (ASPNFP) that can amplify oxidative damage via sono-ferroptosis for bone metastasis treatment. ASPNFP are constructed by encapsulating plasma amine oxidase-based semiconducting polymer nanoparticles (SPNP) and Fe3O4 nanoparticles into singlet oxygen (1O2)-responsive nanocarriers. ASPNFP generate 1O2 under ultrasound (US) irradiation via a sonodynamic effect to destroy the stability of 1O2-responsive nanocarriers, allowing US-triggered releases of SPNP and Fe3O4 nanoparticles. SPNP decompose polyamines in tumor cells to produce acrolein and hydrogen peroxide (H2O2), in which H2O2 promotes Fenton reaction mediated by Fe3O4 nanoparticles for inducing enhanced ferroptosis and generation of hydroxyl radicals (•OH). The generated acrolein, 1O2, and •OH can simultaneously amplify the oxidative damage. ASPNFP thus mediate an amplified sono-ferroptosis effect to inhibit the growth of bone metastasis and restrict tumor metastasis.

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.

Dendritic Macromolecular Architectures: Dendrimer-Based Polyion Complex Micelles.

Polymeric micelles are nanoassemblies that are formed by spontaneous arrangement of amphiphilic block copolymers in aqueous solutions at critical micelle concentration (CMC). They represent an effective system for drug delivery of, for instance, poorly water-soluble anticancer drugs. Then, the development of polyion complexes (PICs) were emphasized. The morphology of these complexes depends on the topology of the polyelectrolytes used and the way they are assembled. For instance, ionic-hydrophilic block copolymers have been used for the preparation of PIC micelles. The main limitation in the use of PIC micelles is their potential instability during the self-assembly/disassembly processes, influenced by several parameters, such as polyelectrolyte concentration, deionization associated with pH, ionic strength due to salt medium effects, mixing ratio, and PIC particle cross-linking. To overcome these issues, the preparation of stable PIC micelles by increasing the rigidity of their dendritic architecture by the introduction of dendrimers and controlling their number within micelle scaffold was highlighted. In this original concise Review, we will describe the preparation, molecular characteristics, and pharmacological profile of these stable nanoassemblies.

Functional LAPONITE Nanodisks Enable Targeted Anticancer Chemotherapy in Vivo.

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

Polyethylenimine Nanogels Incorporated with Ultrasmall Iron Oxide Nanoparticles and Doxorubicin for MR Imaging-Guided Chemotherapy of Tumors.

Development of versatile nanoplatforms for cancer theranostics remains a hot topic in the area of nanomedicine. We report here a general approach to create polyethylenimine (PEI)-based hybrid nanogels (NGs) incorporated with ultrasmall iron oxide (Fe3O4) nanoparticles (NPs) and doxorubicin for T1-weighted MR imaging-guided chemotherapy of tumors. In this study, PEI NGs were first prepared using an inverse emulsion approach along with Michael addition reaction to cross-link the NGs, modified with citric acid-stabilized ultrasmall Fe3O4 NPs through 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide hydrochloride (EDC) coupling, and physically loaded with anticancer drug doxorubicin (DOX). The formed hybrid NGs possess good water dispersibility and colloidal stability, excellent DOX loading efficiency (51.4%), pH-dependent release profile of DOX with an accelerated release rate under acidic pH, and much higher r1 relaxivity (2.29 mM-1 s-1) than free ultrasmall Fe3O4 NPs (1.15 mM-1 s-1). In addition, in contrast to the drug-free NGs that possess good cytocompatibility, the DOX-loaded hybrid NGs display appreciable therapeutic activity and can be taken up by cancer cells in vitro. With these properties, the developed hybrid NGs enabled effective inhibition of tumor growth under the guidance of T1-weighted MR imaging. The developed hybrid NGs may be applied as a versatile nanoplatform for MR imaging-guided chemotherapy of tumors.

Doxorubicin Encapsulated in TPGS-Modified 2D-Nanodisks Overcomes Multidrug Resistance.

