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Development of innovative nanomedicine formulations to traverse the blood-brain barrier (BBB) for effective theranostics of glioma remains a great challenge. Herein, we report the creation of macrophage membrane-camouflaged multifunctional polymer nanogels coloaded with manganese dioxide (MnO2) and cisplatin for magnetic resonance (MR) imaging-guided chemotherapy/chemodynamic therapy (CDT) of orthotopic glioma. Redox-responsive poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) formed via precipitation polymerization were in situ loaded with MnO2 and physically encapsulated with cisplatin to have a mean size of 106.3 nm and coated with macrophage membranes to have a good colloidal stability. The generated hybrid NGs display dual pH- and redox-responsive cisplatin and Mn(II) release profiles and can deplete glutathione (GSH) rich in tumor microenvironment through reaction with disulfide-containing cross-linkers within the NGs and MnO2. The thus created Mn(II) enables enhanced CDT through a Fenton-like reaction and T1-weighted MR imaging, while the loaded cisplatin not only exerts its chemotherapy effect but also promotes the reactive oxygen species generation to enhance the CDT efficacy. Importantly, the macrophage membrane coating rendered the hybrid NGs with prolonged blood circulation time and ability to traverse BBB for specific targeted chemotherapy/CDT of orthotopic glioma. Our study demonstrates a promising self-adaptive and cooperative NG-based nanomedicine platform for highly efficient theranostics of glioma, which may be extended to tackle other difficult cancer types.

Rapid advances in nanotechnology have opened up innovative trails to break through the current limitation in clinical treatments of cancer and other critical diseases that plague human beings. Ultrasmall iron oxide nanoparticles (USIO NPs) with sizes smaller than 5 nm have been emerging as a novel category of nanomaterials with increasing interest in the biomedical domains. To overcome their intrinsic shortcomings, naked USIO NPs can be functionalized, clustered, assembled, or incorporated with other nanomaterials to generate various kinds of intelligent nanoplatforms for single-mode or dynamic magnetic resonance (MR) imaging, multimode imaging, as well as imaging-guided precision therapy. In this spotlight on applications, first, we propose the principal aspects in the design and application of USIO NPs for biomedical uses. Second, we cover the recent design strategies of USIO NP-based nanoplatforms mainly developed by our group, describe the rationale on the combination of other functional materials with USIO NPs, and review their resultant applications in theranostics. In addition, we provide herein a perspective on the possible future directions toward USIO NP-based nanoplatforms as smart nanomedicines.

Rationale: Development of nanosystems that can be integrated with macrophages (MAs), an emerging carrier system, for effective tumor therapy remains to be challenging. We report here the development of MAs specifically loaded with hyaluronic acid (HA) nanogels (NGs) encapsulated with a photothermal agent of polypyrrole (PPy) and anticancer drug doxorubicin (DOX) (HA/DOX@PPy NGs) for tumor homing and combination photothermo-chemotherapy. Methods: Cystamine dihydrochloride-crosslinked HA NGs were first prepared through a double emulsification method, then loaded with PPy via an in-situ oxidization polymerization and physically encapsulated with DOX. The created HA/DOX@PPy NGs were well characterized and subjected to be endocytosed by MAs (MAs-NGs). The MAs-mediated tumor-homing property, phenotype changes and photothermal performance of MAs-NGs were investigated in vitro, and a subcutaneous tumor model was also established to confirm their targeting capability and enhanced antitumor therapy effect in vivo. Results: The generated hybrid NGs possess a size around 77 nm and good colloidal stability, and can be specifically endocytosed by MAs without appreciably affecting their normal biofunctionalities. In particular, NG-loaded MAs display excellent in-vitro cancer cell and in-vivo tumor homing property. Systemic administration of the MAs-NGs leads to the significant inhibition of a subcutaneous tumor model through combination photothermo-chemotherapy under laser irradiation. Conclusions: The developed hybrid HA-based NG nanosystem incorporated with PPy and DOX fully integrates the coordination and heating property of PPy to regulate the optimized DOX release in the tumor region with the assistance of MA-mediated tumor homing, providing a promising cell therapy strategy for enhanced antitumor therapy.

Development of nanoplatforms that can amplify the passive tumor targeting effect based on enhanced permeability and retention (EPR) effect is crucial for precision cancer nanomedicine applications. Herein, we present the development of core-shell tecto dendrimers (CSTDs) as a platform for enhanced tumor magnetic resonance (MR) imaging through an amplified EPR effect. In this work, poly(amidoamine) (PAMAM) dendrimers of generation 5 (G5) were decorated with β-cyclodextrin (CD) and then assembled with G3 PAMAM dendrimers premodified with adamantane (Ad) via supramolecular recognition of CD and Ad. The formed G5-CD/Ad-G3 CSTDs were conjugated with tetraazacyclododecane tetraacetic acid (DOTA)-Gd(III) chelators and further acetylated to neutralize the remaining CSTD periphery amines. We reveal that the formed CSTD.NHAc-DOTA(Gd) (CSTD-D-Gd) complexes have a narrow size distribution and satisfactory colloidal stability, and are cytocompatible within the concentration range studied. Compared to the single dendrimer counterpart of G5.NHAc-DOTA(Gd) (G5-D-Gd) complexes, the CSTD-D-Gd complexes with a higher molecular weight and volume possess a longer rotation correlation time, hence having a longitudinal relaxivity (

The condensed tumor extracellular matrix (ECM) consisting of cross-linked hyaluronic acid (HA) is one of the key factors that result in the aberrant tumor microenvironment and severely impair drug delivery and tumor penetration. Herein, we report a simple design of a hyaluronidase (HAase)-modified layered double hydroxide (LDH) nanoplatform loaded with anticancer drug doxorubicin (DOX) for enhanced tumor penetration and augmented chemotherapy. In our approach, LDH nanodisks were synthesized via a co-precipitation method, modified with HAase by electrostatic attraction, and finally physically loaded with DOX. The formulated DOX/LDH-HAase complexes show a high DOX loading percentage of 34.2% with good colloidal stability, retain 86.1% of the enzyme activity, and release DOX in a pH-responsive manner having a faster release rate under slightly acidic tumor microenvironment than that under a physiological condition. With the catalytic activity of HAase to digest the HA nearby the cancer cells, the developed DOX/LDH-HAase complexes enable more significant uptake by cancer cells and penetration in 3-dimensional tumor spheroids than enzyme-free DOX/LDH complexes, thus displaying much better antitumor efficacy in vitro than the latter. The more significant tumor penetration and inhibition of the DOX/LDH-HAase complexes than that of the DOX/LDH complexes was further demonstrated by in vivo tumor imaging and therapeutic activity assessments. Our study suggests a unique nanomedicine platform combined with both anticancer drug and enzyme for improved tumor penetration and chemotherapy, which is promising for effective chemotherapy of different types of stroma-rich tumors.

