Menopause and MHT in 2024: addressing the key controversies - an International Menopause Society White Paper.

The vision of the International Menopause Society (IMS) is that all women across the world will have easy and equitable access to evidence-based knowledge and health care, empowering them to make fully informed midlife health choices. The aim of this White Paper is to provide a well-balanced educational narrative of the menopause and menopause hormone therapy (MHT) from IMS experts, leading into World Menopause Day 2024. This is achieved by exploring the anthropology and history of menopause, the principles and controversies of prescribing MHT, and by placing this into regulatory and menopause society contexts. The White Paper also lays the groundwork for the forthcoming updated IMS recommendations on menopause and will act as a blueprint for the future ethical management of menopause from practical and aspirational perspectives. An important section of the paper is 'The 5Ws of prescribing MHT': WHO is MHT for; WHAT types and doses of MHT; WHEN should MHT be started and stopped; WHY is MHT important; WHERE can MHT be accessed? A key points summary of this information is provided for healthcare professionals and the public. The summary provides 'easy to access' advice regarding several recent controversial MHT prescribing issues in the healthcare and media spotlights.

Molecular detection of extended-spectrum ß-lactamase- and carbapenemase-producing Klebsiella pneumoniae isolates in southwest Iran.

OBJECTIVE: The global emergence of carbapenem-resistant Klebsiella pneumoniae is considered a significant contemporary concern., as carbapenems are the last resort for treating infections caused by multidrug-resistant Gram-negative bacteria. This study aimed to investigate the carbapenem-resistance genes in extended-spectrum ß-lactamase producing K. pneumoniae isolates. METHODS: Seventy-five non-duplicate clinical K. pneumoniae strains were isolated from urine, blood, sputum, and wound samples. Antimicrobial susceptibility tests for 12 different antibiotics were performed using the disk diffusion method, followed by determining minimum inhibitory concentrations of imipenem and meropenem. Phenotypic detection of extended-spectrum ß-lactamase and carbapenemase enzymes was performed by double-disc synergy test and modified Hodge test, respectively. PCR assay further investigated resistant isolates for extended-spectrum ß-lactamase and carbapenemase-encoding genes. RESULTS: The highest and lowest resistance rates were observed against ampicillin (93.3%) and tigecycline (9.3%). According to phenotypic tests, 46.7% of isolates were positive for extended-spectrum ß-lactamase enzymes and 52.8% for carbapenemase. A total of 11 isolates contained carbapenemase genes, with blaOXA-48 (19.4%; 7/36) being the predominant gene, followed by blaNDM (8.3%; 3/36). CONCLUSION: The study's findings reveal the alarming prevalence of beta-lactamase enzymes in K. pneumoniae strains. Early detection of carbapenem-resistant isolates and effective infection control measures are necessary to minimise further spread, as carbapenem resistance has become a public health concern.

Menopause: Why is Everyone Talking About it Now?

There is an interest in menopause that demands answers and solutions. Menopause affects each women differently and hence it is unique and needs to be talked about. This focus has led to improvement in women's health bringing about better outcome in physical and mental health. Increase in life expectancy has led to menopausal health care, an important issue. Menopause is not disease but causes symptoms that can differ individually. Occasionally, surgery, radiation, and medications can cause menopause. Menopause hormone therapy (MHT), nonhormonal therapy, and lifestyle modifications under supervision can improve menopausal outcome. It also gives window of opportunity to evaluate and reduce risk of cardiovascular, bone, and urogenital health. Menopausal women should be provided with all options that are suitable and feasible for improvement in their life.

Autophagy inhibition mediated via an injectable and NO-releasing hydrogel for amplifying the antitumor efficacy of mild magnetic hyperthermia.

