Cell-Penetrating and Enzyme-Responsive Peptides for Targeted Cancer Therapy: Role of Arginine Residue Length on Cell Penetration and In Vivo Systemic Toxicity.

For the improved delivery of cancer therapeutics and imaging agents, the conjugation of cell-penetrating peptides (CPPs) increases the cellular uptake and water solubility of agents. Among the various CPPs, arginine-rich peptides have been the most widely used. Combining CPPs with enzyme-responsive peptides presents an innovative strategy to target specific intracellular enzymes in cancer cells and when combined with the appropriate click chemistry can enhance theranostic drug delivery through the formation of intracellular self-assembled nanostructures. However, one drawback of CPPs is their high positive charge which can cause nonspecific binding, leading to off-target accumulation and potential toxicity. Hence, balancing cell-specific penetration, toxicity, and biocompatibility is essential for future clinical efficacy. We synthesized six cancer-specific, legumain-responsive RnAANCK peptides containing one to six arginine residues, with legumain being an asparaginyl endopeptidase that is overexpressed in aggressive prostate tumors. When conjugated to Alexa Fluor 488, R1-R6AANCK peptides exhibited a concentration- and time-dependent cell penetration in prostate cancer cells, which was higher for peptides with higher R values, reaching a plateau after approximately 120 min. Highly aggressive DU145 prostate tumor cells, but not less aggressive LNCaP cells, self-assembled nanoparticles in the cytosol after the cleavage of the legumain-specific peptide. The in vivo biocompatibility was assessed in mice after the intravenous injection of R1-R6AANCK peptides, with concentrations ranging from 0.0125 to 0.4 mmol/kg. The higher arginine content in R4-6 peptides showed blood and urine indicators for the impairment of bone marrow, liver, and kidney function in a dose-dependent manner, with instant hemolysis and morbidity in extreme cases. These findings underscore the importance of designing peptides with the optimal arginine residue length for a proper balance of cell-specific penetration, toxicity, and in vivo biocompatibility.

A Smart Intracellular Self-Assembling Bioorthogonal Raman Active Nanoprobe for Targeted Tumor Imaging.

Inspired by the principle of in situ self-assembly, the development of enzyme-activated molecular nanoprobes can have a profound impact on targeted tumor detection. However, despite their intrinsic promise, obtaining an optical readout of enzyme activity with high specificity in native milieu has proven to be challenging. Here, a fundamentally new class of Raman-active self-assembling bioorthogonal enzyme recognition (nanoSABER) probes for targeted tumor imaging is reported. This class of Raman probes presents narrow spectral bands reflecting their vibrational fingerprints and offers an attractive solution for optical imaging at different bio-organization levels. The optical beacon harnesses an enzyme-responsive peptide sequence, unique tumor-penetrating properties, and vibrational tags with stretching frequencies in the cell-silent Raman window. The design of nanoSABER is tailored and engineered to transform into a supramolecular structure exhibiting distinct vibrational signatures in presence of target enzyme, creating a direct causality between enzyme activity and Raman signal. Through the integration of substrate-specific for tumor-associated enzyme legumain, unique capabilities of nanoSABER for imaging enzyme activity at molecular, cellular, and tissue levels in combination with machine learning models are shown. These results demonstrate that the nanoSABER probe may serve as a versatile platform for Raman-based recognition of tumor aggressiveness, drug accumulation, and therapeutic response.

Clinicoradiological outcomes after radical radiotherapy for lung cancer in patients with interstitial lung disease.

Objective: Interstitial lung disease (ILD) is relatively common in patients with lung cancer with an incidence of 7.5%. Historically pre-existing ILD was a contraindication to radical radiotherapy owing to increased radiation pneumonitis rates, worsened fibrosis and poorer survival compared with non-ILD cohorts. Herein, the clinical and radiological toxicity outcomes of a contemporaneous cohort are described. Methods: Patients with ILD treated with radical radiotherapy for lung cancer at a regional cancer centre were collected prospectively. Radiotherapy planning, tumour characteristics, and pre- and post-treatment functional and radiological parameters were recorded. Cross-sectional images were independently assessed by two Consultant Thoracic Radiologists. Results: Twenty-seven patients with co-existing ILD received radical radiotherapy from February 2009 to April 2019, with predominance of usual interstitial pneumonia subtype (52%). According to ILD-GAP scores, most patients were Stage I. After radiotherapy, localised (41%) or extensive (41%) progressive interstitial changes were noted for most patients yet dyspnoea scores (n = 15 available) and spirometry (n = 10 available) were stable. One-third of patients with ILD went on to receive long-term oxygen therapy, which was significantly more than the non-ILD cohort. Median survival trended towards being worse compared with non-ILD cases (17.8 vs 24.0 months, p = 0.834). Conclusion: Radiological progression of ILD and reduced survival were observed post-radiotherapy in this small cohort receiving lung cancer radiotherapy, although a matched functional decline was frequently absent. Although there is an excess of early deaths, long-term disease control is achievable. Advances in knowledge: For selected patients with ILD, long-term lung cancer control without severely impacting respiratory function may be possible with radical radiotherapy, albeit with a slightly higher risk of death.