Development of innovative nanomedicine enabling enhanced theranostics of multidrug-resistant (MDR) tumors remains to be challenging. Herein, we report the development of a newly designed multifunctional yellow-fluorescent carbon dot (y-CD)/dendrimer nanohybrids as a platform for ultrasound (US)-enhanced fluorescence imaging and chemotherapy of MDR tumors. Generation 5 (G5) poly(amidoamine) dendrimers covalently modified with efflux inhibitor of d-α-tocopheryl polyethylene glycol 1000 succinate (G5-TPGS) were complexed with one-step hydrothermally synthesized y-CDs via electrostatic interaction. The formed G5-TPGS@y-CDs complexes were then physically loaded with anticancer drug doxorubicin (DOX) to generate (G5-TPGS@y-CDs)-DOX complexes. The developed nanohybrids display a high drug loading efficiency (40.7%), strong y-CD-induced fluorescence emission, and tumor microenvironment pH-preferred DOX release profile. Attributing to the DOX/TPGS dual drug design, the (G5-TPGS@y-CDs)-DOX complexes can overcome the multidrug resistance (MDR) of cancer cells and effectively inhibit the growth of cancer cells and tumors. Furthermore, the introduction of US-targeted microbubble destruction technology was proven to render the complexes with enhanced intracellular uptake and anticancer efficacy in vitro and improved chemotherapeutic efficacy and fluorescence imaging of tumors in vivo due to the produced sonoporation effect. The developed multifunctional dendrimer/CD nanohybrids may represent an advanced design of nanomedicine for US-enhanced theranostics of different types of MDR tumors., Graphical abstract Image 1, Highlights • Dendrimer and y-CDs can form nanohybrids via electrostatic interaction. • The nanohybrids loaded with two drugs display strong y-CD-induced fluorescence emission. • DOX-loaded nanohybrids have acidic pH-triggered fast release profile. • The dual-drug design can make the nanohybrids overcome the MDR of tumors. • The nanohybrids enables ultrasound-enhanced fluorescence imaging and chemotherapy of MDR tumors.

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

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.

Detection of analytes in biological systems is pivotal to explore their physiological roles and provide diagnostic and treatment options for related diseases, which however remains a great challenge. Optical nanoprobes that exhibit absorption or fluorescence signal changes in response to the targets of interest have emerged as a versatile class of biosensors in the field. Polyethylenimine (PEI) with abundant amine groups plays indispensable roles in the construction of optical nanoprobes and mediating the sensing processes. After interaction with analytes, PEI-based optical nanoprobes can be induced to form aggregates, be disassembled or separated into individual units, or undergo structure/component alterations. As such, the optical properties of these nanoprobes have corresponding changes, allowing for sensitive and selective detection of a wide variety of analytes in biological environment. Up to now, detections of reactive oxygen species, pH, metal ions, biothiols, neurotransmitters, therapeutic agents, oxygen levels, enzyme activities, and virus/bacteria have been successfully demonstrated using PEI-based optical nanoprobes. Herein, we summarize the recent developments of PEI-based optical nanoprobes for biosensing applications and highlight the probe designs and sensing mechanisms. The existing challenges and prospects regarding biosensing applications of PEI-based optical nanoprobes are also briefly discussed.

Nanosystems for monitoring and tracking T cells provide an important basis for evaluating the functionality and efficacy of T cell-based immunotherapy. To this end, we designed herein an efficient nanoprobe for T cell monitoring and tracking using poly(amidoamine) (PAMAM) dendrimer-entrapped gold nanoparticles (Au DENPs) conjugated with Fluo-4 for dual-mode computed tomography (CT) and fluorescence imaging. In this study, PAMAM dendrimers of generation 5 (G5) were modified with hydroxyl-terminated polyethylene glycol (PEG) and then used to entrap 2.0 nm Au NPs followed by acetylation of the excess amine groups on the dendrimer surface. Subsequently, the calcium ion probe was covalently attached to the dendrimer nanohybrids through the PEG hydroxyl end groups to gain the functional {(Au0)25-G5.NHAc-(PEG)14-(Fluo-4)2} nanoprobe. This nanoprobe had excellent water solubility, high X-ray attenuation coefficient, and good cytocompatibility in the given concentration range, as well as a high T cell labeling efficiency. Confocal microscopy and flow cytometry results demonstrated that the nanoprobe was able to fluorescently sense activated T cells. Moreover, the nanoprobe was able to realize both CT and fluorescence imaging of subcutaneously injected T cells in vivo. Thus, the developed novel dendrimer-based nanosystem may hold great promise for advancing and improving the clinical application of T cell-based immunotherapy.

The second near-infrared (NIR-II, 1000-1700 nm) light-based diagnosis and therapy have received extensive attention for neoplastic disease treatments because of the fact that light in the NIR-II window possesses less photon scattering along with deeper tissue penetration than that in the NIR-I (700-950 nm) window. Herein, we present a Gd- and copper sulfide (CuS)-integrated nanogel (NG) platform for magnetic resonance (MR)/photoacoustic (PA) imaging-guided tumor-targeted photothermal therapy (PTT). In our approach, we prepared cross-linked polyethylenimine (PEI) NGs via an inverse emulsion method, modified the PEI NGs with Gd chelates, targeting ligand folic acid (FA) through a polyethylene glycol (PEG) spacer and 1,3-propanesultone, and finally loaded CuS nanoparticles (NPs) within the functional NGs. The as-synthesized Gd/CuS@PEI-FA-PS NGs with a mean size of 85 nm exhibit a good water dispersibility and protein resistance property, admirable r1 relaxivity (11.66 mM-1 s-1), excellent NIR-II absorption feature, high photothermal conversion efficiency (26.7%), and FA-mediated targeting specificity to cancer cells overexpressing FA receptor (FAR). With these properties along with the good cytocompatibility, the developed Gd/CuS@PEI-FA-PS NGs enable MR/PA dual-mode imaging-guided targeted PTT of FAR-overexpressing tumors under the irradiation of an NIR-II (1064 nm) laser. The designed Gd/CuS@PEI-FA-PS NGs may be used as a promising theranostic agent for MR/PA dual-mode imaging-guided PTT of other FAR-expressing tumors.

