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We present the MR properties of a novel bio-responsive phosphorus probe doped with iron for dual proton and phosphorus magnetic resonance imaging ( 1 H/ 31 P-MRI), which provide simultaneously complementary information. The probes consist of non-toxic biodegradable calcium phytate (CaIP 6 ) nanoparticles doped with different amounts of cleavable paramagnetic Fe 3+ ions. Phosphorus atoms in the phytate structure delivered an efficient 31 P-MR signal, with iron ions altering MR contrast for both 1 H and 31 P-MR. The coordinated paramagnetic Fe 3+ ions broadened the 31 P-MR signal spectral line due to the short T 2 relaxation time, resulting in more hypointense signal. However, when Fe 3+ was decomplexed from the probe, relaxation times were prolonged. As a result of iron release, intensity of 1 H-MR, as well as the 31 P-MR signal increase. These 1 H and 31 P-MR dual signals triggered by iron decomplexation may have been attributable to biochemical changes in the environment with strong iron chelators, such as bacterial siderophore (deferoxamine). Analysing MR signal alternations as a proof-of-principle on a phantom at a 4.7 T magnetic field, we found that iron presence influenced 1 H and 31 P signals and signal recovery via iron chelation using deferoxamine.

In this work, we present the synthesis and evaluation of magnetic resonance (MR) properties of novel phosphorus/iron-containing probes for dual 31 P and 1 H MR imaging and spectroscopy (MRI and MRS). The presented probes are composed of biocompatible semitelechelic and multivalent phospho-polymers based on poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC) coordinated with small paramagnetic Fe 3+ ions or superparamagnetic maghemite ( γ -Fe 2 O 3 ) nanoparticles via deferoxamine group linked to the end or along the polymer chains. All probes provided very short 1 H T 1 and T 2 relaxation times even at low iron concentrations. The presence of iron had a significant impact on the shortening of 31 P relaxation, with the effect being more pronounced for probes based on γ -Fe 2 O 3 and multivalent polymer. While the water-soluble probe having one Fe 3+ ion per polymer chain was satisfactorily visualized by both 31 P-MRS and 31 P-MRI, the probe with multiple Fe 3+ ions could only be detected by 31 P-MRS, and the probes consisting of γ -Fe 2 O 3 nanoparticles could not be imaged by either technique due to their ultra-short 31 P relaxations. In this proof-of-principle study performed on phantoms at a clinically relevant magnetic fields, we demonstrated how the different forms and concentrations of iron affect both the 1 H MR signal of the surrounding water molecules and the 31 P MR signal of the phospho-polymer probe. Thus, this double contrast can be exploited to simultaneously visualize body anatomy and monitor probe biodistribution.

The visualization of organs and tissues using 31P magnetic resonance (MR) imaging represents an immense challenge. This is largely due to the lack of sensitive biocompatible probes required to deliver a high-intensity MR signal that can be distinguished from the natural biological background. Synthetic water-soluble phosphorus-containing polymers appear to be suitable materials for this purpose due to their adjustable chain architecture, low toxicity, and favorable pharmacokinetics. In this work, we carried out a controlled synthesis, and compared the MR properties, of several probes consisting of highly hydrophilic phosphopolymers differing in composition, structure, and molecular weight. Based on our phantom experiments, all probes with a molecular weight of ~3–400 kg·mol−1, including linear polymers based on poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), poly(ethyl ethylenephosphate) (PEEP), and poly[bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)]phosphazene (PMEEEP) as well as star-shaped copolymers composed of PMPC arms grafted onto poly(amidoamine) dendrimer (PAMAM-g-PMPC) or cyclotriphosphazene-derived cores (CTP-g-PMPC), were readily detected using a 4.7 T MR scanner. The highest signal-to-noise ratio was achieved by the linear polymers PMPC (210) and PMEEEP (62) followed by the star polymers CTP-g-PMPC (56) and PAMAM-g-PMPC (44). The 31P T1 and T2 relaxation times for these phosphopolymers were also favorable, ranging between 1078 and 2368 and 30 and 171 ms, respectively. We contend that select phosphopolymers are suitable for use as sensitive 31P MR probes for biomedical applications.

Peptide immunogens provide an approach to focus antibody responses to specific neutralizing sites on the HIV envelope protein (Env) trimer or on other pathogens. However, the physical characteristics of peptide immunogens can limit their pharmacokinetic and immunological properties. Here, we have designed synthetic \"star\" nanoparticles based on biocompatible N-[(2-hydroxypropyl)methacrylamide] (HPMA)-based polymer arms extending from a poly(amidoamine) (PAMAM) dendrimer core. In mice, these star nanoparticles trafficked to lymph nodes (LNs) by 4 hours following vaccination, where they were taken up by subcapsular macrophages and then resident dendritic cells (DCs). Immunogenicity optimization studies revealed a correlation of immunogen density with antibody titers. Furthermore, the co-delivery of Env variable loop 3 (V3) and T-helper peptides induced titers that were 2 logs higher than if the peptides were given in separate nanoparticles. Finally, we performed a nonhuman primate (NHP) study using a V3 glycopeptide minimal immunogen that was structurally optimized to be recognized by Env V3/glycan broadly neutralizing antibodies (bnAbs). When administered with a potent Toll-like receptor (TLR) 7/8 agonist adjuvant, these nanoparticles elicited high antibody binding titers to the V3 site. Similar to human V3/glycan bnAbs, certain monoclonal antibodies (mAbs) elicited by this vaccine were glycan dependent or targeted the GDIR peptide motif. To improve affinity to native Env trimer affinity, nonhuman primates (NHPs) were boosted with various SOSIP Env proteins; however, significant neutralization was not observed. Taken together, this study provides a new vaccine platform for administration of glycopeptide immunogens for focusing immune responses to specific bnAb epitopes.

