Magnetic Nanoparticles in Theranostics: From Controlled Synthesis and Surface Engineering to Biological Performance and Clinical Translation

Theranostic nanoparticles integrate diagnostic and therapeutic potential, representing a promising approach in precision medicine. Accordingly, numerous inventions have been patented to protect novel formulations and methods. This review examines the evolution of patented theranostic nanoparticles, focusing on organic nanosystems, particularly polymeric and lipid nanoparticles, to assess their development, technological advances, and patentability. A scoping review approach was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines in the World Intellectual Property Organization (WIPO) and European Patent Office (EPO) database. The search included patents filed within the last ten years (2014–2024) that specifically claimed organic and/or hybrid theranostic nanoparticles. Data extraction focused on nanoparticle composition, synthesis methods, functionalization strategies, and theranostic applications. The search identified 130 patents, of which 13 met the inclusion criteria. These patents were primarily filed by inventors from the United States, Canada, Great Britain, Italy, and China. Polymeric nanoparticles were frequently engineered for targeted drug delivery and imaging, utilizing hyperbranched polyesters, sulfated polymers, or chitosan-based formulations. Lipid nanoparticles were often hybridized with inorganic nanomaterials or magnetic nanostructures to enhance their theranostic potential. While most patents detailed synthesis methods and physicochemical characterizations, only a few provided comprehensive preclinical validation, limiting their demonstrated efficacy. The analysis of recent patents highlights significant advances in the design and application of theranostic nanoparticles. However, a notable gap remains in validating these nanosystems for clinical translation. Future efforts should emphasize robust preclinical data, including in vitro and in vivo assessments, to enhance patent quality and applicability to substantiate the claimed theranostic capabilities.

Magnetic nanoparticles for cancer theranostics: Advances and prospects

Towards rational design of multifunctional theranostic nanoparticles: what barriers do we need to overcome?

Superparamagnetic iron oxide nanoparticles - From synthesis to nanomedicine.

Clinical Significance: Among 1 million cases of newly diagnosed breast cancer worldwide each year, over 170,000 cases will have a distinct type of triple-negative breast cancer (TNBC), which lacks expression of estrogen (ER), progesterone (PR) and human epidermal growth factor receptor 2 (Her-2/neu). The patients with TNBC are usually detected at the late stage, have an aggressive tumor type, an increased likelihood of local and distant recurrence, and a poorer prognosis compared to women with other types of breast cancer. TNBC patients usually receive neoadjuvant therapy to reduce local and distant recurrence. However, more than 50% of TNBC patients are resistant to conventional chemotherapy. Therefore, novel methods for effective therapy are an urgent need for improving survival of the TNBC patients. Methods: We have developed a targeted therapy for TNBC by systemic delivery of biodegradable theranostic magnetic iron oxide nanoparticles (IONPs) that combine targeted drug delivery and non-invasive tumor imaging capabilities. These theranostic IONPs are targeted to urokinase plasminogen activator receptor (uPAR) by conjugating to the amino-terminal fragment (ATF) of the high affinity receptor binding domain of uPA. Results: 1). Our results from analysis of the gene expressing profile of a cohort of 143 breast cancer tissues revealed that uPAR, a potential cell surface target for the development of targeted therapeutics in TNBC, is highly expressed in the TNBC tissues compared to the luminal type of breast cancer (p < 0.0001). The major advantage of targeting uPAR is that the receptor is highly expressed in tumor cells and angiogenic endothelial cells, which facilitates transporting nanoparticles across the endothelium lining tumor vessels. Internalization of ATF-nanoparticle complexes by tumor cells further increases intracellular drug concentration; 2). We demonstrated that systemic delivery of uPAR-targeted theranostic IONPs carrying a chemotherapy drug, doxorubicin, significantly inhibited the growth of primary tumors through anti-tumor and anti-angiogenesis effects, and delayed local and distant recurrence for 8 weeks as compared mice-treated with free doxorubicin in a TNBC-like 4T1 mouse mammary tumor model. The improved therapeutic effect using these targeted theranostic nanoparticles has also been demonstrated in a human breast cancer xenograft model; 3). Targeting theranostic nanoparticles into tumors allow for monitoring intratumoral drug delivery and therapeutic response in the tumors by MRI; and 4). Targeted delivery of doxorubicin using theranostic IONPs reduces systemic toxicity of the drug in normal organs, such as heart and liver. Conclusion: uPAR-targeted theranostic nanoparticles have potential for targeted therapy, timely assessment of therapeutic response of a given therapy, and ultimately, increased survival of TNBC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5482.