While mild hyperthermia holds great potential in the treatment of solid tumors, the thermal stress-triggered self-repairing autophagy significantly compromises its efficacy. To circumvent this obstacle, an injectable hydrogel (NO-Gel) composed of thermosensitive poly(ethylene glycol)-polypeptide copolymers modified with abundant NO donors on their side chains is developed. Meanwhile, ferrimagnetic Zn0.5Fe2.5O4 magnetic nanoparticles (MNPs) with high magnetic-heat conversion efficiency are synthesized and loaded into NO-Gel to obtain MNPs@NO-Gel. The MNPs@NO-Gel system exhibits a sol-gel transition upon heating, and has the ability to perform multiple magnetic hyperthermia therapy (MHT) after only one administration due to the even distribution and strong immobilization of MNPs in NO-Gel. NO can be continuously liberated from NO-Gel and this process is markedly accelerated by MHT. Additionally, MNPs@NO-Gel maintains its integrity in vivo for over one month and the released MNPs are metabolized by the spleen. After a single administration of MNPs@NO-Gel at the tumor site, three mild MHT treatments with similar effects are fulfilled, and the sufficient supply of NO effectively inhibits MHT-induced autophagic flux via blocking the formation of autophagosomes and synchronously destroying lysosomes, thereby substantially boosting the efficacy of mild MHT. As a consequence, CT-26 colon tumors are completely eliminated without causing severe side-effects.

Hormone replacement therapy perspectives.

Hormone replacement therapy (HRT), also known as menopausal hormone therapy (MHT), was looked upon as a fountain of youth that kept women young and reduced cardiovascular disease. This led to a large-scale study called the Women's Health Initiative (WHI) that was conducted to show the cardiovascular benefits of HRT. This study was suspended early because of adverse side effects. The USFDA responded by slapping a "black box" warning on all HRT products. USFDA-approved bioidentical HRT formulations are safe and effective. We propose that these formulations have the "black box" warning removed so that doctors feel more confident in prescribing these products for symptoms of menopause and chronic conditions such as cardiovascular health. We propose eliminating the sale of products containing medroxyprogesterone acetate (MPA) because of the increased risk of heart attacks and breast cancers associated with this medication.

NIR-Responsive Methotrexate-Modified Iron Selenide Nanorods for Synergistic Magnetic Hyperthermic, Photothermal, and Chemodynamic Therapy.

Breast cancer is a malignant tumor with a high mortality rate among women. Therefore, it is necessary to develop novel therapies to effectively treat this disease. In this study, iron selenide nanorods (FeSe2 NRs) were designed for use in magnetic hyperthermic, photothermal, and chemodynamic therapy (MHT/PTT/CDT) for breast cancer. To illustrate their efficacy, FeSe2 NRs were modified with the chemotherapeutic agent methotrexate (MTX). MTX-modified FeSe2 (FeSe2-MTX) exhibited excellent controlled drug release properties. Fe2+ released from FeSe2 NRs induced the release of •OH from H2O2 via a Fenton/Fenton-like reaction, enhancing the efficacy of CDT. Under alternating magnetic field (AMF) stimulation and 808 nm laser irradiation, FeSe2-MTX exerted potent hyperthermic and photothermal effects by suppressing tumor growth in a breast cancer nude mouse model. In addition, FeSe2 NRs can be used for magnetic resonance imaging in vivo by incorporating their superparamagnetic characteristics into a single nanomaterial. Overall, we presented a novel technique for the precise delivery of functional nanosystems to tumors that can enhance the efficacy of breast cancer treatment.

Magnetic Hyperthermia Therapy for High-Grade Glioma: A State-of-the-Art Review.

Magnetic hyperthermia therapy (MHT) is a re-emerging treatment modality for brain tumors where magnetic nanoparticles (MNPs) are locally delivered to the brain and then activated with an external alternating magnetic field (AMF) to generate localized heat at a site of interest. Due to the recent advancements in technology and theory surrounding the intervention, clinical and pre-clinical trials have demonstrated that MHT may enhance the effectiveness of chemotherapy and radiation therapy (RT) for the treatment of brain tumors. The future clinical success of MHT relies heavily on designing MNPs optimized for both heating and imaging, developing reliable methods for the local delivery of MNPs, and designing AMF systems with integrated magnetic particle imaging (MPI) for use in humans. However, despite the progression of technological development, the clinical progress of MHT has been underwhelming. This review aims to summarize the current state-of-the-art of MHT and offers insight into the current barriers and potential solutions for moving MHT forward.