Multidrug resistance (MDR) is regarded as a main obstacle for effective chemotherapy, and P-glycoprotein (P-gp)-mediated drug efflux has been demonstrated to be the key factor responsible for MDR. In this study, a novel pH-responsive hybrid drug delivery system was developed by conjugating d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a kind of P-gp inhibitor, on the surface of laponite nanodisks to overcome MDR. The prepared LM-TPGS display excellent colloidal stability, a high encapsulation efficiency of doxorubicin (DOX), and a pH-responsive drug release profile. In vitro experiments verified that LM-TPGS/DOX could exhibit significantly enhanced therapeutic efficacy in treating DOX-resistant breast cancer cells (MCF-7/ADR) through inhibiting the activity of P-gp-mediated drug efflux and effectively accumulating DOX within cancer cells. In vivo results revealed that LM-TPGS/DOX outstandingly suppressed MCF-7/ADR tumors with low side effects. Therefore, the high drug payload, enhanced inhibition efficacy to drug-resistant cells, and low side effects make the LM-TPGS/DOX a promising nanoplatform to reverse MDR for effective chemotherapy.

Bivalent Peptide- and Chelator-Containing Bioconjugates as Toolbox Components for Personalized Nanomedicine.

While personalized therapy bears an enormous potential in cancer therapy, the development of flexible, tailorable delivery systems remains challenging. Here, we present a "tool-kit" of various avidin-based bioconjugates (BCs) for the preparation of personalized delivery systems. Corresponding BCs were synthesized using the self-assembly of avidin with various biotinylated ligands, such as one cationic glycodendrimer for dendriplex adsorption and two functional ligands for imaging (glycodendrimers with DOTA or NOTA units) or targeting (biotinylated PEG decorated with ligands). Substituting antibodies for targeting small molecules were coupled to biotin-PEG compounds for addressing the folate receptor (FR), epidermal growth factor receptor (EGFR), and prostate-specific membrane antigen (PSMA). After successful characterization and proof of good storage and redispersion properties of BCs, cytotoxicity assays and first in vivo imaging studies with 99mTc-complexing bioconjugates provide evidence that these BCs and their avidin analogues can be used as tool-kit components in theranostic systems for personalized medicine.

Dendrimer-Enabled Therapeutic Antisense Delivery Systems as Innovation in Medicine.

Antisense oligonucleotide (AON)-based therapies concern the treatment for genetic disorders or infections such as a range of neurodegenerative and neuromuscular diseases and have shown benefits in animal models and patients. Nevertheless, successes in the clinic are still strongly limited by unfavorable biodistribution and poor cellular uptake of AONs. Dendrimer macromolecules are synthetically accessible and consist of a core with repeated iterations (named branches) surrounding this core, and on the periphery functional groups which can be modified for ligand attachment. The generations of these branched nanoparticles are based on the number of branches emanating from the core with layered architectures. Dendrimers show promise in several biomedical applications based on their tunable surface modifications allowing the adjustment of their in vivo behavior related to biocompatibility and pharmacokinetic parameters. Dendrimers can be used as nanocarriers of various types of drugs including AONs or nanodrugs. As nanocarriers, polycationic dendrimers can complex multiple negatively charged DNA oligonucleotides on their surface and form stable complexes to promote internalization into the cells based on a good cell membrane affinity. These nanocarriers complexing antisense oligonucleotides must be stable enough to reach the cellular target, but with adequate in vivo global clearance, and have good pharmacokinetic (PK) and pharmacodynamic (PD) profiles. This Review was designed to analyze the development of AONs carried by polycationic and polyanionic (few example) dendrimers. This Review strongly supports the idea that dendrimers, with adequate modulation of their terminal groups, could be used to carry AONs in cells.

99mTc-Labeled Polyethylenimine-Entrapped Gold Nanoparticles with pH-Responsive Charge Conversion Property for Enhanced Dual Mode SPECT/CT Imaging of Cancer Cells.

