Parahydrogen-induced polarization

Parahydrogen-induced polarization (PHIP) is a hyperpolarization method utilizing parahydrogen (one of the two spin isomers of hydrogen), which can temporarily increase the signal intensity commonly in nuclear magnetic resonance (NMR), and has been explored in many demonstrations using magnetic resonance imaging (MRI) experiments.^{[1][2][3][4][5]} PHIP methods are commonly categorized in two ways – hydrogenative PHIP and non-hydrogenative PHIP.^[2][3] In hydrogenative PHIP, the parahydrogen is being added directly to the molecular site via hydrogenation reaction.^[6][2][1] Commonly encountered types of hydrogenative PHIP techniques include PASADENA and ALTADENA.^[7][8][1] In non-hydrogenative PHIP, spin order transfer from the parahydrogen to the target nuclei of interest occurs through a catalyst in a reversible exchange process.^[9][10][3] Common types of non-hydrogenative PHIP methods include SABRE.^[9][10][3] PHIP methods have most commonly been applied to NMR spectroscopy, which can include in-vitro metabolite monitoring, in addition to in-vivo or ex-vivo MRI demonstrations.^{[3][11][5][12][4]}

Conventional non ¹H NMR and MRI signals can be weak due to low nuclear spin polarization levels at thermal equilibrium and/or low natural abundance of NMR compatible nuclear isotopes (e.g., ¹³C, ¹⁵N, etc.).^[2][13] Common methods to improve sensitivity may include increasing sample concentration or using an instrument containing a larger magnetic field.^[2][14] However, hyperpolarization techniques can enhance signal intensity in the fields of NMR and MRI, while using relatively low sample concentrations, and utilizing standard NMR (e.g., 9.4 T) to benchtop NMR (e.g., 1-2 T) magnetic fields.^[2][14] One method of hyperpolarization, named parahydrogen-induced polarization, utilizes parahydrogen to transfer spin order to the target nuclei of interest in a given molecule/sample.^[1][2][3] Exploring the basic underlying spin-order principle and corresponding core experimental applications can further develop broad understanding of PHIP.

PHIP can commonly be categorized in two methods: hydrogenative or reversible exchange (SABRE-family).^[2][3][10] In hydrogenative PHIP, the two hydrogen atoms of a parahydrogen molecule undergo pairwise addition to an unsaturated bond of the molecule of target during catalysis, which allows for hyperpolarization of the target nuclei in that molecule.^[6][7][2] In reversible exchange (e.g., SABRE), parahydrogen spin order is transferred via a metal-based catalyst to the target nuclei of interest in the hyperpolarized molecule via scalar coupling (i.e., J-coupling) network as a reversible process, which leads to the parahydrogen being converted to orthohydrogen to varying degrees depending on conditions.^[9][10][15] This means that after spin order is transferred from parahydrogen to the target nuclei, the system will undergo substrate exchange, which allows for hyperpolarization buildup.^[9][10] The differences between these two common PHIP techniques have practical implications for experiments and applications.

A brief outline of PHIP experimental preparation includes cooling room temperature hydrogen gas (roughly 75% ortho to 25% para) to cryogenic temperatures (e.g., 30 K) using a catalyst to increase parahydrogen purity from roughly 25% at room temperature to, for example, 97%.^[16][17] Then, substrate and catalyst are combined, where enriched parahydrogen is introduced to the system in a magnetic field under specified conditions to generate hyperpolarization, which in turn results in hyperpolarization detection via NMR or MRI.^[2][3][4] Due to the generally short-lived transient nature of hyperpolarization signals due to decay via spin relaxation, instrumental detection must occur quickly.^[2][3]

In chemistry of materials, PHIP has been used as a tool for studying polymer hyperpolarization, and varying catalyst formats/platforms (e.g., immobilized onto polymeric materials).^[18][19][20] In the context of PHIP, the types of polymers can include synthetic polymers and biopolymers/macromolecules, where PHIP helps to counter the sensitivity limitations by conventional NMR for these categories.^[19][21] The following polymer-related chemistry of materials applications in PHIP can include hyperpolarizing polymeric targets, or polymer-enabled hyperpolarization platforms.^[18][19][20] For hyperpolarizing polymeric targets, this depends on whether the polymeric architecture includes PHIP reactive sites/handles (e.g., unsaturated bond) for hydrogenative PHIP, which can be placed at the terminal chain end, or side chains.^[19][21] An example application includes the works of Münnemann et al. in their article titled “Hyperbranched polymers for molecular imaging: designing polymers for parahydrogen induced polarisation (PHIP).”^[19] Additionally, inclusion of polymer-related platforms used in PHIP can be in the form of catalyst immobilization, which can enable improved recyclability of catalyst, and improved polymer support engineering for solvent compatibility.^[18][20] An example of polymer supports compatible with a specific solvent (e.g., water) for catalyst immobilization to enable recyclability can be found in the works of Min et al., in the article titled “Water-Compatible and Recyclable Heterogeneous SABRE Catalyst for NMR Signal Amplification.”^[20] Hence, the applications of PHIP in the chemistry of materials have been demonstrated in varying research studies.^{[18][19][21][20]}