Detection of heavy metal ions in water is of paramount significance for environmental pollution control. Here, we report the use of γ-polyglutamic acid (γ-PGA)-stabilized gold nanoparticles (γ-PGA-Au NPs) as a probe to sense trivalent chromium (Cr3+) in aqueous solution. In our study, γ-PGA-Au NPs were first formed through one-step sodium borohydride reduction of Au salt in the presence of γ-PGA. The formed γ-PGA-Au NPs with a mean particle size of 4.6 nm show desirable colloidal stability and a significant color change from wine red to gray after exposure to Cr3+ ions, which is visible to the naked eye and easily detected by colorimetric assay using UV-vis spectrometry. The limit of detection of Cr3+ ions is 100 ppb by the naked eye and 0.2 ppb by UV-vis spectroscopy, respectively. We further show that the detection of Cr3+ using γ-PGA-Au NPs has excellent selectivity, and the recovery percentage is higher than 82% for different water samples such as lake water, river water, tap water or mineral water. Our study demonstrates that γ-PGA-Au NPs can be utilized as an efficient probe for colorimetric sensing of Cr3+ ions in a water environment.

Preparation of versatile and safe nanovectors for efficient cancer gene therapy remains to be challenging in the current nanomedicine. Herein, we report the formation of dendrimer nanoclusters for enhanced gene delivery toward gene therapy of cancer. Here, poly(amidoamine) (PAMAM) dendrimers of generation 3 (G3) were cross-linked with 4,4'-dithiodibutryic acid (DA) to form nanoclusters (NCs) through 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-induced covalent bonding. The synthesized G3-DA NCs having a hydrodynamic size of 219.3 nm possess good colloidal stability and can condense pDNA, encoding both enhanced green fluorescent protein and tumor suppressor p53 gene to form polyplexes with good cytocompatibility. Strikingly, the created NCs/pDNA polyplexes enable 2.3 and 2.1 times higher gene transfection to cancer cells than the counterpart materials of single G3 and G5 PAMAM dendrimers, respectively, under the same conditions. Furthermore, polyplex-treated cancer cells have upregulated p53 and p21 protein and mRNA expression levels and downregulated Cyclin-D1 and CDK-4 protein and mRNA expressions, thus arresting the cell cycle to the G1 phase

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-1β, 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.

Design of new nanoplatforms that integrates multiple imaging and therapeutic components for precision cancer nanomedicine remains to be challenging. Here, a facile strategy is reported to prepare polydopamine (PDA)‐coated molybdenum disulfide (MoS2) nanoflakes as a nanocarrier to load dual drug cisplatin (Pt) and 1‐methyl‐tryptophan (1‐MT) for precision tumor theranostics. Preformed MoS2 nanoflakes are coated with PDA, modified with methoxy‐polyethylene glycol (PEG)‐amine, and loaded with 1‐MT and Pt. The formed functional 1‐MT‐Pt‐PPDA@MoS2 (the second P stands for PEG) complexes exhibit good colloidal stability and photothermal conversion efficiency (47.9%), dual pH‐, and photothermal‐sensitive drug release profile, and multimodal thermal, computed tomography and photoacoustic imaging capability. Due to the respective components of Pt, MoS2, and 1‐MT that can block the immune checkpoint associated to tumoral indoleamine 2,3‐dioxygenase‐induced tryptophan metabolism, tri‐mode chemo‐photothermo‐immunotherapy of tumors can be realized. In particular, under the near infrared laser irradiation, fast release of both drugs can be facilitated to achieve cooperative tumor therapy effect, and the combined immunogenic cell death induced by the dual‐mode chemo‐photothermo treatment and the 1‐MT‐induced immune checkpoint blockade can boost enhanced antitumor immune response to generate significant cytotoxic T cells for tumor killing. The developed 1‐MT‐Pt‐PPDA@MoS2 complexes may be used as an intelligent nanoplatform for cooperative precision imaging‐guided combinational tumor therapy., A multifunctional polydopamine‐coated molybdenum disulfide nanoplatform is developed to integrate a chemotherapy drug cisplatin and an immune checkpoint blocker 1‐methyl‐tryptophan (1‐MT). The designed functional complexes exhibit pH‐ and photothermal‐sensitive drug release profile and achieve cooperative multimode imaging‐guided tri‐mode chemo‐photothermo‐immunotherapy of tumors, where the immunotherapy is boosted by immune cell death/dendritic cell maturation‐induced cytotoxic T cells and the 1‐MT‐disrupted tryptophan metabolism.

It is highly desirable to develop a new hybrid nanoplatform that integrates diagnosis and treatment elements for effective theranostics of tumors. Herein, we have skillfully designed a nanoplatform of polydopamine (PDA)-coated and perfluorohexane (PFH)-filled gold core/hollow mesoporous silica shell (Au@mSiO2-PFH-PDA, ASPP for short) particles for photoacoustic (PA)/ultrasound (US)/computed tomography (CT)/thermal imaging and photothermal therapy (PTT) of tumors. In this work, we first synthesized Au seed particles with a diameter of 15.8 nm using a sodium citrate reduction method, and coated Au seeds with polyvinylpyrrolidone for further growth of solid silica shell/mesoporous silica outer shell onto the Au seeds. After treatment via selective etching to remove solid silica shell, amination of surface of the particles, and filling of PFH into the internal cavity of the spheres with a diameter of 182.1 nm, PDA coating was performed to render the particles with an external shell thickness of 15.1 nm. The formed hybrid particles with a size of 212.2 nm are colloidally stable and exhibit good cytocompatibility, and display excellent PA/US/CT/thermal imaging property due to the co-presence of PDA, PFH, and Au nanoparticles. Furthermore, the PDA coating renders the platform with a photothermal conversion efficiency of 61.2%, enabling effective photothermal ablation of cancer cells in vitro and a xenografted 4T1 tumor model in vivo under irradiation with an 808 nm laser. More importantly, in the primary 4T1 tumor model, intratumoral injection of the ASPP and irradiation with an 808 nm laser can also completely inhibit the occurrence of lung metastasis induced by the 4T1 tumor. The as-prepared hybrid nanoplatform may hold a great promise to be adopted for multimode imaging and PTT of tumors and inhibition of tumor metastasis.

