Targeted nanoparticles for imaging and therapy of endometriosis.

In this brief review, we discuss our efforts to validate nanoplatforms for imaging and treatment of endometriosis. We specifically highlight our use of nonhuman primates and primate tissues in this effort. Endometriosis is a painful disorder of women and nonhuman primates (NHPs) where endometrium-like tissue exists outside of the uterus. There are no reliable, specific, and noninvasive diagnostic tests for endometriosis. Laparoscopic imaging remains the gold standard for identifying small endometriotic lesions in both women and monkeys. Visualizing and surgically removing microscopic lesions remains a clinical challenge. To address this challenge, we have created nanoparticle reagents that, when administered intravenously, enter endometriotic lesions both passively and by targeting endometriotic cells. The particles can carry payloads, including near-infrared fluorescent dyes and magnetic nanoparticles. These agents can be used for imaging and thermal ablation of diseased tissues. We evaluated this approach on macaque endometriotic cells, human and macaque endometrium engrafted into immunodeficient mice, in endometrium subcutaneously autografted in macaques, and in rhesus monkeys with spontaneous endometriosis. Employing these models, we report that nanoplatform-based reagents can improve imaging and provide thermal ablation of endometriotic tissues.

Unraveling the lost balance: Adrenergic dysfunction in cancer cachexia.

Cancer cachexia, characterized by muscle wasting and widespread inflammation, poses a significant challenge for patients with cancer, profoundly impacting both their quality of life and treatment management. However, existing treatment modalities remain very limited, accentuating the necessity for innovative therapeutic interventions. Many recent studies demonstrated that changes in autonomic balance is a key driver of cancer cachexia. This review consolidates research findings from investigations into autonomic dysfunction across cancer cachexia, spanning animal models and patient cohorts. Moreover, we explore therapeutic strategies involving adrenergic receptor modulation through receptor blockers and agonists. Mechanisms underlying adrenergic hyperactivity in cardiac and adipose tissues, influencing tissue remodeling, are also examined. Looking ahead, we present a perspective for future research that delves into autonomic dysregulation in cancer cachexia. This comprehensive review highlights the urgency of advancing research to unveil innovative avenues for combatting cancer cachexia and improving patient well-being.

Targeted Nanocarriers for Systemic Delivery of IRAK4 Inhibitors to Inflamed Tissues.

Persistent and uncontrolled inflammation is the root cause of various debilitating diseases. Given that interleukin-1 receptor-associated kinase 4 (IRAK4) is a critical modulator of inflammation, inhibition of its activity with selective drug molecules (IRAK4 inhibitors) represents a promising therapeutic strategy for inflammatory disorders. To exploit the full potential of this treatment approach, drug carriers for efficient delivery of IRAK4 inhibitors to inflamed tissues are essential. Herein, the first nanoparticle-based platform for the targeted systemic delivery of a clinically tested IRAK4 inhibitor, PF-06650833, with limited aqueous solubility (57 µg mL-1 ) is presented. The developed nanocarriers increase the intrinsic aqueous dispersibility of this IRAK4 inhibitor by 40 times. A targeting peptide on the surface of nanocarriers significantly enhances their accumulation after intravenous injection in inflamed tissues of mice with induced paw edema and ulcerative colitis when compared to non-targeted counterparts. The delivered IRAK4 inhibitor markedly abates inflammation and dramatically suppresses paw edema, mitigates colitis symptoms, and reduces proinflammatory cytokine levels in the affected tissues. Importantly, repeated injections of IRAK4 inhibitor-loaded nanocarriers have no acute toxic effect on major organs of mice. Therefore, the developed nanocarriers have the potential to significantly improve the therapeutic efficacy of IRAK4 inhibitors for different inflammatory diseases.

From Bench to Bedside: Implications of Lipid Nanoparticle Carrier Reactogenicity for Advancing Nucleic Acid Therapeutics.