Menopausal Hormone Therapy in Women with Type 2 Diabetes Mellitus: An Updated Review.

Menopause is accompanied by several metabolic adaptations, which are related to insulin resistance, increased total body fat mass, and central abdominal fat accumulation, predisposing women to type 2 diabetes mellitus (T2DM) development. Metabolic syndrome has a high prevalence in postmenopausal women, indicating the loss of estrogen protection on metabolic and cardiovascular health. Moreover, earlier age at menopause has been related to increased risk of T2DM. Menopausal hormone therapy (MHT) has favorable results in glucose metabolism. Indeed, it reduces the risk of T2DM in women without this condition and improves glycemic control in women with T2DM. Before MHT initiation in women with clinical indications, it is imperative to assess their cardiovascular disease (CVD) risk, using official electronic algorithms for score calculation. The latter will determine regimen, dose, and administration route of MHT. Oral estrogens are preferable in women with low CVD risk, while transdermal administration is indicated in those with moderate and high CVD risk, as the risk of stroke and venous thromboembolism (VTE) is increased with oral administration. Oral 17ß-estradiol is usually preferred in women with T2DM, as this route has more beneficial effects on glucose metabolism. Oral estrogens are also suggested in perimenopausal or recently postmenopausal women with low CVD risk. Although oral estrogens have favorable effects when indicated, the risk of VTE or stroke should always be considered. Micronized progesterone, dydrogesterone, and transdermal norethisterone are the progestogens used in postmenopausal women with T2DM and intact uterus. MHT should not be initiated in women > 60 years or > 10 years in menopause, as there is an increased thromboembolic risk in women with established atherosclerosis and no additional cardiovascular benefit in women without atherosclerosis. In conclusion, MHT administration in postmenopausal women with T2DM can be safe and effective as long as the therapeutic regimen has been properly selected according to their cardiovascular, metabolic, and fracture risk.

Biosynthesis, characterization, magnetic hyperthermia, and in vitro toxicity evaluation of quercetin-loaded magnetoliposome lipid bilayer hybrid system on MCF-7 breast cancer.

Novel biocompatible and effective hyperthermia (HT) treatment materials for breast cancer therapeutic have recently attracting researchers, because of their effective ablation of cancer cells and negligible damage to healthy cells. Magnetoliposome (MLs) have numerous possibilities for utilize in cancer treatment, including smart drug delivery (SDD) mediated through alternating magnetic fields (AMF). In this work, magnesium ferrite (MgFe2O4) encapsulated with liposomes lipid bilayer (MLs), Quercetin (Q)-loaded MgFe2O4@Liposomes (Q-MLs) nano-hybrid system were successfully synthesized for magnetic hyperthermia (MHT) and SDD applications. The hybrid system was well-investigated by different techniques using X-ray diffraction (XRD), Fourier transforms infrared spectroscopy (FT-IR), Energy dispersive X-ray (EDX), Vibrating sample magnetometer (VSM), Transmission electron microscope (TEM), and Zeta Potential (ZP). The characterization results confirmed the improving quercetin-loading on the MLs surface. TEM analysis indicated the synthesized MgFe2O4, MLs, and Q-MLs were spherical with an average size of 23.7, 35.5, and 329.5 nm, respectively. The VSM results revealed that the MgFe2O4 exhibit excellent and effective saturation magnetization (MS) (40.5 emu/g). Quercetin drug loading and entrapment efficiency were found to be equal to 2.1 ± 0.1% and 42.3 ± 2.2%, respectively. The in-vitro Q release from Q-loaded MLs was found 40.2% at pH 5.1 and 69.87% at pH 7.4, verifying the Q-loading pH sensitivity. The MLs and Q-MLs hybrid system as MHT agents exhibit specific absorption rate (SAR) values of 197 and 205 W/g, correspondingly. Furthermore, the Q-MLs cytotoxicity was studied on the MCF-7 breast cancer cell line, and the obtained data demonstrated that the Q-MLs have a high cytotoxicity effect compared to MLs and free Q.