As a major approach to evaluate the cytocompatibility of materials, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay has been proven to give a false negative result for nanofibrous mats. Herein, we proposed an alternative approach, resazurin microtiter assay (REMA) to get a more reliable cytocompatibility result for electrospun nanofibers. Mouse fibroblasts (L929 cells) were used as model cells. The cell density and incubation time of REMA were optimized. A linear relationship (R2 = 0.99034) between the fluorescence intensity of resorufin (cell metabolite of REMA, which is in direct proportion to cell viability) and cell density is observed when the cell density is less than 5.0 × 105 cells per mL. Moreover, the fluorescence intensity of resorufin is saturated when the cell density is higher than 5.0 × 105 cells per mL. On the other hand, the fluorescence intensity data fit the equation (Y = 2.72 + 6.28 × 0.26X2, R2 = 0.98892) well with the incubation time (up to 10 h), and in order to get the accurate cell viability, the reduction time should not exceed 6 h. In general, REMA is proven to be more convincing than MTT assay since less or no formed resorufin can be absorbed by nanofibrous mats during REMA. We anticipate that our study will provide a general insight for the use of REMA to evaluate the cytocompatibility of other nanofibrous materials.

Polydopamine-coated magnetic mesoporous silica nanoparticles have been designed by loading ultrasmall iron oxide nanoparticles within hollow mesoporous silica nanopartricles and then coating polydopamine onto the particle surface. The developed nanoplatform displayed improved colloidal stability, enhanced r1 relaxivity and near infrared absorption feature, affording their use for multimodal cancer theranostics.

An RGD peptide-targeted low-generation dendrimer-based nanoprobe has been developed through the versatile dendrimer nanotechnology. The poly(amidoamine) dendrimers of generation 2 can be modified or loaded with Mn chelates, RGD peptide, and gold nanoparticles to have desired stability, cytocompatibility, cancer cell targeting specificity, and ability to cross the blood-brain barrier for targeted MR/CT imaging of an orthotopic brain glioma.

Design of powerful nanosystems to overcome multidrug resistance (MDR) for effective chemotherapy of cancer currently remains a great challenge. Herein, we report the development of a poly(amidoamine) (PAMAM) dendrimer/carbon dot nanohybrid for dual drug loading to overcome MDR and simultaneously monitor cancer cells via fluorescence imaging. First, blue-emitting carbon dots (CDs) were synthesized using sodium citrate as a carbon source via the hydrothermal method and used as a carrier to load the anticancer drug doxorubicin (DOX) through non-covalent interactions, thus forming CDs/DOX complexes. In parallel, PAMAM dendrimers of generation 5 (G5) were covalently modified by the targeting ligand cyclic arginine-glycine-aspartic (RGD) peptide and the drug efflux inhibitor D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). Then, through electrostatic interaction, functional dendrimers (G5–RGD–TPGS) were complexed with CDs/DOX complexes to form a dual drug-loaded nanohybrid system. The dual drug-loaded dendrimer/CD nanohybrids were well characterized. We showed that the nanohybrids possessed good colloidal stability and enabled significant inhibition of cancer cells due to the presence of TPGS, which can inhibit P-glycoprotein (P-gp) by decreasing ATP levels and increasing ROS levels; simultaneously, fluorescence imaging of cancer cells could be achieved in vitro due to the luminescence of CDs. In addition, the attached RGD ligands rendered the nanohybrid with targeting specificity to cancer cells expressing αvβ3 integrin receptors. The developed dual drug-loaded dendrimer/CD nanohybrid may be used as a promising theranostic platform to overcome MDR for enhanced chemotherapy as well as for fluorescence imaging of cancer cells.

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

Design of stimuli-responsive nanomedicine with enhanced tumor delivery for combination therapy still remains a great challenge. Here, a unique design of an antifouling-dendrimer-based nanoplatform with dual pH- and redox-responsiveness is reported to meet this challenge. First, generation 5 (G5) poly(amidoamine) dendrimers are modified with targeting ligand cyclic arginine-glycine-aspartic acid (RGD) peptide through a polyethylene glycol (PEG) spacer and zwitterion of thiolated N,N-dimethyl-cysteamine-carboxybetaine (CBT) via pH-responsive benzoicimine bond to form G5.NH

In recent years, the use of poly(amidoamine) (PAMAM) dendrimers of different generations as building blocks or reactive modules to construct core-shell tecto dendrimers (CSTDs) that are superior to the performance of single-generation dendrimers has received great attention in the field of biomedical applications. The CSTDs are always based on high-generation dendrimers as the core and low-generation dendrimers as the shell; not only do they have excellent properties similar to single high-generation dendrimers, but they also have overcome some of the shortcomings (e.g., limited drug loading capacity or enhanced permeability and retention effect due to small size) of single-generation dendrimers in biomedical applications. Herein, the recent advances of CSTDs synthesized by different approaches as nanoplatforms for different biomedical applications, particularly for chemotherapy, gene delivery, and combination therapy, as well as biological imaging, are summarized. In addition, the current challenges and future perspectives of CSTDs are also discussed.

International audience; Poly(amidoamine) (PAMAM) dendrimers, as a family of synthetic macromolecules with highly branched interiors, abundant surface functional groups, and well-controlled architecture, have received immense scientific and technological interests for a range of biomedical applications, in particular cancer nanomedicine. However, due to the drawbacks of single-generation dendrimers with a quite small size (e.g., generation 5 (G5) PAMAM dendrimer has a size of 5.4 nm) such as limited drug loading capacity, restricted tumor passive targeting based on enhanced permeability and retention effect, and lack of versatility to render them with stimuli-responsiveness, superstructured dendrimeric nanoconstructs (SDNs) have been designed to break through these obstacles in their applications in cancer nanomedicine. Here, we review the recent advances related to the creation of SDNs such as dendrimer dumbbells, core–shell tecto dendrimers, dendrimer nanoclusters (NCs), dendrimer nanogels and dendrimer-templated hybrid NCs, and how these SDNs have been designed as nanoplatforms for different biomedical applications related to cancer nanomedicine including MR imaging, drug/gene delivery, combination therapy and theranostics. This review concisely describes the latest key developments in the field and also discusses the possible challenges and perspectives for translation applications.

We report a new use of dendrimer-entrapped gold nanoparticles (Au DENPs) modified with folic acid (FA) as a non-viral vector for targeted gene delivery applications. In this study, amine-terminated generation 5 poly(amidoamine) dendrimers modified with FA via covalent conjugation were used as templates to synthesize gold nanoparticles with an Au salt/dendrimer molar ratio of 25 : 1. The synthesized FA-modified Au DENPs (Au DENPs-FA) were used as a non-viral vector for the delivery of plasmid DNA (pDNA) into a model cancer cell line (HeLa cells) overexpressing high-affinity FA receptors (FAR). The DNA compaction ability of the formed Au DENPs-FA was systematically characterized using a gel retardation assay, zeta potential, and dynamic light scattering. We show that similar to the Au DENPs vector without FA, the Au DENPs-FA vector was able to compact the pDNA encoding enhanced green fluorescent protein (EGFP) at an N/P ratio of 0.5. Transfection results show that the Au DENPs-FA vector enables much higher luciferase and EGFP gene expression in HeLa cells overexpressing FAR than the Au DENPs without FA, demonstrating the role played by FA-mediated targeting for enhanced gene transfection in target cells. With a lower cytotoxicity than that of the Au DENPs without FA proven by a cell viability assay, the developed FA-modified Au DENPs may be used as a promising non-viral vector for safe and targeted gene therapy applications.

