Encapsulation of Gadolinium Oxide Nanoparticle (Gd₂O₃) Contrasting Agents in PAMAM Dendrimer Templates for Enhanced Magnetic Resonance Imaging <i>in Vivo</i>

There has been growing interest in the research of nanomaterials for biomedical applications in recent decades. Herein, a simple approach to synthesize the G4.5-Gd₂O₃-poly­(ethylene glycol) (G4.5-Gd₂O₃-PEG) nanoparticles (NPs) that demonstrate potential as dual (<i>T</i>₁ and <i>T</i>₂) contrasting agents in magnetic resonance imaging (MRI) has been reported in this study. Compared to the clinically popular Gd-DTPA contrasting agents, G4.5-Gd₂O₃-PEG NPs exhibited a longer longitudinal relaxation time (<i>T</i>₁) and better biocompatibility when incubated with macrophage cell line RAW264.7 <i>in vitro</i>. Furthermore, the longitudinal relaxivity (<i>r</i>₁) of G4.5-Gd₂O₃-PEG NPs was 53.9 s^–1 mM^–1 at 7T, which is equivalent to 4.8 times greater than to the Gd-DTPA contrasting agents. An <i>in vivo</i> <i>T</i>₁-weighted MRI results revealed that G4.5-Gd₂O₃-PEG NPs significantly enhanced signals in the intestines, kidney, liver, bladder, and spleen. In addition, the <i>T</i>₂-weighted MRI results revealed darker contrast in the kidney, which proves that G4.5-Gd₂O₃-PEG NPs can be exploited as <i>T</i>₁ and <i>T</i>₂ contrasting agents. In summary, these findings suggest that the G4.5-Gd₂O₃-PEG NPs synthesized by an alternative approach can be used as dual MRI contrasting agents

MoS₂–Gd Chelate Magnetic Nanomaterials with Core–Shell Structure Used as Contrast Agents in <i>in Vivo</i> Magnetic Resonance Imaging

Despite their frequent usages as contrast agents for <i>in vivo</i> MRI imaging, paramagnetic molecules continue to suffer from low resolution, physicochemical instability, and high toxicity. Herein, we present a molybdenum disulfide and gadolinium complex, as an alternative core–shell magnetic nanomaterial that exhibits enhanced paramagnetic property; 4.5-times longer water proton spin–lattice relaxation time (<i>T</i>₁) when compared to commercial gadolinium contrast agents; as well as lowered toxicity, extended blood circulation time, increased stability, and desirable excretion characteristic. Transmission electron microscopy (TEM) revealed smooth core–shell nanoparticles 100 nm in size with a shell width of approximately 10 nm. These findings suggest that the synthesized nanomaterial possesses high potential as a positive contrast agent for the enhancement of MRI imaging

IL‑6 Antibody and RGD Peptide Conjugated Poly(amidoamine) Dendrimer for Targeted Drug Delivery of HeLa Cells

In this study, PAMAM dendrimer (G4.5) was conjugated with two targeting moieties, IL-6 antibody and RGD peptide (G4.5-IL6 and G4.5-RGD conjugates). Doxorubicin anticancer drug was physically loaded onto G4.5-IL6 and G4.5-RGD with the encapsulation efficiency of 51.3 and 30.1% respectively. The cellular internalization and uptake efficiency of G4.5-IL6/DOX and G4.5-RGD/DOX complexes was observed and compared by confocal microscopy and flow cytometry using HeLa cells, respectively. The lower IC₅₀ value of G4.5-IL6/DOX in comparison to G4.5-RGD/DOX is indication that higher drug loading and faster drug release rate corresponded with greater cytotoxicity. The cytotoxic effect was further verified by increment in late apoptotic/necrotic cells due to delivery of drug through receptor-mediated endocytosis. On the basis of these results, G4.5-IL6 is a better suited carrier for targeted drug delivery of DOX to cervical cancer cells

Bioinspired, Manganese-Chelated Alginate–Polydopamine Nanomaterials for Efficient in Vivo <i>T</i>₁‑Weighted Magnetic Resonance Imaging