Reproductive factors, hormonal interventions, and gastric cancer risk in the Stomach cancer Pooling (StoP) Project.

BACKGROUND: Gastric cancer incidence is higher in men, and a protective hormone-related effect in women is postulated. We aimed to investigate and quantify the relationship in the Stomach cancer Pooling (StoP) Project consortium. METHODS: A total of 2,084 cases and 7,102 controls from 11 studies in seven countries were included. Summary odds ratios (ORs) and 95% confidence intervals (CIs) assessing associations of key reproductive factors and menopausal hormone therapy (MHT) with gastric cancer were estimated by pooling study-specific ORs using random-effects meta-analysis. RESULTS: A duration of fertility of ≥ 40 years (vs. < 20), was associated with a 25% lower risk of gastric cancer (OR = 0.75; 95% CI: 0.58-0.96). Compared with never use, ever, 5-9 years and ≥ 10 years use of MHT in postmenopausal women, showed ORs of 0.73 (95% CI: 0.58-0.92), 0.53 (95% CI: 0.34-0.84) and 0.71 (95% CI: 0.50-1.00), respectively. The associations were generally similar for anatomical and histologic subtypes. CONCLUSION: Our results support the hypothesis that reproductive factors and MHT use may lower the risk of gastric cancer in women, regardless of anatomical or histologic subtypes. Given the variation in hormones over the lifespan, studies should address their effects in premenopausal and postmenopausal women. Furthermore, mechanistic studies may inform potential biological processes.

Cobalt ferrite nanoparticle for the elimination of CD133+CD44+ and CD44+CD24-, in breast and skin cancer stem cells, using non-ionizing treatments.

Background: Cancer stem cells (CSCs) are the most challenging issue in cancer treatment, because of their high resistance mechanisms, that can cause tumor recurrence after common cancer treatments such as drug and radiation based therapies, and the insufficient efficiency of common treatments in CSCs removal and the recurrence of tumors after these treatments, it is essential to consider other methods, including non-ionizing treatments likes light-based treatments and magnetic hyperthermia (MHT). Method and material: After synthesis, characterization and investigation, the toxicity of novel on A375 and MAD-MB-231 cell lines, magnetic hyperthermia and light-based treatments were applied. MTT assay and flow cytometry was employed to determine cell survival. the influence of combination therapy on CD44 + CD24-and CD133 + CD44+ cell population, Comparison and evaluation of combination treatments was done respectively using Combination Indices (CIs). Result: The final nanoparticle has a high efficiency in producing hydroxyl radicals and generating heat in MHT. According to CIs, we can conclude that combined using of light-based treatment and MHT in the presence of final synthesized nanoparticle have synergistic effect and a high ability to reduce the population of stem cells in both cell lines compared to single treatments. Conclusion: In this study a novel multi-functional nanoplatform acted well in dual and triple combined treatments, and showed a good performance in the eradication of CSCs, in A375 and MAD-MB-231 cell lines.

Menopausal hormone therapy and risk of seropositive rheumatoid arthritis: A nationwide cohort study in Korea.

