Article

Tumor accumulation of neutron-activatable holmium-containing mesoporous silica nanoparticles in an orthotopic non-small cell lung cancer mouse model

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  • Binghamton University School of Pharmacy and Pharmaceutical Sciences
Article

Tumor accumulation of neutron-activatable holmium-containing mesoporous silica nanoparticles in an orthotopic non-small cell lung cancer mouse model

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Abstract

Mesoporous silica MCM-41 nanoparticles containing the stable isotope holmium-165 (165Ho) were prepared by exposing the approximately 400 nm particles to an aqueous solution of 165Ho acetylacetonate for 24 h at room temperature; the obtained solid was subsequently irradiated in a PULSTAR nuclear reactor (reactor power = 1 MW; thermal neutron flux of approximately 5.5 or 7.7 × 1012 n/cm2s) to produce holmium-166-containing mesoporous silica (166Ho-MCM-41) nanoparticles (20.8 ± 1.9% w/w 166Ho). The 166Ho-MCM-41 nanoparticles were administered intravenously (i.v.) to orthotopic non-small cell lung cancer A549-luciferase tumor-bearing mice. After 24 h, 4.5 ± 3.9% initial dose per gram (ID/g) of tissue was detected in tumors and after 1 week, this value increased to 58.8 ± 34.7% ID/g. These results demonstrate that mesoporous silica MCM-41 nanoparticles can deliver significant amounts of a therapeutic radionuclide to tumors after i.v. injection.

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... A study on the effect of particle size of MSNs on cellular uptake in vitro showed that 30 and 50 nm MSNs were taken up by cells more so than >100 nm MSNs [26]. However, MSNs sized 400 nm have been shown to have therapeutic potential in in vivo models [27]. To explore controlled release of TC using MSNs of different sizes, we prepared two different sized TC-containing MCM-41 type MSNs (41˘4 nm and 406˘55 nm) and investigated their in vitro release profiles in a biological relevant buffer. ...
... MCM-41 nanoparticles of two sizes (MCM-41A and MCM-41B) were synthesized following published procedures [27,28]. TC was loaded by exposing 20 mg of either MCM-41A or MCM-41B to a solution containing 10 mg/mL of TC hydrochloride in Milli-Q water (EMD Millipore; Billerica, MA, USA) and the mixture was stirred vigorously for 24 h at room temperature (r.t.). ...
... MCM-41A MSNs were prepared following previously published procedures with slight modifications [27,28]. NaOH (7 mL, 0.04 M) was added to H 2 O (480 mL) and the solution was heated to 60˝C. ...
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... The lipophilic nature of 5 allows for its encapsulation in mesoporous silica MCM-41 nanoparticles [23,24], to better target tumors. We previously demonstrated that mesoporous silica MCM-41 nanoparticles accumulate in ovarian and NSCLC tumors after intraperitoneal and intravenous (i.v.) injection, respectively [25,26]. Thus, we tested the loading and release of complex 5 from this type of nanoparticle. ...
... Mesoporous silica (MCM-41) nanoparticles were prepared as previously described [26]. The nanoparticles were approximately 400 nm. ...
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... 49−53 Di Pasqua et al. also proposed the use of inorganic mesoporous silica nanoparticles loaded with neutron-activatable holmium-165. 54,55 Taking advantage of the porosity of the nanocarrier, this was later expanded to chemoradiotherapy. 56 Other inorganic materials including holmium iron garnet, mesoporous carbon nanoparticles, and graphene oxide have more recently been explored as holmium nanocarriers. ...
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... Human lung cancer cells primarily take up MSNs by endocytosis [68]. MSNs have also been developed as a carrier for radionuclide isotope holmium-165 (Ho 165 ) and tested in a xenograft tumor model [69]. In this model, MSNs were able to hold the radionuclide without release and withstand long irradiation times. ...