In biomedical applications, nanomaterial-based delivery vehicles, such as lipid nanoparticles, have emerged as promising instruments for improving the solubility, stability, and encapsulation of various payloads. This article provides a formal review focusing on the reactogenicity of empty lipid nanoparticles used as delivery vehicles, specifically emphasizing their application in mRNA-based therapies. Reactogenicity refers to the adverse immune responses triggered by xenobiotics, including administered lipid nanoparticles, which can lead to undesirable therapeutic outcomes. The key components of lipid nanoparticles, which include ionizable lipids and PEG-lipids, have been identified as significant contributors to their reactogenicity. Therefore, understanding the relationship between lipid nanoparticles, their structural constituents, cytokine production, and resultant reactogenic outcomes is essential to ensure the safe and effective application of lipid nanoparticles in mRNA-based therapies. Although efforts have been made to minimize these adverse reactions, further research and standardization are imperative. By closely monitoring cytokine profiles and assessing reactogenic manifestations through preclinical and clinical studies, researchers can gain valuable insights into the reactogenic effects of lipid nanoparticles and develop strategies to mitigate undesirable reactions. This comprehensive review underscores the importance of investigating lipid nanoparticle reactogenicity and its implications for the development of mRNA-lipid nanoparticle therapeutics in various applications beyond vaccine development.

Development and Perspectives: Multifunctional Nucleic Acid Nanomedicines for Treatment of Gynecological Cancers.

Gynecological malignancies are a significant cause of morbidity and mortality across the globe. Due to delayed presentation, gynecological cancer patients are often referred late in the disease's course, resulting in poor outcomes. A considerable number of patients ultimately succumb to chemotherapy-resistant disease, which reoccurs at advanced stages despite treatment interventions. Although efforts have been devoted to developing therapies that demonstrate reduced resistance to chemotherapy and enhanced toxicity profiles, current clinical outcomes remain unsatisfactory due to treatment resistance and unfavorable off-target effects. Consequently, innovative biological and nanotherapeutic approaches are imperative to strengthen and optimize the therapeutic arsenal for gynecological cancers. Advancements in nanotechnology-based therapies for gynecological malignancies offer significant advantages, including reduced toxicity, expanded drug circulation, and optimized therapeutic dosing, ultimately leading to enhanced treatment effectiveness. Recent advances in nucleic acid therapeutics using microRNA, small interfering RNA, and messenger RNA provide novel approaches for cancer therapeutics. Effective single-agent and combinatorial nucleic acid therapeutics for gynecological malignancies have the potential to transform cancer treatment by giving safer, more tailored approaches than conventional therapies. This review highlights current preclinical studies that effectively exploit these approaches for the treatment of gynecological malignant tumors and malignant ascites.

Nanomedicines for Improved Management of Ectopic Pregnancy: A Narrative Review.

Ectopic pregnancy (EP) - the implantation of an embryo outside of the endometrial cavity, often in the fallopian tube - is a significant contributor to maternal morbidity and leading cause of maternal death due to hemorrhage in first trimester. Current diagnostic modalities including human chorionic gonadotropin (hCG) quantification and ultrasonography are effective, but may still misdiagnose EP at initial examination in many cases. Depending on the patient's hemodynamic stability and gestational duration of the pregnancy, as assessed by history, hCG measurement and ultrasonography, management strategies may include expectant management, chemotherapeutic treatment using methotrexate (MTX), or surgical intervention. While these strategies are largely successful, expectant management may result in tubal rupture if the pregnancy does not resolve spontaneously; MTX administration is not always successful and may induce significant side effects; and surgical intervention may result in loss of the already-damaged fallopian tube, further hampering the patient's subsequent attempts to conceive. Nanomaterial-based technologies offer the potential to enhance delivery of diagnostic imaging contrast and therapeutic agents to more effectively and safely manage EP. The purpose of this narrative review is to summarize the current state of nanomedicine technology dedicated to its potential to improve both the diagnosis and treatment of EP.

