Laminated holmium-166-containing electrospun bandages for use against skin cancer.

The number of non-melanoma skin cancer (NMSC) cases in the US will increase significantly over the next decade due to a rise in UV exposure. One of the treatment methods used to remove NMSC lesions is radiation therapy. The two types of radiation therapy used in the clinic are external beam therapy and brachytherapy. However, both require specialized on-site instrumentation and for patients to remain immobile. In this work, we studied an alternative radiation therapy - one that does not require expensive on-site equipment and would allow for enhanced patient mobility and, thus, comfort. We prepared sealed source, nylon-laminated holmium-166-containing radiotherapeutic bandages and used them in C3H/HeN mice with murine SCCVII tumor grafts. Overall, tumor sizes were smallest when treated with therapeutically relevant radiation doses via radiotherapeutic bandages (compared to controls), and no histological evidence of toxicity to tissues was observed. Thus, our optimized radiotherapeutic bandage offers a flexible approach to treating NMSC.

Preparation and Optimization of an Ultraflexible Liposomal Gel for Lidocaine Transdermal Delivery.

The pain caused by lidocaine injections into the face prior to facial plastic surgeries intended to remove growths or tumorous lesions has been reported by many patients to be the worst part of these procedures. However, the lidocaine gels and creams currently on the market do not deliver an equal or better local anesthetic effect to replace these injections. To develop an alternative to the painful local anesthetic injection, we prepared ultraflexible liposomes using soy phosphatidylcholine, lidocaine, and different amounts of sodium cholate, a surfactant. The prepared ultraflexible liposomes (UFLs) were examined for particle size, zeta potential, cytotoxicity, and in vitro release. By using a carbomer as a gelling agent, the prepared UFL lidocaine gels were evaluated for their penetration ability in a Franz diffusion cell, using Strat-M membranes. The formulation achieving the highest amount of penetrated lidocaine was chosen for further pH, viscosity, and stability tests. The local anesthetic efficacy of the formulation was investigated by an in vivo tail-flick test in rats. Our findings suggested that this topical gel formulated with ultraflexible liposomal lidocaine has enhanced skin permeation ability, as well as an improved local analgesic effect from the lidocaine.

Optimization of DOTAP/chol Cationic Lipid Nanoparticles for mRNA, pDNA, and Oligonucleotide Delivery.

Lipid nanoparticles (LNPs) can be used as delivery vehicles for nucleic acid biotherapeutics. In fact, LNPs are currently being used in the Pfizer/BioNTech and Moderna COVID-19 vaccines. Cationic LNPs composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol (chol) LNPs have been classified as one of the most efficient gene delivery systems and are being tested in numerous clinical trials. The objective of this study was to examine the effect of the molar ratio of DOTAP/chol, PEGylation, and lipid to mRNA ratio on mRNA transfection, and explore the applications of DOTAP/chol LNPs in pDNA and oligonucleotide transfection. Here we showed that PEGylation significantly decreased mRNA transfection efficiency of DOTAP/chol LNPs. Among non-PEGylated LNP formulations, 1:3 molar ratio of DOTAP/chol in DOTAP/chol LNPs showed the highest mRNA transfection efficiency. Furthermore, the optimal ratio of DOTAP/chol LNPs to mRNA was tested to be 62.5 µM lipid to 1 µg mRNA. More importantly, these mRNA-loaded nanoparticles were stable for 60 days at 4 °C storage without showing reduction in transfection efficacy. We further found that DOTAP/chol LNPs were able to transfect pDNA and oligonucleotides, demonstrating the ability of these LNPs to transport the cargo into the cell nucleus. The influence of various factors in the formulation of DOTAP/chol cationic LNPs is thus described and will help improve drug delivery of nucleic acid-based vaccines and therapies.

Tirbanibulin: Topical Treatment for Actinic Keratosis.