Background: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype that affects about 20% of breast cancer patients and has a high incidence in young African American women. Currently the only therapeutic options for TNBC patients is chemotherapy, however, more than 60% of TNBC patients are highly resistant to chemotherapeutic treatment. The development of novel therapeutic approaches is essential to enable treatment of patients with chemo-resistant TNBC. Our lab focuses on the development of receptor-targeted theranostic nanoparticles. We have developed a class of urokinase plasminogen activator receptor (uPAR) targeted theranostic magnetic iron oxide nanoparticles (IONPs) carrying therapeutic agents that are clinically beneficial to TNBC patients, including DNA damaging agents, such as doxorubicin (Dox) or cisplatin (Cis). We are targeting uPAR because it is highly expressed in malignant cancers including aggressive breast cancer tissues and tumor stromal cells that are enriched in TNBC tissues. Methods: Tumor fragments from TNBC patients, obtained from a Phase II clinical trial that is ongoing at the Breast Cancer Clinic in the Winship Cancer Institute, were implanted in the mammary fat pad of SCID mice. The tumor xenografts grew to about 1 cm in diameter in 12 to 15 weeks. Tumor fragments were then implanted into the mammary fat pad and passaged through nude mice for testing the therapeutic efficacy of the uPAR-targeted nanoparticle-drugs. Histological analysis of post-chemotherapy TNBC and primary tumor xenograft tissues with or without uPAR-targeted IONP-Dox was conducted using immunohistochemistry and dual immunofluorescence techniques. Results: We have previously reported that the uPAR-targeted IONP-Dox causes tumor growth inhibition following systemic delivery. Using CD44 and uPAR as biomarkers we also reported histological analysis of post-chemotherapy TNBC and primary tumor xenograft tissues showed high levels of CD44+/CD24- tumor cells and up-regulation of uPAR. Primary TNBC xenografts treated with conventional Dox had increased levels of CD44+/CD24- cells and strong uPAR expression. Conversely, the tumor tissues from the uPAR-targeted IONP-Dox treated group showed decreased levels of CD44+/CD24- and uPAR positive cells. We have further investigated the biomarkers insulin-like growth factor 1 receptor (IGF-1R) and Ki67. IGF-1R has been shown to be overexpressed in more than 50% of TNBCs and may be associated with the drug-resistant TNBC phenotype, while Ki67 is a conventional biomarker for proliferation. We observed that uPAR-targeted IONP- Dox treatment decreased IGF-1R expression compared to the control group and the group treated with conventional Dox. We also observed that Ki67 expression was decreased in the uPAR-targeted IONP- Dox treatment group compared to control group and the group treated with conventional Dox. Conclusions: Results of our study demonstrated that uPAR-targeted theranostic IONPs selectively delivers therapeutic payloads of the chemotherapeutic drug Dox to inhibit the growth of uPAR positive tumor cells. It is likely that uPAR expressing tumor cells are an aggressive and potentially drug resistant cell population that overexpress breast cancer stem-like cell biomarker (CD44+/CD24-) as well as up-regulation of a growth factor receptor, IGF-1R. These results support further investigation of theranostic nanoparticles as an approach to overcome drug resistance in TNBC. Citation Format: Jasmine M. Miller-Kleinhenz, Hongyu Zhou, Weiping Qian, Ruth O'Regan, Amelia Zelnak, Toncred Styblo, Lily Yang. uPAR-targeted theranostic nanoparticles effectively decrease expression of IGF-1R and Ki67 in drug-resistant triple-negative breast cancer human xenograft. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B045.