OBJECTIVES: This retrospective cohort study aimed to investigate the impact of menopausal hormone therapy (MHT) on the incidence of rheumatoid arthritis (RA) in postmenopausal women and to examine the effects of each specific MHT drug. METHODS: In this Korean population-based cohort study, 452,124 women aged > 40 years who consulted a healthcare provider for menopause were evaluated from January 1, 2011, to December 31, 2014. After propensity score matching, 138,991 pairs were included in the MHT and non-MHT groups. Participants were followed up until December 31, 2020. RA was defined according to the International Classification of Diseases, 10th edition, limited to seropositive RA (M05). RESULTS: RA developed in 567 (0.4 %) of the 138,424 patients in the MHT group. The RA risk in the MHT group was not significantly increased compared with that of controls (hazard ratio [HR] 1.12, 95 % confidence interval [CI] 0.998-1.256). However, MHT use for ≤ 3 years was associated with an increased risk of RA (HR 1.277, 95 % CI 1.127-1.447). When estrogen/progestogen was used, the HR was 1.24 (95 % CI 1.05-1.46), whereas when tibolone was used, the HR was 1.33 (95 % CI 1.13-1.57). CONCLUSION: The use of MHT did not show a significant impact on the development of RA in postmenopausal women. However, a subanalysis that specifically examined the duration of MHT revealed a noteworthy increase in the risk of RA during the initial 3 years of MHT use.

Uncovering the Resistance Mechanisms in Extended-Drug-Resistant Pseudomonas aeruginosa Clinical Isolates: Insights from Gene Expression and Phenotypic Tests.

(1) Background: The purpose of the study was to describe the activity of mex efflux pumps in Multidrug-Resistant (MDR) clinical isolates of Pseudomonas aeruginosa and to compare the carbapenem-resistance identification tests with PCR; (2) Methods: Sixty MDR P. aeruginosa were analyzed for detection of carbapenemase by disk diffusion inhibitory method, carbapenem inactivation method and Modified Hodge Test. Endpoint PCR was used to detect 7 carbapenemase genes (blaKPC, blaOXA48-like, blaNDM, blaGES-2, blaSPM, blaIMP, blaVIM) and mcr-1 for colistin resistance. The expression of mexA, mexB, mexC, mexE and mexX genes corresponding to the four main efflux pumps was also evaluated; (3) Results: From the tested strains, 71.66% presented at least one carbapenemase gene, with blaGES-2 as the most occurring gene (63.3%). Compared with the PCR, the accuracy of phenotypic tests did not exceed 25% for P. aeruginosa. The efflux pump genes were present in all strains except one. In 85% of the isolates, an overactivity of mexA, mexB and mostly mexC was detected. Previous treatment with ceftriaxone increased the activity of mexC by more than 160 times; (4) Conclusions: In our MDR P. aeruginosa clinical isolates, the carbapenem resistance is not accurately detected by phenotypic tests, due to the overexpression of mex efflux pumps and in a lesser amount, due to carbapenemase production.

An injectable and active hydrogel induces mutually enhanced mild magnetic hyperthermia and ferroptosis.

Magnetic hyperthermia therapy (MHT) is a promising new modality to deal with solid tumors, yet the low magnetic-heat conversion efficacy, magnetic resonance imaging (MRI) artifacts, easy leakage of magnetic nanoparticles, and thermal resistance are the main obstacles to expand its clinical applications. Herein, a synergistic strategy based on a novel injectable magnetic and ferroptotic hydrogel is proposed to overcome these bottlenecks and boost the antitumor efficacy of MHT. The injectable hydrogel (AAGel) exhibiting a sol-gel transition upon heating is made of arachidonic acid (AA)-modified amphiphilic copolymers. Ferrimagnetic Zn0.4Fe2.6O4 nanocubes with high-efficiency hysteresis loss mechanism are synthesized and co-loaded into AAGel with RSL3, a potent ferroptotic inducer. This system maintains the temperature-responsive sol-gel transition, and provides the capacity of multiple MHT and achieves accurate heating after a single injection owing to the firm anchoring and uniform dispersion of nanocubes in the gel matrix. The high magnetic-heat conversion efficacy of nanocubes coupled with the application of echo limiting effect avoids the MRI artifacts during MHT. Besides the function of magnetic heating, Zn0.4Fe2.6O4 nanocubes combined with multiple MHT can sustain supply of redox-active iron to generate reactive oxygen species and lipid peroxides and accelerate the release of RLS3 from AAGel, thus enhancing the antitumor efficacy of ferroptosis. In turn, the reinforced ferroptosis can alleviate the MHT-triggered thermal resistance of tumors by impairment of the protective heat shock protein 70. The synergy strategy achieves the complete elimination of CT-26 tumors in mice without causing local tumor recurrence and other severe side effects.