Peptide-guided lipid nanoparticles deliver mRNA to the neural retina of rodents and nonhuman primates.

Lipid nanoparticle (LNP)-based mRNA delivery holds promise for the treatment of inherited retinal degenerations. Currently, LNP-mediated mRNA delivery is restricted to the retinal pigment epithelium (RPE) and Müller glia. LNPs must overcome ocular barriers to transfect neuronal cells critical for visual phototransduction, the photoreceptors (PRs). We used a combinatorial M13 bacteriophage-based heptameric peptide phage display library for the mining of peptide ligands that target PRs. We identified the most promising peptide candidates resulting from in vivo biopanning. Dye-conjugated peptides showed rapid localization to the PRs. LNPs decorated with the top-performing peptide ligands delivered mRNA to the PRs, RPE, and Müller glia in mice. This distribution translated to the nonhuman primate eye, wherein robust protein expression was observed in the PRs, Müller glia, and RPE. Overall, we have developed peptide-conjugated LNPs that can enable mRNA delivery to the neural retina, expanding the utility of LNP-mRNA therapies for inherited blindness.

Nano-Theranostic Modality for Visualization of the Placenta and Photo-Hyperthermia for Potential Management of Ectopic Pregnancy.

Ectopic pregnancy (EP) is the leading cause of maternity-related death in the first trimester of pregnancy. Approximately 98% of ectopic implantations occur in the fallopian tube, and expedient management is crucial for preventing hemorrhage and maternal death in the event of tubal rupture. Current ultrasound strategies misdiagnose EP in up to 40% of cases, and the failure rate of methotrexate treatment for confirmed EP exceeds 10%. Here the first theranostic strategy for potential management of EP is reported using a near-infrared naphthalocyanine dye encapsulated within polymeric nanoparticles. These nanoparticles preferentially accumulate in the developing murine placenta within 24 h following systemic administration, and enable visualization of implantation sites at various gestational stages via fluorescence and photoacoustic imaging. These nanoparticles do not traverse the placental barrier to the fetus or impact fetal development. However, excitation of nanoparticles localized in specific placentas with focused NIR light generates heat (>43 °C) sufficient for disruption of placental function, resulting in the demise of targeted fetuses with no effect on adjacent fetuses. This novel approach would enable diagnostic confirmation of EP when current imaging strategies are unsuccessful, and elimination of EP could subsequently be achieved using the same nano-agent to generate localized hyperthermia resulting in targeted placental impairment.

Cannabis Consumption Among Patients With a Voice Disorder: A Multicenter E-Survey Study.

INTRODUCTION: Legalization of cannabis consumption in the United States (U.S.) has increased rapidly, impacting consumption rates in the general U.S. POPULATION: The objective of this survey study was to establish prevalence estimates of cannabis consumption among voice patients, in addition to characterizing patterns of cannabis consumption. METHODS: A multicenter, anonymous survey study of cannabis consumption took place at multidisciplinary tertiary voice care clinics in Portland, Oregon (PDX) and Pittsburgh, Pennsylvania (PIT) between April 2017 and December 2018. A convenience sample of 300 consecutively enrolled English-speaking patients 21 years and older with a voice disorder completed the survey. Data were obtained on the prevalence of cannabis consumption, frequency and methods of cannabis consumption, in addition to health impacts and demographics. RESULTS: Agresti-Coull prevalence proportion estimates for cannabis consumption were higher among voice patients in PDX compared to PIT. Current consumers in PDX and PIT showed a similar frequency of cannabis consumption. Combustion methods (eg, joint) were more popular than non-combustion methods (eg, vaping) among current consumers; inhaled methods (eg, joint) were more popular than non-inhaled methods (eg, edibles). Though vocal handicap scores for current consumers were similar across sites and comparable to lifetime non-consumers who also were non-smokers of tobacco, a lifetime history of cannabis consumption was associated with vocal and overall health impacts. CONCLUSIONS: Prevalence estimates for current cannabis consumption among voice patients from tertiary voice care clinics mirrored prevalence estimates reported for large, representative samples from Oregon and Pennsylvania. These findings provide valuable insight on the extent of cannabis consumption among voice patients.