PHIP has been used in magnetic resonance research to create hyperpolarization signals of polymer architectures as macromolecular probes.^[19][18] Once such polymer architectural motif is hyperbranched polymers, which can be used when designing PHIP-active handles.^[19] Münnemann et al. reported hyperpolarization of biocompatible hyperbranched polymers using PHIP, where they stated it as “the first hyperpolarization of polymers using PHIP.”^[19] Specifically, hydrogenation of the terminal alkyne groups of the polymer was reported as the mechanism.^[19] Additionally, NMR signal enhancements of up to 1500-fold were reported on certain polymer structures.^[19] It was concluded from the study that PHIP performance on polymers is dependent on the polymer architecture.^[19] Hence, the authors claimed that the results open potential avenues for polymeric molecular imaging.^[19]

Sensitivity of polymeric/macromolecular samples can be challenging with conventional NMR due to factors such as low concentration, or in general, very large molecules.^[21] An example can be found by Theiss et al., in their research article named “Parahydrogen induced polarization enables the single scan NMR detection of a 236 kDa biopolymer at nanomolar concentrations,” where they report on a synthetic 236 kDa biopolymer.^[21] The researchers demonstrated successful hyperpolarization of the biopolymer (i.e., homopolypeptide) and identified enhanced signals using PHIP in an 11.7 T solution NMR.^[21] More specifically, they used PHIP to study signal enhancement of the synthetic biopolymer as a function of polymer concentration within the micromolar to nanomolar concentration levels.^[21] These results are relevant to polymer characterization because it shows how PHIP can be applied to macromolecules that would otherwise pose challenges via conventional NMR methods.^[21] The researchers utilized PHIP via hydrogenation of an alkyne side chain functional group of synthetic biopolymer, which enabled hyperpolarization.^[21] To sum up, application of PHIP to higher molecular weight polymeric targets has been demonstrated at the research level.^[21][18]

Application of polymers in PHIP are not limited to hyperpolarizing the polymer itself but can extend to hyperpolarization platforms.^[18][20] Specifically, immobilizing catalysts on a polymeric platform can enable recyclability, easier separation, and overall ease of handling, while also being solvent compatible.^[20] For example, Min et al. reported in their article about a polymeric resin-based heterogeneous catalyst for SABRE experiments, which enabled the catalyst to be recyclable and water-compatible.^[20] Interestingly, the paper supports the claim that after more than three times of reuse, catalytic activity in water was still present.^[20] Hence, choice of polymeric support material has been demonstrated to influence solvent choice, recyclability, and overall workflow in PHIP experiments, which have potential applications in analytical or biomedical magnetic resonance experiments at the research level.^[20][18]

The use of polymers as hyperpolarization platforms in PHIP experiments is not limited to polymeric resin support but also extends to nanoscale support platforms.^[22][18] One 2015 study by Shi et al., in their article titled “Nanoscale Catalysts for NMR Signal Enhancement by Reversible Exchange” utilized a PVP polymer-comb catalyst, and titanium oxide (TiO₂)/PMAA core-shell nanoparticles tethered to an iridium-based catalyst for SABRE experiments.^[22] Using these materials, researchers explored how changing the hyperpolarization support platform from a polymer comb to a core-shell nanoparticle affects the catalyst exhibiting heterogeneous and homogeneous conditions, which resulted in ¹H NMR enhancement.^[22] These support platforms enable a better understanding of the system’s homogeneous/heterogeneous behavior.^[22] In contrast to the research findings of Min et al. with an emphasis on polymeric applications for catalyst water compatibility and recyclability, the work by Shi et al. puts a focus on utilizing polymers for hyperpolarization support architecture and interface design.^[20][22]

Chemistry of polymers/materials applications in PHIP has been demonstrated at the research level in several studies but has yet to develop established routines.^[18] A current limitation is that not all polymers can be used in PHIP experiments, which limit their scope.^[18][19][21] Using conventional NMR on these large PHIP compatible molecules yields limitations in sensitivity and broad signals, where PHIP experiments have potential to overcome such challenges.^[21] Additionally, it has been demonstrated that the use of polymers as hyperpolarization platforms further expands their application by utilizing resins/nanoscale catalyst platforms, although these systems are still in the research level of study.^[20][22][18] With increasing advances in polymer application, widening the scope of direct polymer PHIP targets, recyclable and water compatible polymeric supported catalysts, and improved engineering of polymer/nanoparticle interfaces can help further advance PHIP in the field of materials chemistry.^[18][20][22]