Nanomedicine research recently started exploring the combination of therapy and diagnostics, so-called theranostics, as an approach to offer a more flexible, personal, and precise care with improved patient outcomes. As magnetic nanoparticles show great potential in a variety of diagnostic and therapeutic applications, they are prime candidates to be used in a theranostic platform to realize this vision. This Perspective gives an overview of state-of-the-art magnetic imaging techniques and theranostic applications based on magnetic nanoparticles and discusses their opportunities and associated challenges. In order to address these challenges and to exploit these opportunities to the fullest, we discuss three promising research directions. The first considers the use of novel magnetic field sequences to utilize the rich magnetic dynamics of the particles, allowing a more accurate diagnosis and boosting the performance of many nanoparticle-based applications. Second, we introduce the innovative concept of smart theranostics based on feedback mechanisms between the particle applications and their supporting imaging procedure to enhance the performance of both and to allow real-time monitoring of treatment efficiency. Finally, we show the twofold advantage of applying data-driven models to enhance therapy and diagnostics on the one hand and for handling the platform’s large amount of data and associated decision support algorithms on the other. The latter research track is extended to include hybrid models in which physics-based and data-driven models are combined to overcome challenges of applications with limited data, making the data-driven part understandable, as well as in uncovering unknown nanoparticle dynamics. Contrasting other literature works, which mainly focus on developing magnetic nanoparticles with the right characteristics, we put forward advances in magnetic nanoparticle imaging techniques and applications to enable the use of a broader range of magnetic nanoparticles in theranostics. We seek to emphasize the importance of these building blocks as many research opportunities with a very high potential are still left open. Therefore, we encourage researchers to also take these aspects into account to advance theranostic applications of magnetic nanoparticles to real clinical environments.

Prostate cancer (PCa) is a major cause of cancer-associated death in men. A crucial factor in its development and treatment resistance is tumor hypoxia, which drives metabolic reprogramming (especially reconfiguration towards glycolysis), mediated to a great extent by hypoxia-inducible factor-"HIF-1 alpha" (HIF-1a). The present review summarizes (i) the mechanisms underlying hypoxia-induced glycolysis that enhances the aggressiveness of and treatment failure in PCa and (ii) recent developments in the field of theranostic nanoparticles (TNPs) with dual actions of inhibiting HIF-1a and downstream metabolic targets, while facilitating the imaging and treatment of the tumor. We summarize available evidence for the hypoxia-glycolysis signaling in PCa and assess nanotechnology achievable theranostic approaches (i.e., liposomal-, polymer- and metallic nanoplatforms) to promote drug delivery, real-time tumor picture and modulation of hypoxic tumor microenvironments. Hypoxia-inducible factor-1 alpha (HIF-1a) driven hypoxia is a common phenotypic feature that underlies the increased glycolysis and aggressive tumor phenotype. TNPs have been developed with the aim of (a) enhancing the drug bioavailability, (b) enabling the selectivity of tumor and imaging, and (c) reducing the hypoxia-linked metabolic pathways. The use of PCa as a model for TNP development is especially timely as hypoxia crosses the intersection of androgen receptor (AR) signaling heavens (hormone therapy resistance) leading to progression to castration-resistant PCa (CRPC) and as the Prostate-Specific Membrane Antigen (PSMA) is greatly overexpressed and is a validated target for custom imaging and treatment. Compared with other hypoxia mediated solid tumors, hypoxia AR axis and PSMA overexpression have unique biological leverage for precision theranostics in PCa. Nevertheless, translation is limited by the issues of biocompatibility, complexities resulting from systematic regulations and constraints of scale-up manufacturing. TNPs are a promising platform to integrate diagnosis and treatment of PCa as they incorporate features of targeted delivery, on-line monitoring and interference with HIF-1a regulated glycolysis. Future advances will require interdisciplinary optimization, development of better tumor-targeting approaches, and artificial intelligence guided nanoparticle design to facilitate clinical scale up and regulation of technically and clinically acceptable theranostics of nanomedicines for PCa.