Design of dendrimer-based nanoarchitectures for enhanced gene delivery still remains a great challenge. Here, we report the design of core–shell tecto dendrimers using a supramolecular assembly approach for enhanced gene delivery applications. Firstly, β-cyclodextrin (CD)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers (G5-CD) and adamantine (Ad)-modified generation 3 (G3) PAMAM dendrimers (G3-Ad) both having amine termini were synthesized. Through the supramolecular recognition of CD and Ad, G5-CD/Ad-G3 core–shell tecto dendrimers with a G5 core and G3 shell were formed. The formed G5-CD/Ad-G3 core–shell tecto dendrimers with a size of 8.4 nm possess good monodispersity, well-defined three-dimensional structure, and quite low cytotoxicity. Importantly, with the abundant amines on the surface, the core–shell tecto dendrimers are able to transfect the luciferase (Luc) gene with an efficiency 20 times and 170 times higher than the G5-CD and G3-Ad dendrimers, respectively. The higher gene transfection efficiency can also be qualitatively confirmed by transfection of plasmid DNA encoding enhanced green fluorescence protein. Our results suggest that the developed G5-CD/Ad-G3 core–shell tecto dendrimers may be used as a promising vehicle for enhanced gene transfection applications.

Cancer cell metastasis causes 90% of cancer patient death. Detection and targeted capture of cancer cells in vitro are of paramount importance. The development of novel nanodevices for cancer cell capture applications, however, still remains a great challenge. Here we report a facile approach to fabricating multifunctional dendrimer-modified electrospun cellulose acetate (CA) nanofibers for targeted cancer cell capture applications. In this study, hydrolyzed electrospun CA nanofibers with negative surface charge were assembled layer-by-layer with a bilayer of poly(diallyldimethylammonium chloride) (PDADMAC) and polyacrylic acid (PAA) via electrostatic interactions. Thereafter, amine-terminated generation 5 poly(amidoamine) dendrimers pre-modified with folic acid (FA) and fluorescein isothiocyanate were covalently conjugated onto the bilayer-assembled nanofibers via the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride coupling reaction, followed by acetylation to neutralize the remaining dendrimer surface amines. The formation of electrospun CA nanofibers, assembly of the PDADMAC/PAA bilayer onto the CA nanofibers, and the dendrimer modification on the nanofibers were characterized via different techniques. The formed dendrimer-modified CA nanofibers were then used to capture cancer cells overexpressing FA receptors. We show that the bilayer self-assembly and the subsequent dendrimer modification do not appreciably change the fiber morphology. Importantly, the modification of FA-targeted multifunctional dendrimers renders the CA nanofibers with superior capability to specifically capture cancer cells (KB cells, a model cancer cell line) overexpressing high-affinity FA receptors. The approach to modifying electrospun nanofibers with multifunctional dendrimers may be extended to fabricate other functional nanodevices for capturing different types of cancer cells.

We present the development of indocyanine green (ICG)-loaded and folic acid (FA)-modified multiwalled carbon nanotubes (MWCNTs) as a versatile nanoplatform for targeted dual-mode fluorescence (FL)/photoacoustic (PA) imaging, and photothermal therapy (PTT)/photodynamic therapy (PDT) of tumors in vivo. In this study, acid-treated MWCNTs with carboxyl residues were first covalently conjugated with polyethyleneimine (PEI). This was followed by sequential modification of FA via a polyethylene glycol (PEG) segment, fluorescein isothiocyanate (FITC), and succinic anhydride (SAH), multifunctional FA-modified MWCNTs (MWCNT–PEI·SAH–FITC–PEG–FA) were formed. The functional MWCNTs possess exceptional colloidal stability, good hemocompatibility/cytocompatibility in a studied concentration range, and targeting specificity to FA receptor-overexpressing cancerous cells. Via π–π stacking interactions, the MWCNTs enable highly efficient loading of ICG and the ICG-loaded MWCNTs exhibit excellent photostability and can be used for FL imaging/PDT of tumors due to the singlet oxygen (1O2) generation from ICG. In addition, the near-infrared absorption characteristic of ICG also renders the MWCNT nanoplatform with a capacity for simultaneous PA imaging and PTT of tumors. Our study reports a novel theranostic nanosystem that can be used for targeted dual-mode FL/PA imaging and PTT/PDT of tumors in vivo, which may show profound promise for translation into clinical uses.

We develop a convenient approach to loading both gold nanoparticles (AuNPs) and gadolinium (Gd) within alginate nanogels (AG NGs) for enhanced tumor dual-modal MR/CT imaging applications. In this study, polyethyleneimine (PEI) partially modified with polyethylene glycol (PEG) was used to entrap AuNPs and load gadolinium via chelation. The formed PEI-Au-Gd NPs were used as a crosslinker to crosslink AG NGs with activated carboxyl groups obtained through a double emulsion process. The formed hybrid NGs (AG/PEI-Au-Gd NGs) having a size of 83 ± 21 nm exhibit excellent colloidal stability in aqueous solution and good cytocompatibility in the studied concentration range. In particular, the AG/PEI-Au-Gd NGs exhibit a higher r1 relaxivity (9.16 mM−1 s−1) than acetylated PEI-Au-Gd NPs (PEI.Ac-Au-Gd NPs) and a clinical MR contrast agent and a greater X-ray attenuation performance than conventional iodinated CT contrast agents (e.g., Omnipaque), and they can be more significantly taken up by cancer cells than PEI.Ac-Au-Gd NPs. Furthermore, the AG/PEI-Au-Gd NGs enable effective dual mode MR/CT imaging of cancer cells in vitro as well as a subcutaneous tumor model in vivo. Strikingly, the AG/PEI-Au-Gd NGs exhibit a much better dual-modal MR/CT imaging performance than PEI.Ac-Au-Gd NPs and clinical CT or MR agents in in vivo tumor imaging. The developed AG/PEI-Au-Gd NGs with good biosafety confirmed by histological examinations may be potentially employed as an efficient contrast agent for enhanced dual-modal MR/CT imaging applications.

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

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.

