Unsymmetrical Low-Generation Cationic Phosphorus Dendrimers as a Nonviral Vector to Deliver MicroRNA for Breast Cancer Therapy.

The development of nonviral dendritic polymers with a simple molecular backbone and great gene delivery efficiency to effectively tackle cancer remains a great challenge. Phosphorus dendrimers or dendrons are promising vectors due to their structural uniformity, rigid molecular backbones, and tunable surface functionalities. Here, we report the development of a new low-generation unsymmetrical cationic phosphorus dendrimer bearing 5 pyrrolidinium groups and one amino group as a nonviral gene delivery vector. The created AB5-type dendrimers with simple molecular backbone can compress microRNA-30d (miR-30d) to form polyplexes with desired hydrodynamic sizes and surface potentials and can effectively transfect miR-30d to cancer cells to suppress the glycolysis-associated SLC2A1 and HK1 expression, thus significantly inhibiting the migration and invasion of a murine breast cancer cell line in vitro and the corresponding subcutaneous tumor mouse model in vivo. Such unsymmetrical low-generation phosphorus dendrimers may be extended to deliver other genetic materials to tackle other diseases.

Thiacalixarene Carboxylic Acid Derivatives as Inhibitors of Lysozyme Fibrillation.

Amyloid fibroproliferation leads to organ damage and is associated with a number of neurodegenerative diseases affecting populations worldwide. There are several ways to protect against fibril formation, including inhibition. A variety of organic compounds based on molecular recognition of amino acids within the protein have been proposed for the design of such inhibitors. However, the role of macrocyclic compounds, i.e., thiacalix[4]arenes, in inhibiting fibrillation is still almost unknown. In the present work, the use of water-soluble thiacalix[4]arene derivatives for the inhibition of hen egg-white lysozyme (HEWL) amyloid fibrillation is proposed for the first time. The binding of HEWL by the synthesized thiacalix[4]arenes (logKa = 5.05-5.13, 1:1 stoichiometry) leads to the formation of stable supramolecular systems capable of stabilizing the protein structure and protecting against fibrillation by 29-45%. The macrocycle conformation has little effect on protein binding strength, and the native HEWL secondary structure does not change via interaction. The synthesized compounds are non-toxic to the A549 cell line in the range of 0.5-250 µg/mL. The results obtained may be useful for further investigation of the anti-amyloidogenic role of thiacalix[4]arenes, and also open up future prospects for the creation of new ways to prevent neurodegenerative diseases.

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

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

Multifunctional Low-Generation Dendrimer Nanogels as an Emerging Probe for Tumor-Specific CT/MR Dual-Modal Imaging.

The development of nanoprobes that have amplified enhanced permeability and retention (EPR) effect is crucial for their precise cancer diagnosis performance. Here, we present the development of functional dendrimer-based nanogels (DNGs) with the generation three primary amine-terminated poly(amidoamine) (PAMAM) dendrimers (G3·NH2) cross-linked by N,N'-bis(acryloyl) cystamine (BAC). The DNGs were prepared through a Michael addition reaction between G3·NH2 dendrimers and BAC via an inverse microemulsion method and entrapped with gold nanoparticles (Au NPs) to form Au-DNGs. The Au-DNGs were sequentially modified with diethylenetriamine penta-acetic acid (DTPA)-gadolinium (Gd) complex, poly(ethylene glycol) (PEG)-linked arginine-glycine-aspartic (RGD) peptide, and 1,3-propanesultone (1,3-PS). The formed multifunctional RGD-Gd@Au-DNGs-PS (R-G@ADP) possessing an average diameter of 122 nm are colloidally stable and display a high X-ray attenuation coefficient, excellent r1 relaxivity (9.13 mM-1 s-1), desired protein resistance rendered by the zwitterionic modification, and cytocompatibility. With the targeting specificity mediated by RGD and the much better tumor penetration capability than the counterpart material of single dendrimer-entrapped Au NPs, the developed multifunctional R-G@ADP enable targeted and enhanced computed tomography (CT)/magnetic resonance (MR) dual-modal imaging of a pancreatic tumor model in vivo. The current work demonstrates a unique design of targeted and zwitterionic DNGs with prolonged blood circulation time as an emerging nanoprobe for specific tumor CT/MR imaging through amplified passive EPR effect.

Dendrimer-Based Nanogels for Cancer Nanomedicine Applications.

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

Efficient Capture and Separation of Cancer Cells Using Hyaluronic Acid-Modified Magnetic Beads in a Microfluidic Chip.