We review here the pharmacology, pharmacokinetics, efficacy, dosage and administration, and place in therapy of tirbanibulin for the treatment of actinic keratosis (AK). A literature search using PubMed was conducted using the terms tirbanibulin (tirbanibulin) and actinic keratosis from September 2014 to February 2021. All English-language articles evaluating tirbanibulin were analyzed for this review. Tirbanibulin was granted approval for the treatment of AK of the face or scalp as a first-line therapy. It is administered at a dose of 2.5 mg in 250 mg of white or off-white ointment for a 25 cm2 contiguous treatment surface for 5 consecutive days. Adverse effects include flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration. This article discusses the clinical trials that led to the approval of tirbanibulin and comparison with other approved topical ointments indicated for the treatment of AK. In the clinical trials, all participants experienced a decrease in lesion size or saw complete clearance with minimal adverse effects.

A Method for Liposome Co-encapsulation of Phenethyl Isothiocyanate and Cisplatin and Determining Its Toxicity Against Lung and Lung Cancer Cells.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths in the United States. It is extremely difficult to treat, and its survival rate is low. Today, the most effective treatments are still those that implement the platinum anticancer drug cisplatin (CDDP) in combination with other drugs. We previously demonstrated that the naturally occurring compound phenethyl isothiocyanate (PEITC) could be used to sensitize NSCLC cells to CDDP. Furthermore, co-encapsulation of PEITC and CDDP in liposomes enhances their toxicity toward NSCLC cells. We have optimized a liposomal-PEITC-CDDP formulation and investigated its cytotoxicity. We determined that liposomal-PEITC-CDDP is much more toxic toward human NSCLC cell lines than it is toward human normal lung cell lines. In this chapter, we describe detailed methods for preparing liposomal-PEITC-CDDP and determining its cytotoxicity.

Physicochemical Factors That Influence the Biocompatibility of Cationic Liposomes and Their Ability to Deliver DNA to the Nuclei of Ovarian Cancer SK-OV-3 Cells.

Cationic liposomes composed of 3-[N-(N',N'-dimethylaminoethane)-carbamoyl] cholesterol (DC-chol) and dioleoylphosphatidylethanolamine (DOPE) have previously been shown to have applications in gene delivery. Our study aims to explore the effects of inclusion of polyethylene glycol (PEG) and using different molar ratios of DC-chol/DOPE on size, zeta potential, cytotoxicity and DNA delivery of DC-chol/DOPE liposomes. Our results show that PEGylation reduces the cytotoxicity of DC-chol/DOPE liposomes, and, furthermore, PEGylated liposome-DNA lipoplexes are smaller in size and more uniform in size distribution than those that are not PEGylated. Additionally, toxicity against ovarian cancer SKOV-3 cells decreases with the amount of cationic DC-chol present in the formulation; however, decreased delivery of DNA to cellular nuclei is also observed. Transfection with the PEGylated liposomes was successfully demonstrated using plasmid DNA with a known functional outcome. These results offer further insight into physicochemical properties important for cationic liposomes as vehicles for DNA delivery and demonstrate the potential of PEGylated DC-chol/DOPE liposomes as systemic delivery carriers for DNA-mediated ovarian cancer therapy.

Phenethyl Isothiocyanate-Containing Carbomer Gel for Use against Squamous Cell Carcinoma.

It is currently estimated that one in every five Americans will develop skin cancer during their lifetime. Squamous cell carcinoma (SCC) is a common type of skin cancer that can develop due to the skin's exposure to the sun. Herein, we prepared a topical gel containing 0.5% v/w phenethyl isothiocyanate (PEITC) for the treatment of SCC. PEITC is a naturally occurring isothiocyanate that has been shown to have efficacy against various types of cancer in preclinical studies. We first incorporated PEITC into a carbomer gel. A uniform formulation was prepared, and its viscosity was appropriate for topical application. We then demonstrated the release of PEITC from the gel into and through a Strat-M skin-like membrane. Finally, the effects of the PEITC-containing gel were tested against SCC and normal keratinocytes skin cells in culture, and these results were compared to those obtained for free 5-fluoruracil (5-FU), a commonly used skin-cancer drug. Our results show that a homogeneous PEITC-containing topical gel can be prepared and used to kill SCC cells. Thus, our formulation may be useful for treating SCC in the clinic.

Phenethyl Isothiocyanate and Cisplatin Co-Encapsulated in a Liposomal Nanoparticle for Treatment of Non-Small Cell Lung Cancer.