Manganese-based nanomaterials are an emerging new class of magnetic resonance imaging (MRI) contrast agents (CAs) that provide impressive contrast abilities. MRI CAs that can respond to pathophysiological parameters such as pH or redox potential are also highly in demand for MRI-guided tumor diagnosis. Until now, synthesizing nanomaterials with good biocompatibility, physiochemical stability, and good contrast effects remains a challenge. This study investigated two new systems of calcium/manganese cations complexed with either alginate–polydopamine or alginate–dopamine nanogels [AlgPDA­(Ca/Mn) NG or AlgDA­(Ca/Mn) NG]. Under such systems, Ca cations form ionic interactions via carboxylic acids of the Alg backbone to enhance the stability of the synthetic nanogels (NGs). Likewise, complexation of Mn cations also increased the colloidal stability of the synthetic NGs. The magnetic property of the prepared CAs was confirmed with superconducting quantum interference device measurements, proving the potential paramagnetic property. Hence, the <i>T</i>₁ relaxivity measurement showed that PDA-complexed synthetic NGs reveal a strong positive contrast enhancement with <i>r</i>₁ = 12.54 mM^–1·s^–1 in 7.0 T MRI images, whereas DA-complexed synthetic NGs showed a relatively lower <i>T</i>₁ relaxivity effect with <i>r</i>₁ = 10.13 mM^–1·s^–1. In addition, both the synthetic NGs exhibit negligible cytotoxicity with >92% cell viability up to 0.25 mM concentration, when incubated with the mouse macrophage (RAW 264.7) and HeLa cells, and high biocompatibility under in vivo analysis. The in vivo MRI test indicates that the synthetic NG exhibits a high signal-to-noise ratio for longer hours, which provides a longer image acquisition time for tumor and anatomical imaging. Furthermore, <i>T</i>₁-weighted MRI results revealed that PEGylated AlgPDA­(Ca/Mn) NGs significantly enhanced the signals from liver and tumor tissues. Therefore, owing to the enhanced permeability and retention effect, significantly enhanced in vitro and in vivo imagings, low cost, and one-pot synthesis method, the Mn-based biomimetic approach used in this study provides a promising and competitive alternative for noninvasive tumor detection and comprehensive anatomical diagnosis

Sterically Polymer-Based Liposomal Complexes with Dual-Shell Structure for Enhancing the siRNA Delivery

The sterically polymer-based liposomal complexes (SPLexes) were formed by cationic polymeric liposomes and pH-sensitive diblock copolymer were studied for their capabilities in improving the stability with high efficiency of siRNA delivery. The SPLexes were formed a dual-shelled structure and uniform size distribution. The PEGylated outer shell could mitigate the phagocytosis and reduce the cytotoxicity. Moreover, the folated SPLexes improved 42.9× accumulation in vitro and 1.7× tumor uptake in vivo in contrast with nonfolated SPLexes. The protonated copolymer at low pH would improve the siRNA released into cytoplasm following SPLexes fusion with the endo/lysosome membrane and inhibited the protein expression to 75.6 ± 4.5% efficiently. Results of this study significantly contribute to efforts to develop lipoplexes based siRNA delivery systems

Thermosensitive Hydrogel from Oligopeptide-Containing Amphiphilic Block Copolymer: Effect of Peptide Functional Group on Self-Assembly and Gelation Behavior

We reveal that a slight change in the functional group of the oligopeptide block incorporated into the poloxamer led to drastically different hierarchical assembly behavior and rheological properties in aqueous media. An oligo­(l-Ala-<i>co</i>-l-Phe-<i>co</i>-β-benzyl l-Asp)-poloxamer-oligo­(β-benzyl-l-Asp-<i>co</i>-l-Phe-<i>co</i>-l-Ala) block copolymer (OAF-(OAsp­(Bzyl))-PLX-(OAsp­(Bzyl))-OAF, denoted as polymer 1), which possessed benzyl group on the aspartate moiety of the peptide block, was synthesized through ring-opening polymerization. The benzyl group on aspartate was then converted to carboxylic acid to yield oligo­(l-Ala-<i>co</i>-l-Phe-<i>co</i>-l-Asp)-poloxamer-oligo­(l-Asp-<i>co</i>-l-Phe-<i>co</i>-l-Ala) (OAF-(OAsp)-PLX-(OAsp)-OAF, denoted as polymer 2). Characterization of the peptide secondary structure in aqueous media by circular dichroism revealed that the oligopeptide block in polymer 1 exhibited mainly an α-helix conformation, whereas that in polymer 2 adopted predominantly a β-sheet conformation at room temperature. The segmental dynamics of the PEG in polymer 1 remained essentially unperturbed upon heating from 10 to 50 °C; by contrast, the PEG segmental motion in polymer 2 became more constrained above ca. 35 °C, indicating an obvious change in the chemical environment of the block chains. Meanwhile, the storage modulus of the polymer 2 solution underwent an abrupt increase across this temperature, and the solution turned into a gel. Wet-cell TEM observation revealed that polymer 1 self-organized to form microgel particles of several hundred nanometers in size. The microgel particle was retained as the characteristic morphological entity such that the PEG chains did not experience a significant change of their chemical environment upon heating. The hydrogel formed by polymer 2 was found to contain networks of nanofibrils, suggesting that the hydrogen bonding between the carboxylic acid groups led to an extensive stacking of the β sheets along the fibril axis at elevated temperature. The in vitro cytotoxicity of the polymer 2 aqueous solution was found to be low in human retinal pigment epithelial cells. The low cytotoxicity coupled with the sol–gel transition makes the corresponding hydrogel a good candidate for biomedical applications

Thermosensitive Hydrogel from Oligopeptide-Containing Amphiphilic Block Copolymer: Effect of Peptide Functional Group on Self-Assembly and Gelation Behavior