Assessment of knowledge, understanding and awareness of Chinese women clinical staff towards menopause hormone therapy: a survey study.

Menopausal Hormone Therapy (MHT) is recommended for climacteric peri- and postmenopausal symptoms. The rate of use of MHT in China is much lower than the western regions. Therefore, a survey was conducted for the understanding and utilization of MHT among clinical staff in various hospitals of China. A total of 3216 eligible questionnaires were included for the evaluation. According to 19.2% participant opinion, MHT could relieve menopausal symptoms, whereas the majority had no knowledge of the benefits and risks of MHT. The most common concern about MHT was the risk of cancer and about 430 (13.4%) and 176 (5.5%) participants were apprehensive that MHT could increase the risk of breast and endometrial cancer, respectively. This survey demonstrated that the knowledge of clinical staff was not comprehensive and they should be educated more about the use of MHT so that this knowledge can be imbibed into the general population.Impact StatementWhat is already known on this subject? Menopausal Hormone Therapy (MHT) is recommended for climacteric peri- and postmenopausal symptoms. The rate of use of MHT in China is much lower than the western regions.What do the results of this study add? Only 19.2% of the respondents were of the opinion that MHT could relieve menopausal symptoms. The most common concern about MHT was the risk of cancer and about 430 (13.4%) and 176 (5.5%) participants were apprehensive that MHT could increase the risk of breast and endometrial cancer.What are the implications of these findings for clinical practice and/or further research? The survey demonstrated that Chinese medical professionals had some understanding about MHT, but their knowledge was not comprehensive. Thus, it is necessary to educate these medical professionals which in turn will help them to imbibe this knowledge among the general population.

Functional Brain Asymmetry and Menopausal Treatments: Is There a Link?

Background and Objectives: The human brain presents a functional asymmetry for every cognitive function, and it is possible that sexual hormones could have an impact on it. Visual−spatial attention, one of the most lateralized functions and one that is mainly dependent on the right hemisphere, represents a sentinel for functional cerebral asymmetry (FCA). The aim of this study was to evaluate whether menopausal hormone therapy (MHT) or phytoestrogens could modulate FCA in postmenopausal women. Materials and Methods: We enrolled postmenopausal women who were taking MHT or soy isoflavones or receiving no therapy and asked them to perform the line bisection test at study enrollment and after 18 and 36 months. Results: Ninety women completed the follow-up. At zero time, women who had not been subjected to therapy showed a leftward deviation (F = −3.0), whereas, after 36 months, the test results showed a rightward deviation (F = 4.5; p < 0.01). Women taking MHT showed a leftward deviation at the start (F = −3.0) and a persistent leftward deviation after 36 months (F = −4.0; p = 0.08). Conversely, women taking soy isoflavones started with a leftward deviation (F = −3.0) that became rightward (F = 3.0), with a significant difference shown after 36 months (p < 0.01). Conclusions: Our data suggest that hormonal modulation improves the interplay between the two hemispheres and reduces FCA. We propose, therefore, that the functions of the right hemisphere are mainly affected by aging and that this could be one of the reasons why the right hemisphere is more susceptible to the effects of MHT.

The use of menopausal hormone therapy after cancer.

The changing landscape of gynaecological and breast cancers has involved the development of more targeted and effective therapies, and improved survival. Ultimately, these changes result in an increasing number of women surviving their cancer diagnosis, with increasing emphasis on quality-of-life issues by following treatments. Many of these women experience severe menopausal symptoms associated with cancer treatments, but the hormonal nature of many gynaecological and breast cancers complicates the effective management of these symptoms. Generally, there is a paucity of high-quality data directly examining the safety of menopausal hormone therapy (MHT) following many female cancers, and more research is needed with long term follow-up to ensure the provision of comprehensive, patient-focussed care. This article aims to synthesise and evaluate the current evidence to provide comprehensive yet accessible information to clinicians to help guide treatment decisions about the use of MHT in women, who have experienced, or are at increased risk of, both gynaecological and breast cancers. These treatment decisions should often be made in a multi-disciplinary setting which encourages shared decision-making with patients.