Dendrimers have a unique three-dimensional structure, highly branched macromolecular features, and abundant terminal functional groups. These features of dendrimers support their uses as universal nanoplatforms to prepare multifunctional nanodevices for a myriad of biomedical applications, particularly for targeted imaging and therapy of different biosystems. The periphery of the dendrimer enables the attachment of targeting ligands and imaging agents, while the internal cavity allows the embedment of metal nanoparticles (NPs), anticancer drugs, and other inorganic NPs. Meanwhile, the versatile dendrimer nanotechnology enables different types of integration with varied inorganic components. The resulting hybrid dendrimer-based particles are useful in a variety of imaging, therapy, or theranostic applications. This chapter focuses on the latest advances in the dendrimer-based targeting systems for the imaging, therapy, and theranostics of cancer.

Owing to the unique structural characteristics and abundant amine groups, polyethylenimine (PEI) plays a remarkable role in the construction of multifunctional nanosystems for versatile biomedical applications, particular for cancer nanomedicine. Nanoparticles (NPs), polymers, fluorophores, targeting molecules or/and different cargos can be integrated within one single system via PEI-mediated chemistry, thereby allowing for the generation of a range of PEI-based nanoplatforms. On the molecular imaging front, PEI-based NPs serve as contrast agents to transduce biomolecular interactions into various types of signals for single-, dual- or multi-mode imaging of tissues and diseases. With rational modifications, PEI-based nanocarriers can be developed and utilized for targeted and responsive delivery of drugs, genes and proteins. Utilizing the unique features of PEI-based NPs that can convert external stimuli (e.g., magnetic field, light and X-ray) into heat or free radical, in vivo magnetic hyperthermia, phototherapy, and radiotherapy can be realized, achieving excellent anti-tumor therapeutic outcomes. In this review, we summarize the recent progress in the development of PEI-based multifunctional nanosystems for versatile biomedical applications in cancer nanomedicine and discuss the current challenges and future prospects in this related field.

We present here the development of cholesterol (Chol)-modified dendrimer system for targeted chemotherapy of folate (FA) receptor-expressing cancer cells. In our study, poly(amidoamine) (PAMAM) dendrimers of generation 5 (G5) were functionalized step-by-step with Chol, fluorescein isothiocyanate (FI), and FA via a poly(ethylene glycol) (PEG) spacer (PEG-FA), and then acetamide to shield their remaining surface amines. The synthesized G5.NHAc-Chol-FI-PEG-FA (for short, G5-CFPF) dendrimers were utilized to encapsulate 10-hydroxycamptothecin (HCP), a hydrophobic anticancer drug. We find that each G5-CFPF dendrimer can encapsulate 13.8 HCP molecules. The complexes show a slower release profiles of HCP in a pH-dependent manner than the control complexes formed using the same dendrimers without Chol under the same conditions. Thanks to the targeting role played by FA, the complexes display a specific inhibition efficacy to FA receptor-expressing cervical cancer cells. The designed Chol-modified dendrimers may be adopted as a promising carrier for application in targeted cancer therapy.

A Mn(3)O(4) nanoparticle (NP)-based dual-modality probe has been developed for tumor positron emission tomography (PET)/magnetic resonance (MR) imaging. The dual-modality imaging probe was constructed by modifying multifunctional polyethyleneimine (PEI)-coated Mn(3)O(4) NPs with folic acid (FA), followed with the radiolabeling with (64)Cu. The formed imaging probe was utilized for PET/MR imaging of human cervical cancer mouse xenografts, which overexpress folate receptor (FR). The PEI-coated Mn(3)O(4) NPs were synthesized using a solvothermal approach via decomposition of acetylacetone manganese. Multifunctional groups, including fluorescein isothiocyanate (FI), PEGylated FA, and NOTA chelator, were then sequentially loaded onto the surface of the amine groups of the Mn(3)O(4) NPs. The remaining PEI amines were neutralized by the acetylation reaction. The resulting NOTA–FA–FI–PEG–PEI–Ac–Mn(3)O(4) NPs were fully characterized and evaluated in vitro and successfully radiolabeled with (64)Cu for tumor PET/MR imaging in small animals. In vivo blocking experiments were performed to determine the FR binding specificity of NPs. PET imaging results demonstrated that (64)Cu-labeled Mn(3)O(4) NPs display good tracer uptake in the FR-expressing HeLa tumors (tumor-to-muscle (T/M) ratio: 5.35 ± 0.31 at 18 h postinjection (pi)) and substantially reduced tracer uptake in the FR-blocked HeLa tumors (T/M ratio: 2.78 ± 0.68 at 18 h pi). The ex vivo data, including PET imaging and biodistribution, further confirmed the tumor binding specificity of the (64)Cu-labeled Mn(3)O(4) NPs. Moreover, the FR-targeted Mn(3)O(4) NPs exhibited efficient T(1)-weighted MR imaging (MRI), leading to the precise tumor MRI at 18 h pi. PET/MR imaging with the (64)Cu–NOTA–FA–FI–PEG–PEI–Ac– Mn(3)O(4) NPs may offer a new quantitative approach to precisely measure the FR in tumors. The strategy of incorporating PEI nanotechnology into the construction of new biomaterials may be applied for the construction of novel nanoplatforms for cancer diagnosis and therapy.

We present a convenient method to immobilize Au/Ag nanoparticles (NPs) within electrospun polyvinyl alcohol (PVA)/polyethylenimine (PEI) nanofibers by in-situ reduction for catalytic applications. Water-stable electrospun PVA/PEI nanofibers were initially fabricated by crosslinking with glutaraldehyde (GA) vapor. Then, the nanofibers were used as a nanoreactor to bind Au salt via electrostatic interaction with the free PEI amines, followed by NaBH4 reduction to form Au NPs. The formed Au NP-containing nanofibers were then used to bind Ag+ ions via chelation with the free PEI amines, followed by reduction with ascorbic acid to form the Au/Ag NP-loaded PVA/PEI nanofibers. The small size (4.9 ± 1.8 nm) and narrow size distribution of the immobilized Au/Ag NPs reveal that the nanofibrous structure is able to efficiently prevent the aggregation of the NPs. We then evaluated the catalytic activity and reusability of Au/Ag NP-immobilized PVA/PEI nanofiers by catalytic transformation of 4-nitrophenol to 4-aminophenol in aqueous solution. The material exhibited excellent catalytic efficiency and reusability. The developed approach could be applied to create other bimetallic NP-incorporated nanofibers for catalysis, tissue engineering, and environmental remediation applications.