Lung cancer is the leading cause of cancer-related death in the Unites States, and approximately 85% of all lung cancers are classified as non-small cell lung cancer (NSCLC), which is extremely difficult to treat and its survival rate is low. After decades of clinical trials, the most effective treatments are still those that implement the first-generation platinum anticancer agent cisplatin (CDDP) in combination with other drugs. We previously demonstrated that the naturally-occurring compound phenethyl isothiocyanate (PEITC) can be used to sensitize NSCLC cells to CDDP. Furthermore, co-encapsulation of PEITC and CDDP in liposomes enhances their toxicity toward NSCLC cells. We here optimize liposomal-PEITC-CDDP, demonstrate the release of PEITC and CDDP from the nanoparticle, and show that liposomal-PEITC-CDDP is much more toxic toward both A549 and H596 human NSCLC cell lines than toward WI-38 and BEAS-2B human normal lung cell lines. Thus, we have prepared an efficacious therapy that has significantly higher toxicity toward cancer cell lines than normal cell lines.

Brigatinib: Novel ALK Inhibitor for Non-Small-Cell Lung Cancer.

OBJECTIVE: We review here the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, potential drug-drug interactions and place in therapy of brigatinib for abnormal anaplastic lymphoma kinase (ALK) specific non-small-cell lung cancer (NSCLC). DATA SOURCES: A literature search using PubMed was conducted using the terms brigatinib and ALK positive NSCLC from January 2013 to November 2018. STUDY SELECTION AND DATA EXTRACTION: All English-language articles evaluating brigatinib were analyzed for this review. DATA SYNTHESIS: Brigatinib was granted approval for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. It is administered at a dose of 90 mg orally once daily for the first 7 days then, if tolerated, increased to a dose of 180 mg orally once daily. Common adverse effects include nausea, fatigue, diarrhea, increased creatine phosphokinase levels, headache, dyspnea, and hypertension. Serious treatment-emergent adverse effects were pulmonary related. Relevance to Patient Care and Clinical Practice: This article discusses the clinical trials that led to the accelerated approval of brigatinib for its ability to overcome crizotinib-resistant mutations and for its increased central nervous system penetration properties. CONCLUSION: Brigatinib was granted accelerated approval for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. In a subset of NSCLC patients, brigatinib increases survival for approximately 1 year; however, side effects were detected.

Potassium as a pluripotency-associated element identified through inorganic element profiling in human pluripotent stem cells.

Despite their well-known function in maintaining normal cell physiology, how inorganic elements are relevant to cellular pluripotency and differentiation in human pluripotent stem cells (hPSCs) has yet to be systematically explored. Using total reflection X-ray fluorescence (TXRF) spectrometry and inductively coupled plasma mass spectrometry (ICP-MS), we analyzed the inorganic components of human cells with isogenic backgrounds in distinct states of cellular pluripotency. The elemental profiles revealed that the potassium content of human cells significantly differs when their cellular pluripotency changes. Pharmacological treatment that alters cell membrane permeability to potassium affected the maintenance and establishment of cellular pluripotency via multiple mechanisms in bona fide hPSCs and reprogrammed cells. Collectively, we report that potassium is a pluripotency-associated inorganic element in human cells and provide novel insights into the manipulation of cellular pluripotency in hPSCs by regulating intracellular potassium.

Radiotherapeutic bandage for the treatment of squamous cell carcinoma of the skin.

INTRODUCTION: Squamous cell carcinoma (SCC) is the second most common form of skin cancer in the United States. The efficacy of a pharmaceutically elegant radiotherapeutic bandage, previously described by us for application against SCC of the skin, was tested for the first time in vivo using a subcutaneous SCC mouse model and a therapeutically relevant radiation dose. METHODS: Female athymic nude mice were injected with human Colo-16 SCC cells subcutaneously and after eight days (average tumor volume: 35±8.6mm(3)) received no treatment, or were exposed to non-radioactive or radioactive (92.5±18.5MBq) bandages for approximately 1h (n=10 per group). After treatment, tumors were measured over fifteen days, tumor volume ratios (TVRs) compared and histopathology performed. RESULTS: Fifteen days after treatment, the TVR of the radioactive bandage treatment group was 3.3±4.5, while TVRs of the non-radioactive bandage treatment and no treatment control groups were 33.2±14.7 and 26.9±12.6, respectively. At the time of necropsy, there was mild focal epidermal hyperplasia surrounding a small area of epidermal ulceration in the radioactive bandage group. No other examined tissue (i.e., muscle, liver, kidney, lung, spleen and heart) showed significant lesions. CONCLUSIONS: Our radiotherapeutic bandage exhibits promising efficacy against SCC of the skin in a mouse model. It can be individually tailored for easy application on tumor lesions of all shapes and sizes, and could complement or possibly replace surgery in the clinic.