Poly(aspartic acid)-Based Polymeric Nanoparticle for Local and Systemic mRNA Delivery.

Recently, therapeutics based on mRNA (mRNA) have attracted significant interest for vaccines, cancer immunotherapy, and gene editing. However, the lack of biocompatible vehicles capable of delivering mRNA to the target tissue and efficiently expressing the encoded proteins impedes the development of mRNA-based therapies for a variety of diseases. Herein, we report mRNA-loaded polymeric nanoparticles based on diethylenetriamine-substituted poly(aspartic acid) that induce protein expression in the lungs and muscles following intravenous and intramuscular injections, respectively. Animal studies revealed that the amount of polyethylene glycol (PEG) on the nanoparticle surface affects the translation of the delivered mRNA into the encoded protein in the target tissue. After systemic administration, only mRNA-loaded nanoparticles modified with PEG at a molar ratio of 1:1 (PEG/polymer) induce protein expression in the lungs. In contrast, protein expression was detected only following intramuscular injection of mRNA-loaded nanoparticles with a PEG/polymer ratio of 10:1. These findings suggest that the PEG density on the surface of poly(aspartic acid)-based nanoparticles should be optimized for different delivery routes depending on the purpose of the mRNA treatment.

An Advanced Thermal Decomposition Method to Produce Magnetic Nanoparticles with Ultrahigh Heating Efficiency for Systemic Magnetic Hyperthermia.

Due to the limited heating efficiency of available magnetic nanoparticles, it is difficult to achieve therapeutic temperatures above 44 °C in relatively inaccessible tumors during magnetic hyperthermia following systemic administration of nanoparticles at clinical dosage (≤10 mg kg-1 ). To address this, a method for the preparation of magnetic nanoparticles with ultrahigh heating capacity in the presence of an alternating magnetic field (AMF) is presented. The low nitrogen flow rate of 10 mL min-1 during the thermal decomposition reaction results in cobalt-doped nanoparticles with a magnetite (Fe3 O4 ) core and a maghemite (γ-Fe2 O3 ) shell that exhibit the highest intrinsic loss power reported to date of 47.5 nH m2 kg-1 . The heating efficiency of these nanoparticles correlates positively with increasing shell thickness, which can be controlled by the flow rate of nitrogen. Intravenous injection of nanoparticles at a low dose of 4 mg kg-1 elevates intratumoral temperatures to 50 °C in mice-bearing subcutaneous and metastatic cancer grafts during exposure to AMF. This approach can also be applied to the synthesis of other metal-doped nanoparticles with core-shell structures. Consequently, this method can potentially be used for the development of novel nanoparticles with high heating performance, further advancing systemic magnetic hyperthermia for cancer treatment.

Nanoparticle-Based Follistatin Messenger RNA Therapy for Reprogramming Metastatic Ovarian Cancer and Ameliorating Cancer-Associated Cachexia.

This study presents the first messenger RNA (mRNA) therapy for metastatic ovarian cancer and cachexia-induced muscle wasting based on lipid nanoparticles that deliver follistatin (FST) mRNA predominantly to cancer clusters following intraperitoneal administration. The secreted FST protein, endogenously synthesized from delivered mRNA, efficiently reduces elevated activin A levels associated with aggressive ovarian cancer and associated cachexia. By altering the cancer cell phenotype, mRNA treatment prevents malignant ascites, delays cancer progression, induces the formation of solid tumors, and preserves muscle mass in cancer-bearing mice by inhibiting negative regulators of muscle mass. Finally, mRNA therapy provides synergistic effects in combination with cisplatin, increasing the survival of mice and counteracting muscle atrophy induced by chemotherapy and cancer-associated cachexia. The treated mice develop few nonadherent tumors that are easily resected from the peritoneum. Clinically, this nanomedicine-based mRNA therapy can facilitate complete cytoreduction, target resistance, improve resilience during aggressive chemotherapy, and improve survival in advanced ovarian cancer.