Development of tumor dual mode contrast agents is still a great challenge due to the relative low accumulation at tumor site, which result in the poor imaging efficiency. In this study, we constructed functional technetium-99m (99mTc) labeled polyethylenimine (PEI)-entrapped gold nanoparticles (Au PENs) with pH-responsive charge conversion property for enhanced single photon emission computed tomography (SPECT)/computed tomography (CT) dual mode imaging of cancer cells. PEI with amine functional groups (PEI.NH2) was successively modified with monomethyl ether and carboxyl functionalized polyethylene glycol (mPEG-COOH), maleimide and succinimidyl valerate functionalized PEG (MAL-PEG-SVA), diethylenetriaminepentaacetic dianhydride (DTPA), and fluorescein isothiocyanate (FI), and used to entrapped gold nanoparticles inside, followed by conjugation with the alkoxyphenyl acylsulfonamide (APAS) through the PEG maleimide, acetylation of the PEI leftover surface amines and 99mTc labeling. The created nanosystem with the mean Au core diameter of 3.3 nm and with a narrow size distribution displays an excellent colloidal stability and desired cytocompatibility in the investigated Au concentration range. Due to the fact that the attached APAS moieties are responsive to pH, the functionalized Au PENs with a neutral surface charge can switch to be positively charged under slightly acidic pH condition, which could improve the cellular uptake by cancer cells. With these properties, the developed functionalized Au PENs could achieve enhanced dual mode SPECT/CT imaging of cancer cells in vitro. The constructed PEI-based nanodevices may be adopted as an excellent dual mode contrast agent for SPECT/CT imaging of cancer cells of different types.

Zwitterionic Polydopamine-Coated Manganese Oxide Nanoparticles with Ultrahigh Longitudinal Relaxivity for Tumor-Targeted MR Imaging.

We present the design of antifouling zwitterion-functionalized manganese oxide (Mn3O4) nanoparticles (NPs) modified with folic acid (FA) for targeted tumor magnetic resonance (MR) imaging. In the current work, diethylene glycol-stabilized Mn3O4 NPs were initially prepared via a solvothermal approach, coated with polydopamine (PDA), fluorescently labeled with rhodamine B, conjugated with FA via amide bond formation, and finally covered with zwitterions of l-lysine (Lys). The thus-generated multifunctional Mn3O4 NPs display excellent water dispersibility and colloidal stability, good protein resistance ability, and desirable cytocompatibility. With the PDA and Lys modifications, the multifunctional Mn3O4 NPs own an ultrahigh r1 relaxivity (89.30 mM-1 s-1) and enable targeted tumor MR imaging, owing to the linked FA ligands. The designed antifouling zwitterion-functionalized Mn3O4 NPs may be employed as an excellent MR contrast agent for targeted MR imaging of other biological systems.

Acetylated Polyethylenimine-Entrapped Gold Nanoparticles Enable Negative Computed Tomography Imaging of Orthotopic Hepatic Carcinoma.

Developing an effective computed tomography (CT) contrast agent is still a challenging task for precise diagnosis of hepatic carcinoma (HCC). Here, we present the use of acetylated polyethylenimine (PEI)-entrapped gold nanoparticles (Ac-PE-AuNPs) without antifouling modification for negative CT imaging of HCC. PEI was first linked to fluorescein isothiocyanate (FI) and then utilized as a vehicle for the entrapment of AuNPs. The particles were then acetylated to reduce its positive surface potential. The designed Ac-PE-AuNPs were characterized by various techniques. We find that the Ac-PE-AuNPs with a uniform size distribution (mean diameter = 2.3 nm) are colloidally stable and possess low toxicity in the studied range of concentration. Owing to the fact that the particles without additional antifouling modification were mainly gathered in liver, the Ac-PE-AuNPs could greatly improve the CT contrast enhancement of normal liver, whereas poor CT contrast enhancement appeared in liver necrosis region caused by HCC. As a result, HCC could be easily and precisely diagnosed. The designed Ac-PE-AuNPs were demonstrated to have biocompatibility through in vivo biodistribution and histological studies, hence holding an enormous potential to be adopted as an effective negative CT contrast agent for diagnosis of hepatoma carcinoma.

Radiotherapy-Sensitized Tumor Photothermal Ablation Using γ-Polyglutamic Acid Nanogels Loaded with Polypyrrole.