Tetracycline-Containing MCM-41 Mesoporous Silica Nanoparticles for the Treatment of Escherichia coli.

Tetracycline (TC) is a well-known broad spectrum antibiotic, which is effective against many Gram positive and Gram negative bacteria. Controlled release nanoparticle formulations of TC have been reported, and could be beneficial for application in the treatment of periodontitis and dental bone infections. Furthermore, TC-controlled transcriptional regulation systems (Tet-on and Tet-off) are useful for controlling transgene expression in vitro and in vivo for biomedical research purposes; controlled TC release systems could be useful here, as well. Mesoporous silica nanomaterials (MSNs) are widely studied for drug delivery applications; Mobile crystalline material 41 (MCM-41), a type of MSN, has a mesoporous structure with pores forming channels in a hexagonal fashion. We prepared 41 ± 4 and 406 ± 55 nm MCM-41 mesoporous silica nanoparticles and loaded TC for controlled dug release; TC content in the TC-MCM-41 nanoparticles was 18.7% and 17.7% w/w, respectively. Release of TC from TC-MCM-41 nanoparticles was then measured in phosphate-buffered saline (PBS), pH 7.2, at 37 °C over a period of 5 h. Most antibiotic was released from both over this observation period; however, the majority of TC was released over the first hour. Efficacy of the TC-MCM-41 nanoparticles was then shown to be superior to free TC against Escherichia coli (E. coli) in culture over a 24 h period, while blank nanoparticles had no effect.

Chemoradiotherapeutic Magnetic Nanoparticles for Targeted Treatment of Nonsmall Cell Lung Cancer.

Lung cancer is the leading cause of cancer-related death in the United States and approximately 85% of all lung cancers are classified as nonsmall cell (NSCLC). We here use an innovative approach that may ultimately allow for the clinician to target tumors and aggressively reduce tumor burden in patients with NSCLC. In this study, a platinum (Pt)-based chemotherapeutic (cisplatin, carboplatin, or oxaliplatin) and holmium-165 (Ho), which can be neutron-activated to produce the holmium-166 radionuclide, have been incorporated together in a garnet magnetic nanoparticle (HoIG-Pt) for selective delivery to tumors using an external magnet. The synthesized magnetic HoIG nanoparticles were characterized using PXRD, TEM, ICP-MS, and neutron-activation. Platinum(II) drugs were incorporated onto HoIG, and these were characterized using FTIR, EDX, ICP-MS, and zeta potential measurements, and in vitro and in vivo studies were performed using a HoIG-platinum system. Results indicate that neutron-activated (166)HoIG-cisplatin is more toxic toward NSCLC A549 cells than is blank (166)HoIG and free cisplatin, and that when an external magnetic field is applied in vivo, higher tumor to liver ratios of Ho are observed than when no magnet is applied, suggesting that magnetic targeting is achieved using this system. Furthermore, an efficacy study demonstrated the inhibition of tumor growth by chemoradiotherapeutic magnetic nanoparticles, compared to no treatment controls.

Nitric oxide- and cisplatin-releasing silica nanoparticles for use against non-small cell lung cancer.

Nitric oxide (NO) and cisplatin releasing wrinkle-structured amine-modified mesoporous silica (AMS) nanoparticles have been developed for the treatment of non-small cell lung cancer (NSCLC). The AMS and NO- and cisplatin-loaded AMS materials were characterized using TEM, BET surface area, FTIR and ICP-MS, and tested in cell culture. The results show that for NSCLC cell lines (i.e., H596 and A549), the toxicity of NO- and cisplatin-loaded silica nanoparticles (NO-Si-DETA-cisplatin-AMS) is significantly higher than that of silica nanoparticles loaded with only cisplatin (Si-DETA-cisplatin-AMS). In contrast, the toxicity of NO-Si-DETA-cisplatin-AMS toward normal lung cell lines is not significantly different from that of Si-DETA-cisplatin-AMS (normal lung fibroblast cells WI-38) or is even lower than that of Si-DETA-cisplatin-AMS (normal lung epithelial cells BEAS-2B). The NO-induced sensitization of tumor cell death demonstrates that NO is a promising enhancer of platinum-based lung cancer therapy.