We reveal that a slight change in the functional group of the oligopeptide block incorporated into the poloxamer led to drastically different hierarchical assembly behavior and rheological properties in aqueous media. An oligo­(l-Ala-<i>co</i>-l-Phe-<i>co</i>-β-benzyl l-Asp)-poloxamer-oligo­(β-benzyl-l-Asp-<i>co</i>-l-Phe-<i>co</i>-l-Ala) block copolymer (OAF-(OAsp­(Bzyl))-PLX-(OAsp­(Bzyl))-OAF, denoted as polymer 1), which possessed benzyl group on the aspartate moiety of the peptide block, was synthesized through ring-opening polymerization. The benzyl group on aspartate was then converted to carboxylic acid to yield oligo­(l-Ala-<i>co</i>-l-Phe-<i>co</i>-l-Asp)-poloxamer-oligo­(l-Asp-<i>co</i>-l-Phe-<i>co</i>-l-Ala) (OAF-(OAsp)-PLX-(OAsp)-OAF, denoted as polymer 2). Characterization of the peptide secondary structure in aqueous media by circular dichroism revealed that the oligopeptide block in polymer 1 exhibited mainly an α-helix conformation, whereas that in polymer 2 adopted predominantly a β-sheet conformation at room temperature. The segmental dynamics of the PEG in polymer 1 remained essentially unperturbed upon heating from 10 to 50 °C; by contrast, the PEG segmental motion in polymer 2 became more constrained above ca. 35 °C, indicating an obvious change in the chemical environment of the block chains. Meanwhile, the storage modulus of the polymer 2 solution underwent an abrupt increase across this temperature, and the solution turned into a gel. Wet-cell TEM observation revealed that polymer 1 self-organized to form microgel particles of several hundred nanometers in size. The microgel particle was retained as the characteristic morphological entity such that the PEG chains did not experience a significant change of their chemical environment upon heating. The hydrogel formed by polymer 2 was found to contain networks of nanofibrils, suggesting that the hydrogen bonding between the carboxylic acid groups led to an extensive stacking of the β sheets along the fibril axis at elevated temperature. The in vitro cytotoxicity of the polymer 2 aqueous solution was found to be low in human retinal pigment epithelial cells. The low cytotoxicity coupled with the sol–gel transition makes the corresponding hydrogel a good candidate for biomedical applications

Thermosensitive Hydrogel from Oligopeptide-Containing Amphiphilic Block Copolymer: Effect of Peptide Functional Group on Self-Assembly and Gelation Behavior

We reveal that a slight change in the functional group of the oligopeptide block incorporated into the poloxamer led to drastically different hierarchical assembly behavior and rheological properties in aqueous media. An oligo­(l-Ala-<i>co</i>-l-Phe-<i>co</i>-β-benzyl l-Asp)-poloxamer-oligo­(β-benzyl-l-Asp-<i>co</i>-l-Phe-<i>co</i>-l-Ala) block copolymer (OAF-(OAsp­(Bzyl))-PLX-(OAsp­(Bzyl))-OAF, denoted as polymer 1), which possessed benzyl group on the aspartate moiety of the peptide block, was synthesized through ring-opening polymerization. The benzyl group on aspartate was then converted to carboxylic acid to yield oligo­(l-Ala-<i>co</i>-l-Phe-<i>co</i>-l-Asp)-poloxamer-oligo­(l-Asp-<i>co</i>-l-Phe-<i>co</i>-l-Ala) (OAF-(OAsp)-PLX-(OAsp)-OAF, denoted as polymer 2). Characterization of the peptide secondary structure in aqueous media by circular dichroism revealed that the oligopeptide block in polymer 1 exhibited mainly an α-helix conformation, whereas that in polymer 2 adopted predominantly a β-sheet conformation at room temperature. The segmental dynamics of the PEG in polymer 1 remained essentially unperturbed upon heating from 10 to 50 °C; by contrast, the PEG segmental motion in polymer 2 became more constrained above ca. 35 °C, indicating an obvious change in the chemical environment of the block chains. Meanwhile, the storage modulus of the polymer 2 solution underwent an abrupt increase across this temperature, and the solution turned into a gel. Wet-cell TEM observation revealed that polymer 1 self-organized to form microgel particles of several hundred nanometers in size. The microgel particle was retained as the characteristic morphological entity such that the PEG chains did not experience a significant change of their chemical environment upon heating. The hydrogel formed by polymer 2 was found to contain networks of nanofibrils, suggesting that the hydrogen bonding between the carboxylic acid groups led to an extensive stacking of the β sheets along the fibril axis at elevated temperature. The in vitro cytotoxicity of the polymer 2 aqueous solution was found to be low in human retinal pigment epithelial cells. The low cytotoxicity coupled with the sol–gel transition makes the corresponding hydrogel a good candidate for biomedical applications