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... In addition, nano-142 Pr 2 O 3 could be conjugated with other chemotherapeutic drugs, such as drugs that induce apoptosis, to improve its therapeutic characteristics while minimizing its toxicity. It should be noted that, although no targeting moieties were attached to the surface of the particles used by Di Pasqua et al. [23], tumor accumulation of 166 Ho-MCM-41 was exceptionally high after intravenous injection. Therefore, further research should be conducted to investigate the appropriate method to deliver nano-142 Pr 2 O 3 to lung tumors. ...
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... A different approach for 166 Ho radiolabeling was developed by Di Pasqua A.J. et al (2012) who used stable Holmium-155 in conjunction with mesoporous silica MCM-41 nanoparticles, and irradiated the system, thus producing a radioactive complex. This complex was tested in murine models with orthotopic non-small cell lung cancer, giving satisfactory results [95]. As mentioned in the example above, irradiation of a complex containing 165 Ho in order to acquire a radiolabeled with 166 Ho carrier is a common strategy. ...
... They reported the successful selective accumulation of the grafted complex, [ 64 Cu]-TPPF 20 @NH 2 -MCM-41, in Fibrosarcoma tumor cells. Di Pasqua et al. 101 also explored silica MCM-41 NPs as a carrier material for the stable isotope 165 Ho. 166 Ho-MCM-41 NPs were administered intravenously (i.v.) to orthotopic nonsmall cell lung cancer A549-luciferase tumor-bearing mice. The obtained results demonstrated that mesoporous silica MCM-41 NPs can deliver significant amounts of a therapeutic radionuclide to tumors after i.v. ...
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... Thus, the combined delivery of drugs and siRNA had capability for treatment of lung tumor. Di Pasqua et al. [55] developed radiotherapeutic nanoparticles ( 165 Ho-MCM-41) by synthesizing mesoporous silica nanoparticles first and then conjugating it with holmium-165 ( 165 Ho) for nonsmall lung cancer (NSLC) treatment through intravenous route. The solid obtained was eventually irradiated inside PULSTAR nuclear reactor, which further produced holmium-166-containing mesoporous silica ( 166 Ho-MCM-41) nanoparticles having 20.8% AE 1.9% w/w 166 Ho. ...
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A simple one-step procedure is described for the synthesis of spherical mesoporous silica, in which the size of the particles is controlled over a range of diameters from 65 to 740 nm by varying the initial silicate/surfactant concentration under dilute conditions. The particles were characterized using X-ray diffraction, transmission electron microscopy, and liquid nitrogen adsorption. Synthesis using a charged template, cetyltrimethylammonium bromide, under aqueous conditions yielded particles of irregular spherical shape with highly ordered mesoporous channels. Synthesis under ethanol/water cosolvent conditions yielded smooth spheres with a starburst mesopore structure extending from the center of the particle to the circumference. All materials were thermally stable and exhibited two steps in their liquid nitrogen isotherms corresponding to reversible channel filling and non-reversible adsorption between particles. Mesopore volumes varied from 0.64 to 0.93 cm3 g-1 and surface areas varied from 917 to 1373 m2 g-1. From analysis of mesopore geometry and overall particle shape a three-stage mechanism for synthesis is proposed.
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Nanoparticles containing stable holmium ((165) Ho) are prepared by nanotemplate engineering and subsequently irradiated in a neutron flux to yield (166) Ho, a beta-emitting radiotherapeutic isotope. After intraperitoneal injection to mice bearing SKOV-3 ovarian tumors, significant tumor accumulation of the (166) Ho-nanoparticles is observed by SPECT imaging indicating the potential of these neutron activatable nanoparticles for internal radiation therapy of ovarian cancer metastases.