PET/MRI and Bioluminescent Imaging Identify Hypoxia as a Cause of Programmed Cell Death Ligand 1 Image Heterogeneity.

Purpose To examine the association between hypoxia and programmed cell death ligand 1 (PD-L1) expression using bioluminescence imaging (BLI) and PET/MRI in a syngeneic mouse model of triple-negative breast cancer (TNBC). Materials and Methods PET/MRI and optical imaging were used to determine the role of hypoxia in altering PD-L1 expression using a syngeneic TNBC model engineered to express luciferase under hypoxia. Results Imaging showed a close spatial association between areas of hypoxia and increased PD-L1 expression in the syngeneic murine (4T1) tumor model. Mouse and human TNBC cells exposed to hypoxia exhibited a significant increase in PD-L1 expression, consistent with the in vivo imaging data. The role of hypoxia in increasing PD-L1 expression was further confirmed by using The Cancer Genome Atlas analyses of different human TNBCs. Conclusion These results have identified the potential role of hypoxia in contributing to PD-L1 heterogeneity in tumors by increasing cancer cell PD-L1 expression. Keywords: Hypoxia, PD-L1, Triple-Negative Breast Cancer, PET/MRI, Bioluminescence Imaging Supplemental material is available for this article. © RSNA, 2023.

Acyl Hydrazides and Acyl Hydrazones as High-Performance Chemical Exchange Saturation Transfer MRI Contrast Agents.

Chemical exchange saturation transfer (CEST) MRI is a versatile molecular imaging approach that holds great promise for clinical translation. A number of compounds have been identified as suitable for performing CEST MRI, including paramagnetic CEST (paraCEST) agents and diamagnetic CEST (diaCEST) agents. DiaCEST agents are very attractive because of their excellent biocompatibility and potential for biodegradation, such as glucose, glycogen, glutamate, creatine, nucleic acids, et al. However, the sensitivity of most diaCEST agents is limited because of small chemical shifts (1.0-4.0 ppm) from water. To expand the catalog of diaCEST agents with larger chemical shifts, herein, we have systematically investigated the CEST properties of acyl hydrazides with different substitutions, including aromatic and aliphatic substituents. We have tuned the labile proton chemical shifts from 2.8-5.0 ppm from water while exchange rates varied from ~680 to 2340 s-1 at pH 7.2, which allows strong CEST contrast on scanners down to B0 = 3 T. One acyl hydrazide, adipic acid dihydrazide (ADH), was tested on a mouse model of breast cancer and showed nice contrast in the tumor region. We also prepared a derivative, acyl hydrazone, which showed the furthest shifted labile proton (6.4 ppm from water) and excellent contrast properties. Overall, our study expands the catalog of diaCEST agents and their application in cancer diagnosis.

Exploring the potential of the novel imidazole-4,5-dicarboxyamide chemical exchange saturation transfer scaffold for pH and perfusion imaging.

Here, we describe and assess the potential of 14 newly synthesized imidazole-4,5-dicarboxyamides (I45DCs) for pH and perfusion imaging. A number of these aromatic compounds possess large labile proton chemical shifts (up to 7.7 ppm from water) because of their intramolecular hydrogen bonds and a second labile proton to allow for chemical exchange saturation transfer (CEST) signal ratio-based pH measurements. We have found that the contrast produced is strong for a wide range of substitutions and that the inflection points in the CEST signal ratio versus pH plots used to generate concentration-independent pH maps can be adjusted based on these subsitutions to tune the pH range that can be measured. These I45DC CEST agents have advantages over the triiodobenzenes currently employed for tumor and kidney pH mapping, both preclinically and in initial human studies. Finally, as CEST MRI combined with exogenous contrast has the potential to detect functional changes in the kidneys, we evaluated our highest performing anionic compound (I45DC-diGlu) on a unilateral urinary obstruction mouse model and observed lower contrast uptake in the obstructed kidney compared with the unobstructed kidney and that the unobstructed kidney displayed a pH of ~ 6.5 while the obstructed kidney had elevated pH and an increased range in pH values. Based on this, we conclude that the I45DCs have excellent imaging properties and hold promise for a variety of medical imaging applications, particularly renal imaging.