Neural Mechanisms of Cancer Cachexia.

Nearly half of cancer patients suffer from cachexia, a metabolic syndrome characterized by progressive atrophy of fat and lean body mass. This state of excess catabolism decreases quality of life, ability to tolerate treatment and eventual survival, yet no effective therapies exist. Although the central nervous system (CNS) orchestrates several manifestations of cachexia, the precise mechanisms of neural dysfunction during cachexia are still being unveiled. Herein, we summarize the cellular and molecular mechanisms of CNS dysfunction during cancer cachexia with a focus on inflammatory, autonomic and neuroendocrine processes and end with a discussion of recently identified CNS mediators of cachexia, including GDF15, LCN2 and INSL3.

The State of Peptide Receptor Radionuclide Therapy and Its Sequencing among Current Therapeutic Options for Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common form of neuroendocrine neoplasia, but there is no current consensus for the sequencing of approved therapies, particularly with respect to peptide receptor radionuclide therapy (PRRT). This comprehensive review evaluates the data supporting approved therapies for GEP-NETs and recommendations for therapeutic sequencing with a focus on how PRRT currently fits within sequencing algorithms. The current recommendations for PRRT sequencing restrict its use to metastatic, inoperable, progressive midgut NETs; however, this may change with emerging data to suggest that PRRT might be beneficial as neoadjuvant therapy for inoperable tumors, is more tolerable than other treatment modalities following first-line standard dose somatostatin analogs, and can be used as salvage therapy after disease relapse following prior successful cycles of PRRT. PRRT has also been shown to reduce tumor burden, improve quality of life, and prolong the time to disease progression in a broad spectrum of patients with GEP-NETs. As the various potential benefits of PRRT in GEP-NET therapy continues to expand, it is necessary to review and critically evaluate our treatment algorithms for GEP-NETs.

Nanomedicines for Endometriosis: Lessons Learned from Cancer Research.

Endometriosis is an incurable gynecological disease characterized by the abnormal growth of endometrium-like tissue, characteristic of the uterine lining, outside of the uterine cavity. Millions of people with endometriosis suffer from pelvic pain and infertility. This review aims to discuss whether nanomedicines that are promising therapeutic approaches for various diseases have the potential to create a paradigm shift in endometriosis management. For the first time, the available reports and achievements in the field of endometriosis nanomedicine are critically evaluated, and a summary of how nanoparticle-based systems can improve endometriosis treatment and diagnosis is provided. Parallels between cancer and endometriosis are also drawn to understand whether some fundamental principles of the well-established cancer nanomedicine field can be adopted for the development of novel nanoparticle-based strategies for endometriosis. This review provides the state of the art of endometriosis nanomedicine and perspective for researchers aiming to realize and exploit the full potential of nanoparticles for treatment and imaging of the disorder.

Nanoparticle-Based Platform for Activatable Fluorescence Imaging and Photothermal Ablation of Endometriosis.