The efficient isolation and specific discrimination of circulating tumor cells (CTCs) is expected to provide valuable information for understanding tumor metastasis and play an important role in the treatment of cancer patients. In this study, we developed a novel and rapid method for efficient capture and specific identification of cancer cells using hyaluronic acid (HA)-modified SiO2-coated magnetic beads in a microfluidic chip. First, polyacrylamide-surfaced SiO2-coated magnetic beads (SiO2@MBs) were covalently conjugated with HA, and the created HA-modified SiO2@MBs (HA-SiO2@MBs) display binding specificity to HeLa cells (a human cervical carcinoma cell line) overexpressing CD44 receptors. After incubating the HA-SiO2@MBs with cancer cells for 1 h, the mixture of MBs and cells was drawn into a designed microfluidic channel with two inlets and outlets. Through the formation of lamellar flow, cells specifically bound with the HA-SiO2@MBs can be separated under an external magnetic field with a capture efficiency of up to 92.0%. The developed method is simple, fast, and promising for CTC separation and cancer diagnostics applications.

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

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

Multifunctional nanoprobe for real-time in vivo monitoring of T cell activation.

Genetically engineered T cells are a powerful new modality for cancer immunotherapy. However, their clinical application for solid tumors is challenging, and crucial knowledge on cell functionality in vivo is lacking. Here, we fabricated a nanoprobe composed of dendrimers incorporating a calcium sensor and gold nanoparticles, for dual-modal monitoring of engineered T cells within a solid tumor. T cells engineered to express a melanoma-specific T-cell receptor and loaded with the nanoprobe were longitudinally monitored within melanoma xenografts in mice. Fluorescent imaging of the nanoprobe's calcium sensor revealed increased intra-tumoral activation of the T cells over time, up to 24 h. Computed tomography imaging of the nanoprobe's gold nanoparticles revealed the cells' intra-tumoral distribution pattern. Quantitative analysis revealed the intra-tumoral T cell quantities. Thus, this nanoprobe reveals intra-tumoral persistence, penetration and functional status of genetically engineered T cells, which can advance T cell-based immunotherapy and promote next-generation live cell imaging.

Synthesis and Shaping of Core-Shell Tecto Dendrimers for Biomedical Applications.

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.

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

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

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

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

Targeted Combination of Antioxidative and Anti-Inflammatory Therapy of Rheumatoid Arthritis using Multifunctional Dendrimer-Entrapped Gold Nanoparticles as a Platform.

Abundant reactive oxygen species and tumor necrosis factor-α (TNF-α) cytokine supply of M1-type macrophages boost rheumatoid arthritis (RA) pathological process. For efficient RA therapy, here a multifunctional nanoplatform is presented based on generation 5 (G5) poly(amidoamine) dendrimer-entrapped gold nanoparticles (Au DENPs) to achieve co-delivery of antioxidant alpha-tocopheryl succinate (α-TOS) and anti-inflammatory anti-TNF-α siRNA to macrophage cells. G5 dendrimers with amine termini are sequentially functionalized with 1,3-propane sultone (1,3-PS), α-TOS through a polyethylene glycol (PEG) spacer, and PEGylated folic acid (FA), and subsequently entrapped with Au NPs. The generated functional Au DENPs exhibit desired cytocompatibility, zwitterion-rendered antifouling property, and FA-mediated targeting specificity, enabling serum-enhanced siRNA delivery to M1-type macrophage cells. Meanwhile, the attached α-TOS affords enhanced oxidation resistance of macrophage cells. In vivo investigation shows that the treatment of a collagen-induced arthritis mouse model using α-TOS-modified Au DENPs/TNF-α siRNA polyplexes can achieve excellent combination therapy effect in inflammatory cytokines downregulation of RA lesion and bone erosions. The therapeutic efficacy is also supported by 3D micro-computed tomography analysis and TNF-α cytokine reduction of RA lesion joints in the mRNA, protein, and histology levels. The created multifunctional nanoplatform may be employed in antioxidative and anti-inflammatory combination therapy of RA.

Design of DNA Aptamer-Functionalized Magnetic Short Nanofibers for Efficient Capture and Release of Circulating Tumor Cells.