Protein and peptide engineering for chemical exchange saturation transfer imaging in the age of synthetic biology.

At the beginning of the millennium, the first chemical exchange saturation transfer (CEST) contrast agents were bio-organic molecules. However, later, metal-based CEST agents (paraCEST agents) took center stage. This did not last too long as paraCEST agents showed limited translational potential. By contrast, the CEST field gradually became dominated by metal-free CEST agents. One branch of research stemming from the original work by van Zijl and colleagues is the development of CEST agents based on polypeptides. Indeed, in the last 2 decades, tremendous progress has been achieved in this field. This includes the design of novel peptides as biosensors, genetically encoded recombinant as well as synthetic reporters. This was a result of extensive characterization and elucidation of the theoretical requirements for rational designing and engineering of such agents. Here, we provide an extensive overview of the evolution of more precise protein-based CEST agents, review the rationalization of enzyme-substrate pairs as CEST contrast enhancers, discuss the theoretical considerations to improve peptide selectivity, specificity and enhance CEST contrast. Moreover, we discuss the strong influence of synthetic biology on the development of the next generation of protein-based CEST contrast agents.

Unlabeled aspirin as an activatable theranostic MRI agent for breast cancer.

Rationale: Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is emerging as an alternative to gadolinium-based contrast MRI. We have evaluated the possibility of CEST MRI of orthotopic breast tumor xenografts with unlabeled aspirin's conversion to salicylic acid (SA) through various enzymatic activities, most notably inhibition of cyclooxygenase (COX)-1/-2 enzymes. Methods: We measured the COX-1/-2 expression in four breast cancer cell lines by Western Blot analysis and selected the highest and lowest expressing cell lines. We then performed CEST MRI following aspirin treatment to detect SA levels and ELISA to measure levels of downstream prostaglandin E2 (PGE2). We also injected aspirin into the tail vein of mice growing orthotopic tumor xenografts which expressed high and low COX-1/-2 and acquired SA CEST MR images of these tumor xenografts for up to 70 minutes. Tumors were then harvested to perform Western Blot and ELISA experiments to measure COX-1/-2 expression and PGE2 levels, respectively. Results: Western Blots determined that SUM159 cells contained significantly higher COX-1/-2 expression levels than MDA-MB-231 cells, in line with higher levels of downstream PGE2. SA CEST MRI yielded similar contrast at approximately 3% for both cell lines, independent of COX-1/-2 expression level. PGE2 levels decreased by about 50% following aspirin treatment. Results from our mouse study aligned with cultured cells, the overall SA CEST MRI contrast in both MDA-MB-231 and SUM159 tumor xenograft models was 5~8% at one hour post injection. PGE2 levels were ten times higher in SUM159 than MDA-MB-231 and decreased by 50%. The CEST contrast directly depended on the injected dose, with ~6%, ~3% and ~1.5% contrast observed following injection of 100 µL of 300 mM, 200 mM and 150 mM aspirin, respectively. Conclusions: Our data demonstrate the feasibility of using aspirin as a noninvasive activatable CEST MRI contrast agent for breast tumor detection.

Dynamic Contrast Enhanced-MR CEST Urography: An Emerging Tool in the Diagnosis and Management of Upper Urinary Tract Obstruction.