In cancer care's dynamic landscape, targeted imaging is pivotal for advancing precision medicine. This review focuses on the role of magnetic nanoparticles (MNPs), particularly magnetic iron oxide nanoparticles (MIONPs) and superparamagnetic iron oxide nanoparticles (SPIONs), in personalized diagnostics and treatments for oncology. Current trends and future directions in MNP imaging, addressing challenges like biocompatibility, toxicity, and regulatory considerations, are discussed. The review explores MIONPs' theranostic potential, especially in brain drug delivery monitoring through magnetic resonance imaging (MRI) or magnetic particle imaging (MPI). Variousnanoparticle types, including SPIONs as MRI contrast agents, are highlighted. The article covers challenges in nanoparticle modification, including methoxy- polyethylene glycol (mPEG), and discusses gold nanoparticles (AuNPs) for photoacoustic imaging, as well as insights into fluorescent semiconductor quantum dots (QDs). The conclusion emphasizes rapid and accurate tumoridentification, introduces carbon nanotubes (CNTs) for cancer therapy and diagnosis, and underscores the transformative role of lipid-based nanocarriers incancer research. The multifaceted applications of nanotechnology in cancer diagnostics and treatment are discussed throughout, showcasing a paradigm shift.Crucial challenges in unlocking nanotechnology's full potential in cancer care, such as safety concerns, robust clinical trials, synthesis methods standardization, regulatory approval, biodegradability, tailoring nanotherapies, economic viability, ethical considerations, and interdisciplinary collaboration, are addressed. Addressing these challenges holds the promise of elevating nanotechnology into a potent force in the ongoing battle against cancer.

For the past few decades biomedical engineering has imprinted its significant impact on the map of science through its wide applications on many other fields. An important example obviously proving this fact is the versatile application of magnetic nanoparticles in theranostics. Due to preferable properties such as biocompatibility, non-toxicity compared to other metal derivations, iron oxide-based magnetic nanoparticles was chosen to be addressed in this review. Aim of this review is to give the readers a whole working window of these magnetic nanoparticles in the current context of science. Thus, preparation of magnetic iron oxide nanoparticles with the so-far techniques, methods of characterizing the nanoparticles as well as their most recent biomedical applications will be stated.

