Recent Advances of Manganese-Based Hybrid Nanomaterials for Cancer Precision Medicine

Cancer precision medicine (CPM) could tailor the best treatment for individual cancer patients, while imaging techniques play important roles in its application. With the characteristics of noninvasion, nonionized, radiation-free, multidimensional imaging function, and real-time monitoring, magnetic resonance imaging (MRI) is an effective way for early tumor detection, and it has become a tower of strength in CPM imaging techniques. Due to linkage with nephrogenic systemic fibrosis (NSF), gadolinium (Gd)-based contrast agent (CA), which was long used in MRI, has been restricted by the Food and Drug Administration (FDA). In this review, we would like to introduce the manganese (Mn)-based CAs that could significantly increase the safety of MRI CAs by realizing more superior performance and functions simultaneously in the diagnosis and treatment of tumors. Also, recent advances in Mn-based hybrid nanomaterials for CPM are summarized and discussed.


INTRODUCTION
Cancer precision medicine (CPM), evolved with the development of novel nanoparticles (NPs) for cancer diagnosis and treatment, could tailor the best treatment for individual cancer patients. Nowadays, CPM has become popular in clinical and bioscience worldwide, with the conventionally used cancer therapies (e.g., chemotherapy, radiotherapy, and surgery) suffering from lower therapeutic efficiency and ineluctable side effects (1)(2)(3)(4).
Owing to superb soft tissue imaging contrast, high spatial resolution, multidimensional imaging, and absence of ionizing radiation, MRI becomes increasingly available for early detection of tumors with gadolinium (Gd)-based contrast agents (CAs) most frequently used (9,10). Unfortunately, Gdbased CA is in restricted use by the Food and Drug Administration (FDA) due to possibly Gd-based CA-linked medical conditions known as nephrogenic systemic fibrosis (NSF), chronic kidney disease (CKD), and severe complexities, which led to new concerns on the safety of Gd as MRI CAs clinically (11)(12)(13)(14).
To increase the safety of MRI CAs, manganese (Mn) ion (Mn 2+ ), a non-lanthanide metal, a necessary element in cell biology, and the earliest reported CAs used for enhancing T1weighted MRI, became an optimal choice due to its paramagnetic nature, low toxicity, and high biosafety (15).
To sum up, the paramagnetism and Fenton-like property of Mn 2+ have made Mn-based hybrid nanoparticles with multiple effects, including great performance in MRI, drug delivery, and imaging-guided therapy theranostic systems to integrate diagnosis and treatment into a nanoplatform. Mn-based hybrid nanomaterials have brought a new dawn to the treatment of tumors (26).
In this review, we aimed to provide an overview of recent advances in a possible workflow of Mn-based hybrid nanomaterials used for CPM by reviewing recent emerging techniques and treatments that have been used or will be potentially used. The Mn-based hybrid nanomaterials as imaging agents, carriers for drug delivery, and theranostic agents are summarized in sections Manganese-Based Hybrid Nanomaterials as Imaging Agents, Manganese-Based Hybrid Nanomaterials as Carriers for Drug Delivery, and Manganese-Based Hybrid Nanomaterials as Theranostic Agents, respectively. We will discuss how Mn-based hybrid nanomaterials can be used as CAs for detecting and monitoring cancer progression; how they act as chemotherapeutic drug carriers to increase therapeutic index; and how they can function as theranostic agents in imaging-guided PTT, PDT, SDT, and radiation therapy, etc. Here, we highlight the Mn-based hybrid nanomaterials as theranostic agents, and such an imaging-guided nanotheranostic platform would help to develop optimized and individualized regimens in light of patient's response and offer an opportunity to develop CPM. The progress and perspective are summarized in section Perspective.