Radiotherapeutic bandage based on electrospun polyacrylonitrile containing holmium-166 iron garnet nanoparticles for the treatment of skin cancer.

Radiation therapy is used as a primary treatment for inoperable tumors and in patients that cannot or will not undergo surgery. Radioactive holmium-166 ((166)Ho) is a viable candidate for use against skin cancer. Nonradioactive holmium-165 ((165)Ho) iron garnet nanoparticles have been incorporated into a bandage, which, after neutron-activation to (166)Ho, can be applied to a tumor lesion. The (165)Ho iron garnet nanoparticles ((165)HoIG) were synthesized and introduced into polyacrylonitrile (PAN) polymer solutions. The polymer solutions were then electrospun to produce flexible nonwoven bandages, which are stable to neutron-activation. The fiber mats were characterized using scanning electron microscopy, transmission electron microscopy, powder X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetric analysis and inductively coupled plasma mass spectrometry. The bandages are stable after neutron-activation at a thermal neutron-flux of approximately 3.5 × 10(12) neutrons/cm(2)·s for at least 4 h and 100 °C. Different amounts of radioactivity can be produced by changing the amount of the (165)HoIG nanoparticles inside the bandage and the duration of neutron-activation, which is important for different stages of skin cancer. Furthermore, the radioactive bandage can be easily manipulated to irradiate only the tumor site by cutting the bandage into specific shapes and sizes that cover the tumor prior to neutron-activation. Thus, exposure of healthy cells to high energy ß-particles can be avoided. Moreover, there is no leakage of radioactive material after neutron activation, which is critical for safe handling by healthcare professionals treating skin cancer patients.

Enhanced toxicity of cisplatin with chemosensitizer phenethyl isothiocyanate toward non-small cell lung cancer cells when delivered in liposomal nanoparticles.

Naturally occurring phenethyl isothiocyanate (PEITC) was previously shown to sensitize human non-small cell lung cancer (NSCLC) cells to the platinum anticancer drug cisplatin (CDDP). Here, CDDP and PEITC were encapsulated in approximately 130 nm liposomes composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and L-α-phosphatidylglycerol (EPG). The liposomal formulation enhanced the toxicity of this doublet (1:2 molar ratio of CDDP/PEITC) toward NCI-H596 NSCLC cells; the percent survival of cells was 30.2±6.2% after treatment with the nanoparticle formulation, compared to 50.9±3.5% when administered together free. Thus, such a treatment modality could prove useful in the clinic for the treatment of NSCLC.

Solid dispersions of the penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA): formulation design and optimization studies.

The penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was incorporated into a solid dispersion for oral administration by the solvent evaporation method using blends of polyvinylpyrrolidone (PVP), Eudragit® RL PO and α-tocopherol. D-optimal mixture design was used to optimize the formulation. Formulations that had a high concentration of both Eudragit® RL PO and α-tocopherol exhibited low water absorption and enhanced stability of the DTPA prodrug. Physicochemical properties of the optimal formulation were evaluated using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). In vitro release of the prodrug was evaluated using the USP Type II apparatus dissolution method. DSC studies indicated that the matrix had an amorphous structure, while FTIR spectrometry showed that DTPA penta-ethyl ester and excipients did not react with each other during formation of the solid dispersion. Dissolution testing showed that the optimized solid dispersion exhibited a prolonged release profile, which could potentially result in a sustained delivery of DTPA penta-ethyl to enhance bioavailability. In conclusion, DTPA penta-ethyl ester was successfully incorporated into a solid matrix with high drug loading and improved stability compared to prodrug alone.

Species-dependent effective concentration of DTPA in plasma for chelation of 241Am.