Magnetic iron oxide nanoparticles have attracted broad interests in many biomedical areas, such as magnetic resonance imaging (MRI) contrast enhancement, magnetic hyperthermia, magnetic bio-sensing, and cell labeling [1]. To avoid nanoparticle aggregation and enhance their colloidal stability, carboxylate surfactants are widely used as coating materials to form steric repulsions between nanoparticles [2]. Lauric acid is one of the classical carboxylate materials, and is already approved for use in pharmaceuticals and food industry, which makes it a very promising coating material for nanoparticles in biomedical application. [3] Various methods, like mechanical milling, microemulsion, co-precipitation, thermal decomposition, etc., have been widely attempted to prepare nanoparticles. However, it is reported that the synthesis route has great impact on the properties of nanoparticle products, such as aluminium oxide nanoparticles, cobalt ferrite nanoparticles, and so on [4, 5]. Therefore, it is worthwhile to investigate the effects of different synthesis methods on the properties of lauric acid coated magnetic iron oxide nanoparticles. The research outcome can enable the synthesis of magnetic nanoparticles with desired features. Here, lauric acid coated iron oxide nanoparticles (LAIONPs) were prepared through two methods, co-precipitation and thermal decomposition. The products were characterized by using transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared (FT-IR), dynamic light scattering (DLS), thermo gravimetric analysis (TGA), and vibrating sample magnetometry (VSM). The iron-oxide-core average size could be tuned from 9 nm (CP-1), 11 nm (CP-2) to 13 nm (CP-3) by using different stirring speed of 1200 rpm, 800 rpm, and 400 rpm, respectively in co-precipitation experiments, while the core average size could be adjusted from 7 nm (TD-1), 11 nm (TD-2) to 17 nm (TD-3) by following different heating process in thermal decomposition experiments. (Fig. 1) The nanoparticles obtained through thermal decomposition (LAIONPs-TD) showed more uniform sizes and morphologies than the ones got from co-precipitation (LAIONPs-CP). Higher mass ratio of lauric acid in TD samples than CP samples, as indicated in TGA results (Fig. 2a and 2b), implies higher surface cover density of lauric acid surfactant on LAIONPs-TD than LAIONPs-CP. All the six LAIONPs samples exhibited superparamagnetic behavior at room temperature (Fig. 2c and 2d). The saturated magnetization (M s ) of LAIONPs increased as the particle size increased. Such a trend can be observed in the samples obtained through co-precipitation (CP-1, 54 emu/g; CP-2, 58 emu/g; and CP-3, 63 emu/g) and also in the samples obtained through thermal decomposition (TD-1, 53 emu/g; TD-2, 64 emu/g; TD-3, and 78 emu/g). For the LAIONPs with similar average core size of 11 nm, M s value of TD-2 obtained by thermal decomposition (64 emu/g) was higher than CP-2 obtained by co-precipitation (58 emu/g). As shown in Fig. 2e, in colloidal solution with solvent of chloroform, smaller mean hydrodynamic sizes and narrower hydrodynamic size distributions were observed on IONPs-TD samples, compared with IONPs-CP samples. This work revealed the influences of two different synthesis methods on the core size, morphology, hydrodynamic size, surfactant coating mass ratio, and magnetic behavior of the final products. Our comparative study provides insights into the influence of synthesis conditions on the geometrical and magnetic properties of lauric acid coated iron oxide nanoparticles.

Theranostic magnetic nanoparticles: Synthesis, properties, toxicity, and emerging trends for biomedical applications

Recent advances in the use of magnetic nanoparticles to promote neuroregeneration.

Substances at nanoscale commonly known as “nanomaterials” have always grabbed the attention of the researchers for hundreds of years. Among these different types of nanomaterials, magnetic nanomaterials have been the focus of overwhelming attention during the last two decades as evidenced by an extraordinary increase in number of research papers. Iron oxide magnetic nanoparticles have occupied a vital position in imaging phenomena; as drug vehicles, controlled/sustained release phenomena and hyperthermia; atherosclerosis diagnosis; prostate cancer. In fact, these are wonderful “theranostic” agents with some are under clinical trials for human use. In this review, we have attempted to highlight the advances taking place in the field of magnetic nanoparticles as theranostic agents. Extensive progress has been made in the two most important parameters viz. control over size and shape which decide the importance of iron oxide magnetic nanoparticles by developing suitable procedures like precipitation, co-precipitation, thermal decomposition, hydrothermal synthesis, microemulsion synthesis and plant mediated synthesis. After suitable synthetic route, workers encounter the most daunting task linked with the materials at nanoscale i.e. the protection against corrosion. Only properly protected iron oxide magnetic nanoparticles can be further connected to different functional systems to make building blocks for application in catalysis, biology and medicines. Finally, iron oxide magnetic nanoparticles play a key role in imaging applications for diagnostic purposes, drug delivery vehicles and above all the combined effect of previous two phenomena “theranostics”. With all the potential uses, toxicity of the of iron oxide magnetic nanoparticles has also been discussed. In the end, attention has been drawn to address the future of research trends of iron oxide magnetic nanoparticles in theranostics.

Chapter 6 - Nanostructures for Externally Triggered Chemo/Thermal Therapies