Article
This article describes the preparation of biocompatible radioactive holmium-loaded particles with appropriate nanoscale size for radionuclide intratumoral administration by the targeted multitherapy (TMT) technique. For this objective, holmium acetylacetonate has been encapsulated in poly-L-lactide (PLLA)-based nanoparticles (NP) by oil-in-water emulsion-solvent evaporation method. NP sizes ranged between 100 and 1,100 m being suitable for the TMT administration method. Elemental holmium loading was found to be around 18% wt/wt and the holmium acetylacetonate trihydrate (HoAcAc) encapsulation efficacy was about 90%. Different experiments demonstrated an amorphous state of HoAcAc after incorporation in NPs. The NPs were irradiated in a nuclear reactor with a neutron flux of 1.1 x 10(13) n/cm(2)/s for 1 h, which yielded a specific activity of about 27.4 GBq/g of NPs being sufficient for our desired application. Microscopic analysis of irradiated NPs showed some alteration after neutron irradiation as some NPs looked partially coagglomerated and a few pores appeared at their surface because of the locally released heat in the irradiation vials. Furthermore, differential scanning calorimetry (DSC) results indicated a clear decrease in PLLA melting point and melting enthalpy reflecting a decrease in polymer crystallinity. This was accompanied by a clear decrease in polymer molecular weights, which can be ascribed to a radiation-induced chain scission mechanism. However, interestingly, other experiments confirmed the chemical identity retention of both HoAcAc and PLLA in irradiated NPs despite this detected decrease in the polymer crystallinity and molecular weight. Although neutron irradiation has induced some NPs damage, these NPs kept out their overall chemical composition, and their size distribution remained suitable for the TMT administration technique. Coupled with the TMT technique, these NPs may represent a novel potential radiopharmaceutical agent for intratumoral radiotherapy.
Article
Mesoporous silica nanoparticles (MSNs) are a promising material for drug delivery. In this Full Paper, MSNs are first shown to be well tolerated, as demonstrated by serological, hematological, and histopathological examinations of blood samples and mouse tissues after MSN injection. Biodistribution studies using human cancer xenografts are carried out with in vivo imaging and fluorescent microscopy imaging, as well as with inductively coupled plasma mass spectroscopy. The results show that MSNs preferentially accumulate in tumors. Finally, the drug-delivery capability of MSNs is demonstrated by following tumor growth in mice treated with camptothecin-loaded MSNs. These results indicate that MSNs are biocompatible, preferentially accumulate in tumors, and effectively deliver drugs to the tumors and suppress tumor growth.
Article
MCM-41, a mesoporous silica nanomaterial with a high surface area for adsorption of small molecules, is a potential new type of delivery vehicle for therapeutic and diagnostic agents. In this report, we show that MCM-41 adsorbs the front-line anticancer drug carboplatin, [Pt(CBDCA-O,O')(NH3)2] (CBDCA=cyclobutane-1,1-dicarboxylate; 1), which is used to treat ovarian, lung, and other types of cancer. UV/Visible difference absorption spectroscopy shows that MCM-41 adsorbs 1.8+/-0.2% of its own weight of carboplatin after a 24 h exposure to 26.9 mM drug in H2O. The pseudo-first-order rate constant for adsorption of carboplatin by MCM-41, measured using [1H,15N] heteronuclear single quantum coherence (HSQC) NMR, and 15N-labeled carboplatin is k(1)=2.92+/-2.17 x 10(-6) s(-1) at ca. 25 degrees.
Article
Biodegradable Poly(L-lactic acid) microspheres containing neutron-activable 165Ho were designed for internal radiation therapy of hepatic tumors. Spheres composed of Poly(L-lactic acid) (PLA) were prepared with excellent reproducibility containing up to 36% of a holmium complex. The prepared spheres were irradiated in a high neutron flux converting 165Ho to 166Ho (Emax = 1.84 MeV, half-life = 26.9 hr). Thus, these microspheres can be prepared under conditions that do not require the handling of a hazardous radionuclide, and then irradiated just prior to administration. In vitro studies in plasma (n = 6) revealed 97.3% (+/- 1.9) retention of 166Ho in the microspheres after 240 hr. PLA spheres administered via the portal vein in rabbits (n = 6) show 94.5% (+/- 3.4) retention of the original 166Ho activity in the liver after 6 days.