MANGANESE-BASED HYBRID NANOMATERIALS AS IMAGING AGENTS
The noninvasive, nonionized, and radiation-free characteristics make MRI one of the most extensively utilized clinical imaging tools. However, conventional signal intensity-based MRI is still limited to its semiquantitative nature, which is susceptible to many factors. Recently, various Mn-based hybrid nanomaterials could increase T1-weighted MRI effect even in acid environment with good biocompatibility or multimodal imaging free from the effects of various conditions in the TME (14,27,28). The Mnbased hybrid nanomaterials as imaging agents are summarized in Table 1, with the schematic diagram and examples of imaging effect shown in Figure 1.
T1-T2 dual-modal CAs could enable both T1 bright and T2 dark contrasts. Zhao et al. (27) prepared the multifunctional DNA-Mn-based nanoflower (DMNF), showing enhanced T1weighted MRI effect even in acid environment and high spatial resolution imaging of kidneys and liver. What is worth mentioning is that Zhou et al. (28) made a 1,4,7-triazacyclononane-N,N',N''triacetic acid-conjugated truncated Evans blue (NEB), and after chelating with Mn (MnNEB) and bovine serum albumin (Mn-NEB+BSA), it could be used as novel T1-T2 dual-modal MRI CA. This study opens a new avenue for contrast-enhanced MRI diagnosis, and it also shows extraordinary promise for CPM (28).

MANGANESE-BASED HYBRID NANOMATERIALS AS CARRIERS FOR DRUG DELIVERY
Nanotechnology acts a great role in drug delivery to help revolutionize CPM. Mn-based hybrid nanomaterials, such as  (5). Also, they hold great potential to simultaneously codeliver more drugs in combination therapy. The delivery of non-cytotoxic prodrugs to cancer cells is one of the newer applications (29). Furthermore, drugs can be formulated at a nanoscale level to increase its therapeutic efficiency. Nanoscale drug delivery systems (nano-DDSs) have already been proposed as a promising way to realize tumor-specific treatment by being adaptable and responsive to many endogenous substances and external stimuli, such as acidity, overexpressed hydrogen peroxide (23), pH, enzyme, light, temperature, and magnetic field.

MANGANESE-BASED HYBRID NANOMATERIALS AS THERANOSTIC AGENTS
Many efforts have been made for cancer therapy, and the idea of theranostics could help develop a smart nanoparticle to integrate cancer diagnosis, drug delivery, and therapy monitoring simultaneously in a system (50). The intelligent stimuliresponsive manner could offer an efficient strategy for CPM by employing the unique features of TME or clinical external irradiations. With the improvement of polymerization and emulsifying techniques, nanoparticles could be made with hydrophilic and hydrophobic facets to load with different active materials for theranostics. The Mn-based hybrid nanomaterials as imaging agents and carriers for drug delivery have been summarized and discussed in this section, and the Mn-based hybrid nanomaterials as theranostic agents are summarized in Table 3, with the schematic diagram and examples shown in Figure 3.

Imaging-Guided Photothermal Therapy
PTT, a combination of photothermal nanomaterials and light irradiation, becomes a clinically promising modality for cancers. It could controllably and selectively heat the target area to minimize thermal damage.

Imaging-Guided Photodynamic Therapy
PDT has emerged as a promising therapeutic option for cancers, and it could generate cytotoxic oxygen-based molecular species via photosensitizer to ablate tumor growth by inducing cell apoptosis, necrosis, or autophagy. As a new noninvasive modality, PDT could enhance the conventional cancer treatment by overcoming drug resistance or escape pathways. A lot of Mn-based hybrid nanoparticles were synthesized for imaging-guided PDT diagnosis and treatment (10,54,55,79,80). For example, Zhang et al. (10) have proven that Mn-doped iron oxide nanoparticles modified with denatured BSA (MnIO-dBSA) and Fmoc-L-L/Mn 2+ /Ce6 nanoparticles (FMCNPs) could improve antitumor PDT efficacy. Also, oxygen-generating theranostic nanoparticles (CDM NPs) with MnO 2 could be applied for trimodal imaging-guided combined PDT in breast cancer (69). A multifunctional DNA-templated silver nanoclusters/porphyrin/MnO 2 nanoplatform could be used for non-labeled fluorescence images of Zn 2+ and 635-nm red lighttriggered PDT (56). The MnO 2 NP-based PDT nanocomplex could generate oxygen to overcome the limitation of insufficient oxygen level in tumors (55).