The isolation of viable circulating tumor cells (CTCs) from blood is of paramount significance for early stage detection and individualized therapy of cancer. Currently, CTCs isolated by conventional magnetic separation methods are tightly coated with magnetic materials even after attempted coating removal treatments, which is not conducive for subsequent analysis of CTCs. Herein, we developed DNA aptamer-functionalized magnetic short nanofibers (aptamer-MSNFs) for efficient capture and release of CTCs. In our work, polyethylenimine (PEI)-stabilized Fe3O4 nanoparticles with a mean diameter of 22.6 nm were first synthesized and encapsulated within PEI/poly(vinyl alcohol) nanofibers via a blended electrospinning process. After a homogenization treatment to acquire the MSNFs, surface conjugation of the DNA aptamer was performed through thiol-maleimide coupling. The formed aptamer-MSNFs, with a mean diameter of 350 nm and an average length of 9.6 µm, display a saturated magnetization of 12.3 emu g-1, are capable of specifically capturing cancer cells with an efficiency of 87%, and enable the nondestructive release of cancer cells with a release efficiency of 91% after nuclease treatment. In particular, the prepared aptamer-MSNFs displayed a significantly higher release efficiency than commercial magnetic beads. The designed aptamer-MSNFs may hold great promise for CTC capture and release as well as for other cell sorting applications.

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.

Multifunctional Dendrimer-Entrapped Gold Nanoparticles for Labeling and Tracking T Cells Via Dual-Modal Computed Tomography and Fluorescence Imaging.

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.

Characterization of zwitterion-modified poly(amidoamine) dendrimers in aqueous solution via a thorough NMR investigation.

Zwitterions are a class of unique molecules that can be modified onto nanomaterials to render them with antifouling properties. Here we report a thorough NMR investigation of dendrimers modified with zwitterions in terms of their structure, hydrodynamic size, and diffusion time in aqueous solution. In this present work, poly(amidoamine) (PAMAM) dendrimers of generation 5 (G5) were partially decorated with carboxybetaine acrylamide (CBAA), 2-methacryloyloxyethyl phosphorylcholine (MPC), and 1,3-propane sultone (1,3-PS), respectively with different modification degrees. The formed zwitterion-modified G5 dendrimers were characterized using NMR techniques. We show that the zwitterion modification leads to increased G5 dendrimer size in aqueous solution, suggesting that the modified zwitterions can form a hydration layer on the surface of G5 dendrimers. In addition, the hydrodynamic sizes of G5 dendrimers modified with different zwitterions but with the same degree of surface modification are discrepant depending on the type of zwitterions. The present study provides a new physical insight into the structure of zwitterion-modified G5 dendrimers by NMR techniques, which is beneficial for further design of different biomedical applications.

Zwitterionic Modification of Nanomaterials for Improved Diagnosis of Cancer Cells.

Nanomaterials have been ubiquitously employed as platforms to load imaging agents for cancer diagnosis. In general, the majority of nanomaterials are accumulated in the reticuloendothelial system (RES)-associated organs such as liver, spleen, and lung after systemic administration. Although the adopted strategy used to modify nanomaterials with polyethylene glycol (PEG) has relieved this problem to some extent, challenges still remain for further clinical applications. Recently, nanomaterials with zwitterionic surface modification have been found to have a better antifouling property than those with PEGylation modification. This Topical Review reports the recent progress in the development of zwitterion-modified nanomaterials for improved cancer cell diagnosis, including zwitterionic modification of hybrid nanoparticles for enhanced fluorescence, computed tomography (CT), magnetic resonance (MR), and dual-mode imaging of cancer cells, and the zwitterionic modification of nanofibers for specific capture of circulating tumor cells with improved capture purity and efficiency. Challenges and future perspectives in this particular field are also discussed.

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.

Construction of iron oxide nanoparticle-based hybrid platforms for tumor imaging and therapy.

The aim of this original review is to highlight and analyze the most recent progress and challenges in the synthesis and surface modifications of superparamagnetic iron oxide (Fe3O4) nanoparticles (NPs) for multimodal imaging and therapy applications, which represent important fields in medicine in general and cancer in particular. Thus, the oncology domain is rapidly moving to a more personalized medicine including precision imaging and theranostic approaches. Novel biocompatible Fe3O4 nanoparticulate systems have been designed for enhanced and targeted cellular uptake by surface layer coating modifications, to have improved r2 relaxivity for sensitive magnetic resonance (MR) imaging applications, to have the ability to be used for dual mode imaging, and to be used for imaging-guided cancer therapy. In this review, we analyzed in depth the new strategies for generating biocompatible multifunctional Fe3O4 nanoplatforms for both the diagnosis and therapy of cancer.