We report here a facile method for one-step loading of gold (Au) and gadolinium oxide (Gd2O3) nanoparticles (NPs) within polyethylenimine (PEI) premodified with polyethtylene glycol (PEG) for dual mode computed tomography (CT) and magnetic resonance (MR) imaging of tumors. PEGylated PEI was used as a template to complex Au(III) and Gd(III) salts, followed by sodium borohydride reduction and acetylation of remaining PEI surface amines to generate the hybrid PEI@Au/Gd2O3 NPs. The hybrid NPs exhibit a remarkable colloidal stability and cytocompatibility and possess a high X-ray attenuation efficacy and r1 relaxivity, enabling their uses for dual mode CT/MR imaging of tumors.

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.

Capture and detection of circulating tumor cells (CTCs) is of great significance in the early diagnosis, prognosis evaluation and personalized therapy of cancer. Herein, we report a unique microfluidic platform integrated with zwitterion-modified aligned polyethyleneimine/polyvinyl alcohol nanofibers for efficient capture and rapid release of CTCs. We show that zwitterions of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) can be immobilized onto the aligned nanofibers via an atomic transfer radical polymerization approach. The combined strategy of using aligned nanofibers instead of random nanofibers and PMPC immobilization endows the nanofibers with excellent antifouling properties against protein adsorption and blood cell attachment, thereby significantly improving the capture purity of cancer cells. Meanwhile, the targeting ligand folic acid (FA) can be modified onto the surface of nanofibers via a redox-sensitive disulfide bond to specifically and efficiently capture cancer cells overexpressing FA receptors and to rapidly release the cancer cells in a non-destructive manner through tris(2-carboxyethyl)phosphine treatment. The dynamic capture assay using the fiber-integrated microfluidic platform demonstrates that FA receptor-expressing cancer cells can be isolated with a high capture efficiency (92.7%) and considerable purity (43.4%) in a time period of 30 min and can be rapidly detached from the nanofibrous substrates within 5 min with a release efficiency up to 98.9%. These results as well as the isolation and detection of CTCs from the blood of cancer patients suggest that the developed microfluidic chip may be potentially used for clinical cancer diagnosis applications.

International audience; We report the construction and characterization of polyethylenimine (PEI)-entrapped gold nanoparticles (AuNPs) chelated with gadolinium (Gd) ions for targeted dual mode tumor CT/MR imaging in vivo. In this work, polyethylene glycol (PEG) monomethyl ether-modified PEI was sequentially modified with Gd chelator and folic acid (FA)-linked PEG (FA-PEG) was used as a template to synthesize AuNPs, followed by Gd(III) chelation and acetylation of the remaining PEI surface amines. The formed FA-targeted PEI-entrapped AuNPs loaded with Gd (FA-Gd-Au PENPs) were well characterized in terms of structure, composition, morphology, and size distribution. We show that the FA-Gd-Au PENPs with an Au core size of 3.0 nm are water dispersible, colloidally stable, and noncytotoxic in a given concentration range. Thanks to the coexistence of Au and Gd elements within one nanoparticulate system, the FA-Gd-Au PENPs display a better X-ray attenuation property than clinical iodinated contrast agent (e.g. Omnipaque) and reasonable r1 relaxivity (1.1-mM-1s-1). These properties allow the FA-targeted particles to be used as an efficient nanoprobe for dual mode CT/MR imaging of tumors with excellent FA-mediated targeting specificity. With the demonstrated organ biocompatibility, the designed FA-Gd-Au PENPs may hold a great promise to be used as a nanoprobe for CT/MR dual mode imaging of different FA receptor-overexpressing tumors.

Amplification of endoplasmic reticulum stress (ERS) to realize enhanced cancer therapy has been considered to be unique in current cancer nanomedicine design. Herein, we report the design of metal-phenolic network-coated dendrimer-drug conjugates as a novel theranostic nanoplatform based on ERS amplification. In our design, acetylated generation 5 poly(amidoamine) dendrimers were conjugated with an ERS drug toyocamycin (Toy) through the attached phenylboronic acid moiety, and coated with iron (Fe)-tannic acid (TF) network. The generated nanocomplexes with a size of 50.2 nm are stable under a physiological environment, and can rapidly release Toy under the tumor microenvironment due to the pH- and reactive oxygen species-responsive boronic ester bonds to effectively inhibit the ERS-mediated cancer cell adaptation. Meanwhile, the coated TF network enables the nanocomplexes to generate cytotoxic hydroxyl radicals through a Fenton reaction, amplifying the ERS for improved chemotherapy/chemodynamic therapy of cancer cells in vitro and a xenografted breast tumor model in vivo. Moreover, the coating of TF also renders the complexes with an eminent r1 relaxivity for in vivo T1 -weighted tumor magnetic resonance imaging. The created intelligent nanocomplexes may represent an advanced nanomedicine formulation uniquely integrated with metal-phenolic network and dendrimer nanotechnology for imaging-guided cancer therapy through ERS amplification. This article is protected by copyright. All rights reserved.

The development of a novel multifunctional nanoplatform to overcome the blood-brain barrier (BBB), increase diagnostic sensitivity, and improve the therapeutic effects of glioma for precision theranostics remains a serious challenge. Herein, through supramolecular assembly based on the host-guest recognition between β-cyclodextrin (CD) and adamantane (Ad), we developed a modular design approach to generate multifunctional core-shell tecto dendrimers with acetyl termini (M-CSTD.NHAc) for theranostics of orthotopic glioma. In our design, the CSTDs composed of CD-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers as cores and Ad-functionalized G3 PAMAM dendrimers (G3. NH2-Ad) as shells were constructed, in which the G3.NH2-Ad dendrimers acted as standalone modules to be modified with pyridine for copper (Cu(II)) complexation, dermorphin for BBB crossing and arginine-glycine-aspartic acid peptide for glioma targeting, respectively. We show that the formed M-CSTD.NHAc exhibit the good ability to resist protein adsorption, to penetrate BBB and to target glioma cells in vitro, and the created M-CSTD.NHAc/Cu(II) complexes can react with self-supplying hydrogen peroxide inside the glioma cells to produce hydroxyl radicals through Fenton-like reaction to cause lipid peroxidation and cell death. With the displayed r1 relaxivity of 0.7331 mM−1s−1, the developed M-CSTD.NHAc/Cu(II) complexes are able to act as an intelligent platform to cross the BBB and target orthotopic glioma for MR imaging and chemodynamic therapy of glioma after intravenous injection. The developed modular design strategy to produce multifunctional CSTDs may be extended to prepare other nanoplatforms for various precision medicine applications.

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.