Imaging-Guided Sonodynamic Therapy
SDT is an alternative promising method for cancers by generating reactive oxygen species (ROS), ROS to induce cell death with low-intensity ultrasound irradiation combined with nontoxic sonosensitizers (81,82). It is characterized by high therapeutic efficiency with the advantages of noninvasiveness and mitigated side effects.
Mn-based theranostic agents could integrate imaging and therapy into a single nano-platform for imaging-guided SDT. It has been reported that even in the presence of skull, sinoporphyrin sodium (DVDMS) chelating with Mn (DVDMS-Mn-LPs) could effectively inhibit the tumor growth (57). The efficacy of SDT could be severely inhibited by hypoxia and high glutathione in TME, while a Mn porphyrin-based metal-organic framework   (Mn-MOF) could improve antitumor immunity and immunosuppressive microenvironment upon ultrasound irradiation to show great potential for hypoxic cancer therapy (58).

Other Imaging-Guided Therapies
Mn-based hybrid nanomaterials also hold great potential for many other traceable therapies for cancer, such as chemodynamic therapy (CDT) (60,61), radiation therapy (83), magnetic hyperthermia therapy, and combination therapy (70,84,85). For pH-responsive traceable gas therapy-primed CDT, a gphase Mn sulfide nanotheranostics using bovine serum albumin (MnS@BSA) could greatly suppress tumor growth (59). During radiation therapy, ionizing radiation will damage both normal   tissues and tumors (86), and hypoxia within TME would often lead to the resistance to radiotherapy. To improve the effect of radiation therapy, radionuclide 131 I-labeled human serum albumin (HSA)-bound MnO 2 nanoparticles ( 131 I-HSA-MnO 2 ) could function as an effective agent to show great efficacy in tumor treatment (62). The novel room-temperature ferromagnetic wüstite iron-manganese oxide nanoflowers (FIMO-NFs) could harness the advantages and potential of dual-mode MRI and magnetic hyperthermia therapy to induce cancer cell apoptosis (65). Mn 2+ -doped bio-response theranostic NP could be designed for tumor-specific enhanced combination therapy under the guidance of multimodal imaging (64,66,87,88). Pd@Au bimetallic NP-decorated hollow mesoporous MnO 2 (H-MnO 2 ) NPs could achieve both nucleus-targeted PTT and TME hypoxia relief-enhanced PDT (89). As an intelligent nanoflower composite with multistage H 2 O 2 /pH/GSH-responsive properties, FHCPC@MnO 2 could realize the specific release of drugs in tumor and significantly increase the synergetic therapeutic effect (72).

PERSPECTIVE
Cancer still remains a significant challenge worldwide, and the new discovered theranostic nanomaterials, such as Mn-based hybrid nanomaterials, which make diagnosis and treatment together in a unified platform, provide a novel therapy specialized for tumors. Since nanomaterials for theranostics create great new opportunities in developing CPM, this review focused on Mn-based nanoparticles with various applications (used as imaging agents, drug delivery, and theranostic agents) in CPM. Although a multitude of Mn-based hybrid nanomaterials have not been successfully used in the clinic, several welldesigned Mn-based hybrid nanoparticles provide a new promising treatment option in the near future. What is worth emphasizing is that the novel nanoparticles should be thoroughly characterized, whether used as imaging agents, carriers for drugs, or theranostic platforms, and the toxicity studies in both cell culture and animal models are needed before they can be applied clinically. A future perspective is proposed for further research and development of complex targeted, multistage responsive nanomedical drug delivery systems with high intelligence, precision, and minimum toxicity for personalized cancer diagnosis and effective therapy. A major obstacle in designing theranostic Mn-based hybrid nanomaterials might be that providing target specificity to biomaterials for enhancing therapeutic effect and visualization in CPM. With the aid of multimode imaging, theranostic nanoparticles can visualize and monitor drug delivery and therapeutic responses at tumor site.

AUTHOR CONTRIBUTIONS
XL and PR contributed to the conception, design, writing, and final approval of the article. All authors contributed to the article and approved the submitted version.