Development of versatile nanoscale platforms for cancer diagnosis and therapy is of great importance for applications in translational medicine. In this work, we present the use of γ-polyglutamic acid (γ-PGA) nanogels (NGs) to load polypyrrole (PPy) for thermal/photoacoustic (PA) imaging and radiotherapy (RT)-sensitized tumor photothermal therapy (PTT). First, a double emulsion approach was used to prepare the cystamine dihydrochloride (Cys)-cross-linked γ-PGA NGs. Next, the cross-linked NGs served as a reactor to be filled with pyrrole monomers that were subjected to in situ oxidation polymerization in the existence of Fe(III) ions. The formed uniform PPy-loaded NGs having an average diameter of 38.9 ± 8.6 nm exhibited good water-dispersibility and colloid stability. The prominent near-infrared (NIR) absorbance feature due to the loaded PPy endowed the NGs with contrast enhancement in PA imaging. The hybrid NGs possessed excellent photothermal conversion efficiency (64.7%) and stability against laser irradiation, and could be adopted for PA imaging and PTT of cancerous cells and tumor xenografts. Importantly, we also explored the cooperative PTT and X-ray radiation-mediated RT for enhanced tumor therapy. We show that PTT of tumors can be more significantly sensitized by RT using the sequence of laser irradiation followed by X-ray radiation as compared to using the reverse sequence. Our study suggests a promising theranostic platform of hybrid NGs that may be potentially utilized for PA imaging and combination therapy of different types of tumors.

Facile Formation of Gold-Nanoparticle-Loaded γ-Polyglutamic Acid Nanogels for Tumor Computed Tomography Imaging.

The formation of gold nanoparticle (Au NP)-loaded γ-polyglutamic acid (γ-PGA) nanogels (NGs) for computed tomography (CT) imaging of tumors is reported. γ-PGA with carboxyl groups activated by 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide hydrochloride is first emulsified to form NGs and then in situ chemically cross-linked with polyethylenimine (PEI)-entrapped Au NPs with partial polyethylene glycol (PEG) modification ([(Au0)200-PEI·NH2-mPEG]). The formed γ-PGA-[(Au0)200-PEI·NH2-mPEG] NGs with a size of 108.6 ± 19.1 nm display an X-ray attenuation property better than commercial iodinated small-molecular-contrast agents and can be uptaken by cancer cells more significantly than γ-PGA-stabilized single Au NPs at the same Au concentrations. These properties render the formed NGs with an ability to be used as an effective contrast agent for the CT imaging of cancer cells in vitro and a tumor model in vivo. The developed hybrid NGs may be promising for the CT imaging or theranostics of different biosystems.

Short-Term Dynamic Observation of the Color Change and Enhancement Effect of Polyethylenimine-Entrapped Gold Nanoparticles Used for Indirect Lymphography.

AIMS: To dynamically observe the color change and enhancement effect of gadolinium-loaded polyethylenimine-entrapped gold nanoparticles (Gd-Au PENPs) as a dual-mode CT/MRI contrast agent for sentinel lymph node (SLN) identification. METHODS: In 6 rabbits, Gd-Au PENPs were injected into the right side tongue submucosa, after which the color change of cervical draining lymph nodes was observed. Then the draining lymph nodes were examined by CT/MRI scan. Another 6 rabbits were randomly divided into a CT lymphography (CT-LG) and a MRI lymphography (MRI-LG) group and examined by CT/MRI scan 1 and 30 min after injection. Then SLNs were identified under the guidance of CT/MRI-LG. RESULTS: The ipsilateral afferent lymphatic vessels, cervical draining lymph nodes and efferent lymphatic vessels were stained black orderly and constantly after Gd-Au PENPs injection. Thirty minutes after injection, all cervical lymph nodes were excised to be examined by CT/MRI scan, and only the black-stained draining lymph nodes were enhanced. The 6 rabbits with CT/MRI-LG showed clear enhancement of SLNs. With indirect lymphography, the black-stained SLNs were easily visualized at autopsy. In all rabbits, the identification rate of lingual SLNs was 100%. CONCLUSIONS: Rabbit lingual SLNs could be identified with indirect lymphography using Gd-Au PENPs as a dual-mode contrast agent.