We present a facile particle-based cell manipulation method using acoustic radiation forces. In this work, we selected several representative particles including poly(lactic-co-glycolic acid) (PLGA) microspheres, silica-coated magnetic microbeads, polydimethylsiloxane (PDMS) microspheres and investigated the responses of these particle systems to ultrasonic standing waves (USWs) in a microfluidic chip. We show that depending on the nature (positive or negative acoustic contrast factors) of the particles, these particle systems display different alignment behaviors along the microfluidic channel under USWs. Specifically, PLGA microspheres and silica-coated magnetic microbeads are able to be aligned in the middle of the microfluidic channel, while PDMS microspheres are translocated to the side walls of the channel, which is beneficial for cell trapping and manipulation. Further results demonstrate that the functional PDMS microspheres with a negative acoustic contrast factor can be used to trap cells to the pressure antinodes in the acoustofluidic chip. Cell viability tests reveal that the ultrasonic manipulation does not exert any harmful effect to the cells. This acoustic-based particle and cell manipulation technique may hold a great promise for the development of rapid, noninvasive, continuous assays for detecting of cells and separation of biological samples.

Development of multifunctional nanoplatforms for tumor multimode imaging and therapy is of great necessity. Herein, we report a new type of Au nanostar (NS)-coated, perfluorohexane (PFH)-encapsulated hollow mesoporous silica nanocapsule (HMS) modified with poly(ethylene glycol) (PEG) for tumor multimode ultrasonic (US)/computed tomography (CT)/photoacoustic (PA)/thermal imaging, and photothermal therapy (PTT). HMSs were first synthesized, silanized to have thiol surface groups, and coated with gold nanoparticles via a Au-S bond. Followed by growth of Au NSs on the surface of the HMSs, encapsulation of PFH in the interior of the HMSs, and surface conjugation of thiolated PEG, multifunctional HMSs@Au-PFH-mPEG NSs (for short, HAPP) were formed and well-characterized. We show that the HAPP are stable in a colloidal manner and noncytotoxic in the studied range of concentrations, possess multimode US/CT/PA/thermal imaging ability, and can be applied for multimode US/CT/PA/thermal imaging of tumors in vivo after intravenous or intratumoral injection. Additionally, the near-infrared absorption property of the HAPP enables the use of the HAPP for photothermal ablation of cancer cells in vitro and a tumor model in vivo after intratumoral injection. The developed multifunctional HAPP may be used as a novel multifunctional theranostic nanoplatform for tumor multimode imaging and PTT.

We report the facile synthesis of polyaniline (PANI)-loaded γ-polyglutamic acid (γ-PGA) nanogels (NGs) for photoacoustic (PA) imaging-guided photothermal therapy (PTT) of tumors. In this work, γ-PGA NGs were first formed via a double emulsion approach, followed by crosslinking with cystamine dihydrochloride (Cys) via 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride coupling chemistry. The formed γ-PGA/Cys NGs were employed as a nanoreactor to load aniline monomers via an electrostatic interaction for subsequent in situ polymerization in the presence of ammonium persulfate. The resulting γ-PGA/Cys@PANI NGs were thoroughly characterized. It is shown that the γ-PGA/Cys@PANI NGs with an average size of 71.9 nm are dispersible in water, colloidally stable, and cytocompatible and hemocompatible in the concentration range studied. The strong near-infrared (NIR) absorbance renders the NGs with good PA imaging contrast enhancement and photothermal conversion properties. With these excellent properties and biocompatibility, the developed γ-PGA/Cys@PANI NGs are able to be used for PA imaging-guided PTT of cancer cells in vitro and a xenografted tumor model in vivo. This unique theranostic nanoplatform may be further loaded with other imaging or therapeutic elements, or modified with targeting ligands, thereby providing a ubiquitous platform for multimode imaging and combinational therapy of different biosystems.

We report the synthesis and characterization of antifouling zwitterion carboxybetaine acrylamide (CBAA)-modified dendrimer-entrapped gold nanoparticles (Au DENPs) for enhanced CT imaging applications. The CBAA-modified nanodevice displays a better protein resistance property, less macrophage cellular uptake and liver accumulation, and longer blood half-delay time than the PEGylated counterpart material, thereby enabling enhanced blood pool, lymph node, and tumor CT imaging.

RNA interference (RNAi) has been considered as a promising strategy for effective treatment of cancer. However, the easy degradation of small interfering RNA (siRNA) limits its extensive applications in gene therapy. For safe and effective delivery of siRNA, a novel vector system possessing excellent biocompatibility, highly efficient transfection efficiency and specific targeting properties has to be considered. In this study, we report the use of polyethyleneimine (PEI)-entrapped gold nanoparticles (Au PENPs) modified with an arginine-glycine-aspartic (Arg-Gly-Asp, RGD) peptide via a poly(ethylene glycol) (PEG) spacer as a vector for Bcl-2 (B-cell lymphoma-2) siRNA delivery to glioblastoma cells. The synthesized Au PENPs were well characterized. The efficiency of siRNA delivery was appraised by flow cytometry, confocal microscopy imaging, and the protein expression level. Our results revealed that the Au PENPs were capable of delivering Bcl-2 siRNA to glioblastoma cells with an excellent transfection efficiency, leading to specific gene silencing in the target cells (22% and 25.5% Bcl-2 protein expression in vitro and in vivo, respectively) thanks to the RGD peptide-mediated targeting pathway. The designed RGD-targeted Au PENPs may hold great promise to be used as a novel vector for specific cancer gene therapy applications.

Nanoparticles (NPs) have provided new opportunities to diagnose and treat various types of cancers, while it still remains a great challenge to develop novel and effective nanoscale platforms for these applications. In this study, we report a facile hydrothermal route to generate size- and shape-controlled gadolinium hydroxide (Gd(OH)3) NPs and polyethylenimine (PEI)-stabilized Gd(OH)3@Au core/shell nanostars (NSs). We show that Gd(OH)3 NPs with controlled size and shape can be synthesized through varying the stabilizer, reaction time and solvent. The formed Gd(OH)3 nanorods can be transformed into rice-shaped counterparts in the presence of trisodium citrate dehydrate. Furthermore, the introduction of PEI does not alter the morphology, rather have an impact on the size of the products. This facile synthetic route can also be utilized to synthesize Gd(OH)3@Au nanocomposite particles that can act as seeds to form Gd(OH)3@Au NSs in the Au growth solution. Further modification of PEI endows these NSs with excellent water-solubility and colloidal stability. Due to the strong surface plasmon resonance peak in the near-infrared region, the as-prepared Gd(OH)3@Au-PEI NSs display a high photothermal conversion efficiency under laser irradiation. The developed size- and shape-controlled Gd(OH)3 NPs and PEI-stabilized Gd(OH)3@Au core/shell NSs may be further developed as theranostic agents for various biomedical applications.