Upper urinary tract obstructions (UTOs) are blockages that inhibit the flow of urine through its normal course, leading to impaired kidney function. Imaging plays a significant role in the initial diagnosis of UTO, with anatomic imaging (primarily ultrasound (US) and non-contrast computed tomography (CT)) serving as screening tools for the detection of the dilation of the urinary collecting systems (i.e., hydronephrosis). Whether hydronephrosis represents UTO or a non-obstructive process is determined by functional imaging (typically nuclear medicine renal scintigraphy). If these exams reveal evidence of UTO but no discernable source, multiphase contrast enhanced CT urography and/or dynamic contrast enhanced MR urography (DCE-MRU) may be performed to delineate a cause. These are often performed in conjunction with direct ureteroscopic evaluation. While contrast-enhanced CT currently predominates, it can induce renal injury due to contrast induced nephropathy (CIN), subject patients to ionizing radiation and is limited in quantifying renal function (traditionally assessed by renal scintigraphy) and establishing the extent to which hydronephrosis is due to functional obstruction. Traditional MRI is similarly limited in its ability to quantify function. DCE-MRU presents concerns regarding nephrogenic systemic fibrosis (NSF), although decreased with newer gadolinium-based contrast agents, and regarding cumulative gadolinium deposition in the basal ganglia. DCE-MR CEST urography is a promising alternative, employing new MRI contrast agents and imaging schemes and allowing for concurrent assessment of renal anatomy and functional parameters. In this review we highlight clinical challenges in the diagnosis and management of UTO, identify key advances in imaging agents and techniques for DCE-MR CEST urography and provide perspective on how this technique may evolve in clinical importance.

Redesigned reporter gene for improved proton exchange-based molecular MRI contrast.

Reporter gene imaging allows for non-invasive monitoring of molecular processes in living cells, providing insights on the mechanisms underlying pathology and therapy. A lysine-rich protein (LRP) chemical exchange saturation transfer (CEST) MRI reporter gene has previously been developed and used to image tumor cells, cardiac viral gene transfer, and oncolytic virotherapy. However, the highly repetitive nature of the LRP reporter gene sequence leads to DNA recombination events and the expression of a range of truncated LRP protein fragments, thereby greatly limiting the CEST sensitivity. Here we report the use of a redesigned LRP reporter (rdLRP), aimed to provide excellent stability and CEST sensitivity. The rdLRP contains no DNA repeats or GC rich regions and 30% less positively charged amino-acids. RT-PCR of cell lysates transfected with rdLRP demonstrated a stable reporter gene with a single distinct band corresponding to full-length DNA. A distinct increase in CEST-MRI contrast was obtained in cell lysates of rdLRP transfected cells and in in vivo LRP expressing mouse brain tumors ([Formula: see text], n = 10).

Amplified detection of phosphocreatine and creatine after supplementation using CEST MRI at high and ultrahigh magnetic fields.

Creatine is an important metabolite involved in muscle contraction. Administration of exogenous creatine (Cr) or phosphocreatine (PCr) has been used for improving exercise performance and protecting the heart during surgery including during valve replacements, coronary artery bypass grafting and repair of congenital heart defects. In this work we investigate whether it is possible to use chemical exchange saturation transfer (CEST) MRI to monitor uptake and clearance of exogenous creatine and phosphocreatine following supplementation. We were furthermore interested in determining the limiting conditions for distinguishing between creatine (1.9 ppm) and phosphocreatine (2.6 ppm) signals at ultra-high fields (21 T) and determine their concentrations could be reliably obtained using Bloch equation fits of the experimental CEST spectra. We have tested these items by performing CEST MRI of hind limb muscle and kidneys at 11.7 T and 21.1 T both before and after intravenous administration of PCr. We observed up to 4% increase in contrast in the kidneys at 2.6 ppm which peaked ~30 min after administration and a relative ratio of 1.3 in PCr:Cr signal. Overall, these results demonstrate the feasibility of independent monitoring of PCr and Cr concentration changes using CEST MRI.

CT and CEST MRI bimodal imaging of the intratumoral distribution of iodinated liposomes.

BACKGROUND: To develop liposomes loaded with iodinated agents as nanosized CT/MRI bimodal contrast agents for monitoring liposome-mediated drug delivery. METHODS: Rhodamine-labeled iodixanol (VisipaqueTM)-loaded liposomes (IX-lipo) were prepared and tested for their properties as a diamagnetic CEST contrast agent in vitro. Mice bearing subcutaneous CT26 colon tumors were injected i.v. with 1 g/kg (535 mg iodine/kg) IX-lipo, and in vivo CT and CEST MR images were acquired on day 3. CT and CEST MR images were also acquired for tumor-bearing mice co-injected with IX-lipo and tumor necrosis factor (TNF-α). RESULTS: In addition to CT contrast, IX-lipo exhibited a strong CEST contrast similar to its non-liposomal form, with a detectability of ~2 nM per liposome. Both CT imaging and CEST MRI showed that i.v. injection of IX-lipo resulted in a rim enhancement of CT26 tumors with a heterogeneous central distribution. In contrast, co-injection of TNF-α caused a significantly augmented CT/MRI contrast in the tumor center. The intratumoral biodistribution of IX-lipo correlated well to the rhodamine patterns observed with fluorescence microscopy. CONCLUSIONS: We have developed a CT/MRI bimodal imaging approach for monitoring the delivery and biodistribution of liposomes by loading them with the clinically approved X-ray/CT contrast agent iodixanol. Our approach may be easily adapted for other-FDA approved iodinated agents and thus has great translational potential.