Endometriosis is a painful disorder where endometrium-like tissue forms lesions outside of the uterine cavity. Intraoperative identification and removal of these lesions are difficult. This study presents a nanoplatform that concurrently delineates and ablates endometriosis tissues using real-time near-infrared (NIR) fluorescence and photothermal therapy (PTT). The nanoplatform consists of a dye, silicon naphthalocyanine (SiNc), capable of both NIR fluorescence imaging and PTT, and a polymeric nanoparticle as a SiNc carrier to endometriosis tissue following systemic administration. To achieve high contrast during fluorescence imaging of endometriotic lesions, nanoparticles are constructed to be non-fluorescent prior to internalization by endometriosis cells. In vitro studies confirm that these nanoparticles activate the fluorescence signal following internalization in macaque endometrial stromal cells and ablate them by increasing cellular temperature to 53 ° C upon interaction with NIR light. To demonstrate in vivo efficiency of the nanoparticles, biopsies of endometrium and endometriosis from rhesus macaques are transplanted into immunodeficient mice. Imaging with the intraoperative Fluobeam 800 system reveals that 24 h following intravenous injection, nanoparticles efficiently accumulate in, and demarcate, endometriotic grafts with fluorescence. Finally, the nanoparticles increase the temperature of endometriotic grafts up to 47 °C upon exposure to NIR light, completely eradicating them after a single treatment.

Cannabis Inhalation and Voice Disorders: A Systematic Review.

IMPORTANCE: Widespread legalization of cannabis throughout the United States has created a knowledge gap that leaves practitioners who manage voice disorders uninformed about this substance, commonly referred to as marijuana. The association of cannabis inhalation and voice disorders is rarely reported. However, studies on the association between cannabis inhalation and respiration have been published; therefore, these studies may serve as a surrogate for studies on the association between cannabis and phonation. OBJECTIVE: To review the literature on the association of cannabis-only consumption via smoking and vaping with the health and function of the vocal mechanism to aid clinical recommendations for patients with voice disorders. EVIDENCE REVIEW: This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. An electronic search in MEDLINE via PubMed, CINAHL, Scopus, and Cochrane Library databases for original research on inhaled cannabis was performed from January 1, 2007, through August 10, 2018. The search strategy included Medical Subject Heading terms and keywords marijuana, cannabis, respiratory, lungs, larynx, voice, phonation, and vocal with Boolean operators (AND, OR). Studies of participants of legal age (≥18 years) who had cannabis-only clinical data and used nonsynthetic cannabinoids were included in the review. FINDINGS: This systematic review identified 6 clinical science studies and 13 basic science or animal studies. The only study to date that has evaluated the association between laryngeal symptoms and inhaling cannabis found that human smokers assessed by indirect laryngoscopy with mirror examination exhibited dark vocal folds. Analyses of 6 other clinical science articles indicated an association between cannabis inhalation and respiratory problems that were reduced with smoking cessation or switching to vaporizing. Lung function was maintained in light cannabis smoke exposure after long-term use. Analyses of basic science and animal articles indicated that cannabis smoking was associated with lung and throat injuries attributable to smoking degradation by-products, similar to injuries seen in human tobacco smoking. CONCLUSIONS AND RELEVANCE: The findings suggest that cannabis-only smoking is associated with changes in vocal fold appearance, respiratory symptoms, and negative lung function changes, especially in heavy smokers. Details about patterns of cannabis consumption appear to be relevant to gather in patients with voice disorders. Results further suggest that cannabis smokers presenting with a voice disorder should undergo laryngeal imaging and complete pulmonary function testing when indicated and receive education about consumption methods and their association with voice disorders.

Transarterial Delivery of a Biodegradable Single-Agent Theranostic Nanoprobe for Liver Tumor Imaging and Combinatorial Phototherapy.

PURPOSE: To assess selective accumulation of biodegradable nanoparticles within hepatic tumors after transarterial delivery for in vivo localization and combinatorial phototherapy. MATERIALS AND METHODS: A VX2 hepatic tumor model was used in New Zealand white rabbits. Transarterial delivery of silicon naphthalocyanine biodegradable nanoparticles was performed using a microcatheter via the proper hepatic artery. Tumors were exposed via laparotomy, and nanoparticles were observed by near-infrared (NIR) fluorescence imaging. For phototherapy, a handheld NIR laser (785 nm) at 0.6 W/cm2 was used to expose tumor or background liver, and tissue temperatures were assessed with a fiberoptic temperature probe. Intratumoral reactive oxygen species formation was assessed using a fluorophore (2',7'-dichlorodihydrofluorescein diacetate). RESULTS: Nanoparticles selectively accumulated within viable tumor by NIR fluorescence. Necrotic portions of tumor did not accumulate nanoparticles, consistent with a vascular distribution. NIR-dependent heat generation was observed with nanoparticle-containing tumors, but not in background liver. No heat was generated in the absence of NIR laser light. Reactive oxygen species were formed in nanoparticle-containing tumors exposed to NIR laser light, but not in background liver treated with NIR laser or in tumors in the absence of NIR light. CONCLUSIONS: Biodegradable nanoparticle delivery to liver tumors from a transarterial approach enabled selective in vivo tumor imaging and combinatorial phototherapy.