Biocompatible metal-free agents are emerging as a promising alternative to commercial magnetic resonance (MR) contrast agents, but there is an additional need for novel probes with enhanced responsiveness in preclinical MR testing to effectively target diverse pathological conditions. To address this, we develop hydrophilic phospho-/fluoropolymers as dual MR probes. Incorporating thiophosphoester groups (P = S) into the polymer structure produces a distinct chemical shift (~59 ppm) in phosphorus MR (31P-MR), reducing biological signals interference. Reactive oxygen species (ROS) oxidize the P = S groups, causing a detectable shift in 31P-MR, enabling precise localization of ROS, abundant in inflammation and cancer. To enhance this capability, bioinert trifluoromethyl groups (CF3) are added, creating a “hotspot” for fluorine MR (19F-MR), aiding in vivo localization. Both in vitro and in vivo testing demonstrate the probe’s high specificity and responsiveness, underscoring its potential as a sensitive ROS sensor and dual MR-traceable tool in cancer research.Magnetic resonance imaging lack biocompatible metal-free contrast agents with specific functionality. Here, hydrophilic phospho-/fluoropolymers are developed as 31P/ 19 F-MR probes for in vivo detection of reactive oxygen species.

Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide–TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens ( n  = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity. Cancer vaccines that self-assemble into uniform nanoparticles improve tumor clearance.

Vaccine efficacy is enhanced by optimizing the design of polymeric particles for adjuvant and antigen delivery. The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer–TLR-7/8a) and evaluated how different physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo . Particle formation by polymer–TLR-7/8a was the most important factor for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer–TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular approach in which protein antigens are site-specifically linked to temperature-responsive polymer–TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo . Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.

The visualization of organs and tissues using [sup.31]P magnetic resonance (MR) imaging represents an immense challenge. This is largely due to the lack of sensitive biocompatible probes required to deliver a high-intensity MR signal that can be distinguished from the natural biological background. Synthetic water-soluble phosphorus-containing polymers appear to be suitable materials for this purpose due to their adjustable chain architecture, low toxicity, and favorable pharmacokinetics. In this work, we carried out a controlled synthesis, and compared the MR properties, of several probes consisting of highly hydrophilic phosphopolymers differing in composition, structure, and molecular weight. Based on our phantom experiments, all probes with a molecular weight of ~3–400 kg·mol[sup.−1], including linear polymers based on poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), poly(ethyl ethylenephosphate) (PEEP), and poly[bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)]phosphazene (PMEEEP) as well as star-shaped copolymers composed of PMPC arms grafted onto poly(amidoamine) dendrimer (PAMAM-g-PMPC) or cyclotriphosphazene-derived cores (CTP-g-PMPC), were readily detected using a 4.7 T MR scanner. The highest signal-to-noise ratio was achieved by the linear polymers PMPC (210) and PMEEEP (62) followed by the star polymers CTP-g-PMPC (56) and PAMAM-g-PMPC (44). The [sup.31]P T[sub.1] and T[sub.2] relaxation times for these phosphopolymers were also favorable, ranging between 1078 and 2368 and 30 and 171 ms, respectively. We contend that select phosphopolymers are suitable for use as sensitive [sup.31]P MR probes for biomedical applications.

Teicoplanin is a natural lipoglycopeptide antibiotic with a similar activity spectrum as vancomycin; however, it has with the added benefit to the patient of low cytotoxicity. Both teicoplanin and vancomycin antibiotics are actively used in medical practice in the prophylaxis and treatment of severe life-threatening infections caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, Enterococcus faecium and Clostridium difficile. The expression of vancomycin Z (vanZ), encoded either in the vancomycin A (vanA) glycopeptide antibiotic resistance gene cluster or in the genomes of E. faecium, as well as Streptococcus pneumoniae and C. difficile, was shown to specifically compromise the antibiotic efficiency through the inhibition of teicoplanin binding to the bacterial surface. However, the exact mechanisms of this action and protein structure remain unknown. In this study, the three-dimensional structure of VanZ from E. faecium EnGen0191 was predicted by using the I-TASSER web server. Based on the VanZ structure, a benzimidazole based ligand was predicted to bind to the VanZ by molecular docking. Importantly, this new ligand, named G3K, was further confirmed to specifically inhibit VanZ-mediated resistance to teicoplanin in vivo.

We present the MR properties of a novel bio-responsive phosphorus probe doped with iron for dual proton and phosphorus magnetic resonance imaging ( H/ P-MRI), which provide simultaneously complementary information. The probes consist of non-toxic biodegradable calcium phytate (CaIP ) nanoparticles doped with different amounts of cleavable paramagnetic Fe ions. Phosphorus atoms in the phytate structure delivered an efficient P-MR signal, with iron ions altering MR contrast for both H and P-MR. The coordinated paramagnetic Fe ions broadened the P-MR signal spectral line due to the short T relaxation time, resulting in more hypointense signal. However, when Fe was decomplexed from the probe, relaxation times were prolonged. As a result of iron release, intensity of H-MR, as well as the P-MR signal increase. These H and P-MR dual signals triggered by iron decomplexation may have been attributable to biochemical changes in the environment with strong iron chelators, such as bacterial siderophore (deferoxamine). Analysing MR signal alternations as a proof-of-principle on a phantom at a 4.7 T magnetic field, we found that iron presence influenced H and P signals and signal recovery via iron chelation using deferoxamine.