Furin-mediated intracellular self-assembly of olsalazine nanoparticles for enhanced magnetic resonance imaging and tumour therapy.

Among the strategies used for enhancement of tumour retention of imaging agents or anticancer drugs is the rational design of probes that undergo a tumour-specific enzymatic reaction preventing them from being pumped out of the cell. Here, the anticancer agent olsalazine (Olsa) was conjugated to the cell-penetrating peptide RVRR. Taking advantage of a biologically compatible condensation reaction, single Olsa-RVRR molecules were self-assembled into large intracellular nanoparticles by the tumour-associated enzyme furin. Both Olsa-RVRR and Olsa nanoparticles were readily detected with chemical exchange saturation transfer magnetic resonance imaging by virtue of exchangeable Olsa hydroxyl protons. In vivo studies using HCT116 and LoVo murine xenografts showed that the OlsaCEST signal and anti-tumour therapeutic effect were 6.5- and 5.2-fold increased, respectively, compared to Olsa without RVRR, with an excellent 'theranostic correlation' (R2 = 0.97) between the imaging signal and therapeutic response (normalized tumour size). This furin-targeted, magnetic resonance imaging-detectable platform has potential for imaging tumour aggressiveness, drug accumulation and therapeutic response.

A fluorinated aza-BODIPY derivative for NIR fluorescence/PA/19F MR tri-modality in vivo imaging.

A fluorinated aza-BODIPY derivative BDPF was developed as a small molecule contrast agent, which displayed highly efficient near infrared fluorescence/photoacoustic/19F MR tri-modality tumor imaging.

Free-base porphyrins as CEST MRI contrast agents with highly upfield shifted labile protons.

PURPOSE: CEST has become a preeminent technology for the rapid detection and grading of tumors, securing its widespread use in both laboratory and clinical research. However, many existing CEST MRI agents exhibit a sensitivity limitation due to small chemical shifts between their exchangeable protons and water. We propose a new group of CEST MRI agents, free-base porphyrins and chlorin, with large exchangeable proton chemical shifts from water for enhanced detection. METHODS: To test these newly identified CEST agents, we acquired a series of Z-spectra at multiple pH values and saturation field strengths to determine their CEST properties. The data were analyzed using the quantifying exchange using saturation power method to quantify exchange rates. After identifying several promising candidates, a porphyrin solution was injected into tumor-bearing mice, and MR images were acquired to assess detection feasibility in vivo. RESULTS: Based on the Z-spectra, the inner nitrogen protons in free-base porphyrins and chlorin resonate from -8 to -13.5 ppm from water, far shifted from the majority of endogenous metabolites (0-4 ppm) and Nuclear Overhauser enhancements (-1 to -3.5 ppm) and far removed from the salicylates, imidazoles, and anthranillates (5-12 ppm). The exchange rates are sufficiently slow to intermediate (500-9000 s-1 ) to allow robust detection and were sensitive to substituents on the porphyrin ring. CONCLUSION: These results highlight the capabilities of free-base porphyrins and chlorin as highly upfield CEST MRI agents and provide a new scaffold that can be integrated into a variety of diagnostic or theranostic agents for biomedical applications.

Constitutive androstane receptor 1 is constitutively bound to chromatin and 'primed' for transactivation in hepatocytes.