Diethylenetriaminepentaacetic acid (DTPA) is a chelating agent that is used to facilitate the elimination of radionuclides such as americium from contaminated individuals. Its primary site of action is in the blood, where it competes with various biological ligands, including transferrin and albumin, for the binding of radioactive metals. To evaluate the chelation potential of DTPA under these conditions, the competitive binding of Am between DTPA and plasma proteins was studied in rat, beagle, and human plasma in vitro. Following incubation of DTPA and Am in plasma, the Am-bound ligands were fractionated by ultrafiltration and ion-exchange chromatography, and each fraction was assayed for Am content by gamma scintillation counting. Dose response curves of DTPA for Am binding were established, and these models were used to calculate the 90% maximal effective concentration, or EC90, of DTPA in each plasma system. The EC90 were determined to be 31.4, 15.9, and 10.0 µM in rat, beagle, and human plasma, respectively. These values correspond to plasma concentrations of DTPA that maximize Am chelation while minimizing excess DTPA. Based on the pharmacokinetic profile of DTPA in humans, after a standard 30 µmol kg intravenous bolus injection, the plasma concentration of DTPA remains above EC90 for approximately 5.6 h. Likewise, the effective duration of DTPA in rat and beagle were determined to be 0.67 and 1.7 h, respectively. These results suggest that species differences must be considered when translating DTPA efficacy data from animals to humans and offer further insights into improving the current DTPA treatment regimen.

Preparation of alginate beads containing a prodrug of diethylenetriaminepentaacetic acid.

A penta-ethyl ester prodrug of the radionuclide decorporation agent diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was encapsulated in alginate beads by the ionotropic gelation method. An optimal formulation was found by varying initial concentrations of DTPA penta-ethyl ester, alginate polymer, Tween 80 surfactant and calcium chloride. All prepared alginate beads were ~1.6mm in diameter, and the optimal formulation had loading and encapsulation efficiencies of 91.0±1.1 and 72.6±2.2%, respectively, and only 3.2±0.8% water absorption after storage at room temperature in ~80% relative humidity. Moreover, Fourier transform infrared spectroscopy showed that DTPA penta-ethyl ester did not react with excipients during formation of the DTPA penta-ethyl ester-containing alginate beads. Release of prodrug from alginate beads was via anomalous transport, and its stability enhanced by encapsulation. Collectively, these data suggest that this solid dosage form may be suitable for oral administration after radionuclide contamination.

Neutron-activatable holmium-containing mesoporous silica nanoparticles as a potential radionuclide therapeutic agent for ovarian cancer.

UNLABELLED: Mesoporous silica nanoparticles (MSNs) were explored as a carrier material for the stable isotope (165)Ho and, after neutron capture, its subsequent therapeutic radionuclide, (166)Ho (half-life, 26.8 h), for use in radionuclide therapy of ovarian cancer metastasis. METHODS: (165)Ho-MSNs were prepared using (165)Ho-acetylacetonate and MCM-41 silica particles, and stability was determined after irradiation in a nuclear reactor (reactor power, 1 MW; thermal neutron flux of approximately 5.5 × 10(12) neutrons/cm(2)s). SPECT/CT and tissue biodistribution studies were performed after intraperitoneal administration of (166)Ho-MSNs to SKOV-3 ovarian tumor-bearing mice. Radiotherapeutic efficacy was studied by using PET/CT with (18)F-FDG to determine tumor volume and by monitoring survival. RESULTS: The holmium-MSNs were able to withstand long irradiation times in a nuclear reactor and did not release (166)Ho after significant dilution. SPECT/CT images and tissue distribution results revealed that (166)Ho-MSNs accumulated predominantly in tumors (32.8% ± 8.1% injected dose/g after 24 h; 81% ± 7.5% injected dose/g after 1 wk) after intraperitoneal administration. PET/CT images showed reduced (18)F-FDG uptake in tumors, which correlated with a marked increase in survival after treatment with approximately 4 MBq of (166)Ho-MSNs. CONCLUSION: The retention of holmium in nanoparticles during irradiation and in vivo after intraperitoneal administration as well as their efficacy in extending survival in tumor-bearing mice underscores their potential as a radiotherapeutic agent for ovarian cancer metastasis.