Molecular characterization of NDM-1-producing Pseudomonas aeruginosa isolates from hospitalized patients in Iran.

BACKGROUND: The emergence of carbapenem-resistant Pseudomonas aeruginosa is one of the most important challenges in a healthcare setting. The aim of this study is double-locus sequence typing (DLST) typing of blaNDM-1 positive P. aeruginosa isolates. METHODS: Twenty-nine blaNDM-1 positive isolates were collected during three years of study from different cities in Iran. Modified hodge test (MHT), double-disk synergy test (DDST) and double-disk potentiation test (DDPT) was performed for detection of carbapenemase and metallo-beta-lactamase (MBL) producing blaNDM-1 positive P. aeruginosa isolates. The antibiotic resistance genes were considered by PCR method. Clonal relationship of blaNDM-1 positive was also characterized using DLST method. RESULTS: Antibiotic susceptibility pattern showed that all isolates were resistant to imipenem and ertapenem. DDST and DDPT revealed that 15/29 (51.8%) and 26 (89.7%) of blaNDM-1 positive isolates were MBL producing isolates, respectively. The presence of blaOXA-10, blaVIM-2, blaIMP-1 and blaSPM genes were detected in 86.2%, 41.4%, 34.5% and 3.5% isolates, respectively. DLST typing results revealed the main cluster were DLST 25-11 with 13 infected or colonized patients. CONCLUSIONS: The presence of blaNDM-1 gene with other MBLs encoding genes in P. aeruginosa is a potential challenge in the treatment of microorganism infections. DLST showed partial diversity among 29 blaNDM-1 positive isolates.

Novel Nanoparticle-Based Cancer Treatment, Effectively Inhibits Lung Metastases and Improves Survival in a Murine Breast Cancer Model.

Sarah Nanoparticles (SaNPs) are unique multicore iron oxide-based nanoparticles, developed for the treatment of advanced cancer, following standard care, through the selective delivery of thermal energy to malignant cells upon exposure to an alternating magnetic field. For their therapeutic effect, SaNPs need to accumulate in the tumor. Since the potential accumulation and associated toxicity in normal tissues are an important risk consideration, biodistribution and toxicity were assessed in naïve BALB/c mice. Therapeutic efficacy and the effect on survival were investigated in the 4T1 murine model of metastatic breast cancer. Toxicity evaluation at various timepoints did not reveal any abnormal clinical signs, evidence of alterations in organ function, nor histopathologic adverse target organ toxicity, even after a follow up period of 25 weeks, confirming the safety of SaNP use. The biodistribution evaluation, following SaNP administration, indicated that SaNPs accumulate mainly in the liver and spleen. A comprehensive pharmacokinetics evaluation, demonstrated that the total percentage of SaNPs that accumulated in the blood and vital organs was ~78%, 46%, and 36% after 4, 13, and 25 weeks, respectively, suggesting a time-dependent clearance from the body. Efficacy studies in mice bearing 4T1 metastatic tumors revealed a 49.6% and 70% reduction in the number of lung metastases and their relative size, respectively, in treated vs. control mice, accompanied by a decrease in tumor cell viability in response to treatment. Moreover, SaNP treatment followed by alternating magnetic field exposure significantly improved the survival rate of treated mice compared to the controls. The median survival time was 29 ± 3.8 days in the treated group vs. 21.6 ± 4.9 days in the control, p-value 0.029. These assessments open new avenues for generating SaNPs and alternating magnetic field application as a potential novel therapeutic modality for metastatic cancer patients.