Dendrimer-assisted formation of fluorescent nanogels for drug delivery and intracellular imaging.

Although, in general, nanogels present a good biocompatibility and are able to mimic biological tissues, their unstability and uncontrollable release properties still limit their biomedical applications. In this study, a simple approach was used to develop dual-cross-linked dendrimer/alginate nanogels (AG/G5), using CaCl2 as cross-linker and amine-terminated generation 5 dendrimer (G5) as a cocrosslinker, through an emulsion method. Via their strong electrostatic interactions with anionic AG, together with cross-linker Ca(2+), G5 dendrimers can be used to mediate the formation of more compact structural nanogels with smaller size (433 ± 17 nm) than that (873 ± 116 nm) of the Ca(2+)-cross-linked AG nanogels in the absence of G5. Under physiological (pH 7.4) and acidic (pH 5.5) conditions, the sizes of Ca(2+)-cross-linked AG nanogels gradually decrease probably because of their degradation, while dual-cross-linked AG/G5 nanogels maintain a relatively more stable structure. Furthermore, the AG/G5 nanogels effectively encapsulate the anticancer drug doxorubicin (Dox) with a loading capacity 3 times higher than that of AG nanogels. The AG/G5 nanogels were able to release Dox in a sustained way, avoiding the burst release observed for AG nanogels. In vitro studies show that the AG/G5-Dox NGs were effectively taken up by CAL-72 cells (a human osteosarcoma cell line) and maintain the anticancer cytotoxicity levels of free Dox. Interestingly, G5 labeled with a fluorescent marker can be integrated into the nanogels and be used to track the nanogels inside cells by fluorescence microscopy. These findings demonstrate that AG/G5 nanogels may serve as a general platform for therapeutic delivery and/or cell imaging.

Biomimetic Dual-Target Theranostic Nanovaccine Enables Magnetic Resonance Imaging and Chemo/Chemodynamic/Immune Therapy of Glioma.

Development of theranostic nanomedicines to tackle glioma remains to be challenging. Here, we present an advanced blood-brain barrier (BBB)-crossing nanovaccine based on cancer cell membrane-camouflaged poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) incorporated with MnO2 and doxorubicin (DOX). We show that the disulfide bond-cross-linked redox-responsive PVCL NGs can be functionalized with dermorphin and imiquimod R837 through cell membrane functionalization. The formed functionalized PVCL NGs having a size of 220 nm are stable, can deplete glutathione, and responsively release both Mn2+ and DOX under the simulated tumor microenvironment to exert the chemo/chemodynamic therapy mediated by DOX and Mn2+, respectively. The combined therapy induces tumor immunogenic cell death to maturate dendritic cells (DCs) and activate tumor-killing T cells. Further, the nanovaccine composed of cancer cell membranes as tumor antigens, R837 as an adjuvant with abilities of DC maturation and macrophages M1 repolarization, and MnO2 with Mn2+-mediated stimulator of interferon gene activation of tumor cells can effectively act on both targets of tumor cells and immune cells. With the dermorphin-mediated BBB crossing, cell membrane-mediated homologous tumor targeting, and Mn2+-facilitated magnetic resonance (MR) imaging property, the designed NG-based theranostic nanovaccine enables MR imaging and combination chemo-, chemodynamic-, and imnune therapy of orthotopic glioma with a significantly decreased recurrence rate.

Nanogel-based nitric oxide-driven nanomotor for deep tissue penetration and enhanced tumor therapy.

Antitumor agents often lack effective penetration and accumulation to achieve high therapeutic efficacy in treating solid tumors. Nanomotor-based nanomaterials offer a potential solution to address this obstacle. Among them, nitric oxide (NO) based nanomotors have garnered attention for their potential applications in nanomedicine. However, there widespread clinical adoption has been hindered by their complex preparation processes. To address this limitation, we have developed a NO-driven nanomotor utilizing a convenient and scalable nanogel preparation procedure. These nanomotors, loaded with the fluorescent probe / sonosensitizer chlorin e6 (Ce6), were specifically engineered for sonodynamic therapy. Through comprehensive in vitro investigations using both 2D and 3D cell models, as well as in vivo analysis of Ce6 fluorescent signal distribution in solid tumor models, we observed that the self-propulsion of these nanomotors significantly enhances cellular uptake and tumor penetration, particularly in solid tumors. This phenomenon enables efficient access to challenging tumor regions and, in some cases, results in complete tumor coverage. Notably, our nanomotors have demonstrated long-term in vivo biosafety. This study presents an effective approach to enhancing drug penetration and improving therapeutic efficacy in tumor treatment, with potential clinical relevance for future applications.