The constitutive androstane receptor (CAR) is a xenobiotic sensor expressed in hepatocytes that activates genes involved in drug metabolism, lipid homeostasis, and cell proliferation. Much progress has been made in understanding the mechanism of activation of human CAR by drugs and xenobiotics. However, many aspects of the activation pathway remain to be elucidated. In this report, we have used viral constructs to express human CAR, its splice variants, and mutant CAR forms in hepatocytes from Car-/- mice in vitro and in vivo. We demonstrate CAR expression rescued the ability of Car-/- hepatocytes to respond to a wide range of CAR activators including phenobarbital. Additionally, two major splice isoforms of human CAR, CAR2 and CAR3, were inactive with almost all the agents tested. In contrast to the current model of CAR activation, ectopic CAR1 is constitutively localized in the nucleus and is loaded onto Cyp2b10 gene in the absence of an inducing agent. In studies to elucidate the role of threonine T38 in CAR regulation, we found that the T38D mutant was inactive even in the presence of CAR activators. However, the T38A mutant was activated by CAR inducers, showing that T38 is not essential for CAR activation. Also, using the inhibitor erlotinib, we could not confirm a role for the epidermal growth factor receptor in CAR regulation. Our data suggest that CAR is constitutively bound to gene regulatory regions and is regulated by exogenous agents through a mechanism which involves protein phosphorylation in the nucleus.

Detection and differentiation of Cys, Hcy and GSH mixtures by 19F NMR probe.

Simultaneous detection and differentiation of biomolecules is of significance in biological research. Biothiols such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) play an important role in regulating the vital functions of living organisms. However, existing methods for simultaneous detection and differentiation of Cys, Hcy, and GSH are still challenging because of their similarity in structure and chemical properties. Herein we report a probe that simultaneously detects and discriminates between mixtures of Cys, Hcy and GSH using 19F nuclear magnetic resonance (NMR). This 19F NMR probe responds rapidly to biothiols through the Michael addition reaction and subsequent intramolecular cyclization reaction allowing differentiation between Cys, Hcy and GSH through 19F NMR chemical shift. We demonstrate that this 19F NMR probe is a powerful method for analysis of complex mixtures.

Salicylic Acid-Based Polymeric Contrast Agents for Molecular Magnetic Resonance Imaging of Prostate Cancer.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is an innovative molecular imaging technique in which contrast agents are labeled by saturating their exchangeable proton spins by radio-frequency irradiation. Salicylic acid and its analogues are a promising class of highly sensitive, diamagnetic CEST agents. Herein, polymeric agents grafted with salicylic acid moieties and a known high-affinity ligand targeting prostate-specific membrane antigen in approximately 10:1 molar ratio were synthesized to provide sufficient MRI sensitivity and receptor specificity. The proton-exchange properties of the contrast agent in solution and in an experimental murine model are reported to demonstrate the feasibility of receptor-targeted CEST MRI of prostate cancer. Furthermore, the CEST imaging data were validated with an 111 In-labeled analogue of the agent by in vivo single photon emission computed tomographic imaging and tissue biodistribution studies.

Potential detection of cancer with fluorinated silicon nanoparticles in 19F MR and fluorescence imaging.

Fluorescence is widely used for cell imaging due to its high sensitivity and rich color choices but limited for in vivo imaging because of its low light penetration. Meanwhile, magnetic resonance imaging (MRI) is widely applied for in vivo diagnosis but not suitable for cell imaging because of its low resolution. As a result of rare background in living organisms, 19F-MRI stands out in several fields of clinical application. Herein, we report a one-pot microwave synthesis of fluorinated silicon nanoparticles (19FSiNPs), for detection of cancer cells and tumors. Based on the quantum effects of the nano-sized nanoparticles, 19FSiNPs can act as a label free dye for ultracontrast cell fluorescence imaging. Our experiments demonstrated that these nanoprobes significantly enhanced in vivo19F/1H MRI contrast in rats with non-small cell lung tumors. Moreover, the resulting 19FSiNPs exhibited high water dispersibility and excellent biocompatibility, which make them promising for both cell imaging and in vivo imaging applications.

Two decades of dendrimers as versatile MRI agents: a tale with and without metals.

Dendrimers or dendritic polymers are a class of compounds with great potential for nanomedical use. Some of their properties, including their rigidity, low polydispersity and the ease with which their surfaces can be modified make them particularly well suited for use as MRI diagnostic or theranostic agents. For the past 20 years, researchers have recognized this potential and refined dendrimer formulations to optimize these nanocarriers for a host of MRI applications, including blood pool imaging agents, lymph node imaging agents, tumor-targeted theranostic agents and cell tracking agents. This review summarizes the various types of dendrimers according to the type of MR contrast they can provide. This includes the metallic T1 , T2 and paraCEST imaging agents, and the non-metallic diaCEST and fluorinated (19 F) heteronuclear imaging agents. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Implantable Materials and Surgical Technologies > Nanomaterials and Implants.