Sucralose-Enhanced Degradation of Electronic Cigarette Liquids during Vaping.

Electronic cigarette liquids (e-liquids) with sweetener additives such as sucralose, a synthetic chlorinated disaccharide, are popular among some e-cigarette consumers; sucralose can be added either by the manufacturer or by the consumer. The prevalence of sucralose in commercial e-liquids is not known, nor is the typical concentration of sucralose when present; labels are not required to disclose ingredient information. Here, we report the effects of sucralose on e-liquid degradation upon e-cigarette vaping as studied using 1H NMR spectroscopy, ion chromatography, and gas chromatography coupled with detection by mass spectrometry or flame ionization detector. Sucralose was found to be subject to degradation when included in propylene glycol + glycerol based e-liquids and vaped; the presence of sucralose in the e-liquids also resulted in altered and enhanced solvent degradation. In particular, production of aldehydes (carbonyls) and hemiacetals (which have implications for health) was enhanced, as demonstrated by 1H NMR. The presence of sucralose at 0.03 mol % (0.14 wt %) in an e-liquid also resulted in production of potentially harmful organochlorine compounds and catalyzed the cyclization of aldehydes with solvents to acetals upon vaping; the presence of chloride in e-liquid aerosols was confirmed by ion chromatography. Quantities of sucralose as low as 0.05 mol % (0.24 wt %) in e-liquids lead to significant production of solvent degradation products.

Biocompatible Nanoclusters with High Heating Efficiency for Systemically Delivered Magnetic Hyperthermia.

Despite its promising therapeutic potential, nanoparticle-mediated magnetic hyperthermia is currently limited to the treatment of localized and relatively accessible cancer tumors because the required therapeutic temperatures above 40 °C can only be achieved by direct intratumoral injection of conventional iron oxide nanoparticles. To realize the true potential of magnetic hyperthermia for cancer treatment, there is an unmet need for nanoparticles with high heating capacity that can efficiently accumulate at tumor sites following systemic administration and generate desirable intratumoral temperatures upon exposure to an alternating magnetic field (AMF). Although there have been many attempts to develop the desired nanoparticles, reported animal studies reveal the challenges associated with reaching therapeutically relevant intratumoral temperatures following systemic administration at clinically relevant doses. Therefore, we developed efficient magnetic nanoclusters with enhanced heating efficiency for systemically delivered magnetic hyperthermia that are composed of cobalt- and manganese-doped, hexagon-shaped iron oxide nanoparticles (CoMn-IONP) encapsulated in biocompatible PEG-PCL (poly(ethylene glycol)- b-poly(ε-caprolactone))-based nanocarriers. Animal studies validated that the developed nanoclusters are nontoxic, efficiently accumulate in ovarian cancer tumors following a single intravenous injection, and elevate intratumoral temperature up to 44 °C upon exposure to safe and tolerable AMF. Moreover, the obtained results confirmed the efficiency of the nanoclusters to generate the required intratumoral temperature after repeated injections and demonstrated that nanocluster-mediated magnetic hyperthermia significantly inhibits cancer growth. In summary, this nanoplatform is a milestone in the development of systemically delivered magnetic hyperthermia for the treatment of cancer tumors that are difficult to access for intratumoral injection.