Facile formation of folic acid-modified dendrimer-stabilized gold-silver alloy nanoparticles for potential cellular computed tomography imaging applications.

We report a facile approach to fabricating dendrimer-stabilized gold-silver alloy nanoparticles (Au-Ag alloy DSNPs) for targeted in vitro computed tomography (CT) imaging of cancer cells. In this study, folic acid (FA)-modified amine-terminated generation 5 poly(amidoamine) dendrimers (G5·NH2-FA) were used as stabilizers to prepare Au-Ag alloy DSNPs by simultaneously reducing both gold and silver salts, followed by acetylation of the dendrimer terminal amines. The formed Au-Ag alloy DSNPs were characterized via different techniques. We show that the formed Au-Ag alloy DSNPs are spherical in shape with a relatively narrow size distribution, have good water solubility and colloidal stability, and display higher X-ray attenuation intensity than the iodine-based contrast agent of Omnipaque at the same molar concentration of the active element (i.e., Au plus Ag, or iodine). Cytotoxicity assay results show that the Au-Ag alloy DSNPs are cytocompatible in a given concentration range. Importantly, the formed Au-Ag alloy DSNPs are able to be specifically taken up by cancer cells overexpressing FA receptors and enable targeted CT imaging of the cancer cells. Given the unique structural characteristics of dendrimers and the facile synthesis of DSNPs, the developed Au-Ag alloy DSNPs may be used for various biomedical applications in sensing, diagnosis, and therapeutics.

Charge-reversible and biodegradable chitosan-based microgels for lysozyme-triggered release of vancomycin.

INTRODUCTION: High-dose drug administration for the conventional treatment of inflammatory bowel disease induces cumulative toxicity and serious side effects. Currently, few reports have introduced smart carriers for intestinal inflammation targeting toward the treatment of inflammatory bowel disease. OBJECTIVES: For the unique lysozyme secretory microenvironment of the inflamed intestine, vancomycin-loaded chitosan-polyaniline microgels (CH-PANI MGs) were constructed for lysozyme-triggered VM release. METHODS: Aniline was first grafted to chitosan to form polymers that were crosslinked by glutaraldehyde to achieve CH-PANI MGs using the inverse (water-in-oil) miniemulsion method. Interestingly, CH-PANI MGs exhibit polyampholyte behaviour and display charge-reversible behaviour (positive to negative charges) after treatment with a NaCl solution. RESULTS: The formed negatively charged N-CH-PANI MG aqueous solution is employed to load cationic vancomycin with a satisfactory loading efficiency of 91.3%, which is significantly higher than that of chitosan-based MGs. Moreover, N-CH-PANI MGs present lysozyme-triggered biodegradation and controllable vancomycin release upon the cleavage of glycosidic linkages of chitosan. In the simulated inflammatory intestinal microenvironment, vancomycin is rapidly released, and the cumulative release reaches approximately 76.9%. Remarkably, N-CH-PANI@VM MGs not only exhibit high resistance to harsh gastric acidity but also prevent the premature leakage of vancomycin in the healthy gastrointestinal tract. Encouragingly, the N-CH-PANI@VM MGs show obvious antibacterial activity against Staphylococcus aureus at a relatively low concentration of 20 µg/mL. CONCLUSION: Compared to other pH-responsive carriers used to treat inflammatory bowel disease, the key advantage of lysozyme-responsive MGs is that they further specifically identify healthy and inflammatory intestines, achieving efficient inflammatory bowel disease treatment with few side effects. With this excellent performance, the developed smart MGs might be employed as a potential oral delivery system for inflammatory bowel disease treatment.

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.