Article
Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a tumor necrosis factor superfamily member that induces apoptosis through the death receptors DR4 and/or DR5 in various cancer cell types but not in most normal cells. Several lung cancer cell lines express DR4 and DR5 and undergo apoptosis in vitro in response to Apo2L/TRAIL. We investigated the efficacy of recombinant soluble human Apo2L/TRAIL and its interaction with chemotherapy in xenograft models based on human NCI-H460 non-small cell lung carcinoma cells. In vitro, Taxol enhanced caspase activation and apoptosis induction by Apo2L/TRAIL. In vivo, Apo2L/TRAIL or Taxol plus carboplatin chemotherapy partially delayed progression of established subcutaneous tumor xenografts, whereas combined treatment caused tumor regression and a substantially longer growth delay. Apo2L/TRAIL, chemotherapy, or the combination of both inhibited growth of preformed orthotopic lung parenchymal tumors versus control by 60%, 57%, or 97%, respectively (all P < 0.01; n = 8-10). Furthermore, combination treatment improved day-90 survival relative to control (7 of 15 versus 1 of 15; P = 0.0003 by Mantel-Cox) as well as to Apo2L/TRAIL (3 of 14; P = 0.031) or chemotherapy (3 of 15; P = 0.035). These studies provide evidence for in vivo activity of Apo2L/TRAIL against lung tumor xenografts and underscore the potential of this ligand for advancing current lung cancer treatment strategies.
Article
The purpose of this study was to evaluate the long-term tumor response after phase IIb clinical study and the safety of percutaneous holmium-166 ((166)Ho)/chitosan complex injection (PHI) therapy for small hepatocellular carcinoma as a local ablative treatment. (166)Ho is a radioactive isotope derived from natural holmium-165. We developed a (166)Ho/chitosan complex (Milican, Dong Wha Pharmaceutical Co., Seoul, Korea) using chitosan as a vehicle to retain the radioactive material within the tumor. Forty patients with single hepatocellular carcinoma < 3 cm in maximal diameter were enrolled in this study. The patients either had refused surgery or were poor surgical candidates and were treated with only single session of PHI. Two months after PHI, complete tumor necrosis was achieved in 31 of 40 patients (77.5%) with hepatocellular carcinoma lesions < 3 cm and in 11 of 12 patients (91.7%) with hepatocellular carcinoma < 2 cm. Tumors recurred in 28 patients during the long-term follow-up period, of which 24 recurred at another intrahepatic site. The 1-year and 2-year cumulative local recurrence rates were 18.5% and 34.9%, respectively. The survival rates at 1, 2, and 3 years were 87.2%, 71.8%, and 65.3%, respectively. Transient bone marrow depression was serious adverse event requiring hospitalization in two patients. PHI was found to be a safe and novel local ablative procedure for the treatment of small hepatocellular carcinoma and could be used as a bridge to transplantation. A phase III randomized active control trial is clearly warranted among a larger study population.
Article
In this paper the preparation and characterization of holmium-loaded alginate microspheres is described. The rapid development of medical imaging techniques offers new opportunities for the visualisation of (drug-loaded) microparticles. Therefore, suitable imaging agents have to be incorporated into these particles. For this reason, the element holmium was used in this study in order to utilize its unique imaging characteristics. The paramagnetic behaviour of this element allows visualisation with MRI and holmium can also be neutron-activated resulting in the emission of gamma-radiation, allowing visualisation with gamma cameras, and beta-radiation, suitable for therapeutic applications. Almost monodisperse alginate microspheres were obtained by JetCutter technology where alginate droplets of a uniform size were hardened in an aqueous holmium chloride solution. Ho(3+) binds via electrostatic interactions to the carboxylate groups of the alginate polymer and as a result alginate microspheres loaded with holmium were obtained. The microspheres had a mean size of 159 microm and a holmium loading of 1.3 +/- 0.1% (w/w) (corresponding with a holmium content based on dry alginate of 18.3 +/- 0.3% (w/w)). The binding capacity of the alginate polymer for Ho(3+) (expressed in molar amounts) is equal to that for Ca(2+), which is commonly used for the hardening of alginate. This indicates that Ho(3+) has the same binding affinity as Ca(2+). In line herewith, dynamic mechanical analyses demonstrated that alginate gels hardened with Ca(2+) or Ho(3+) had similar viscoelastic properties. The MRI relaxation properties of the microspheres were determined by a MRI phantom experiment, demonstrating a strong R(2)* effect of the particles. Alginate microspheres could also be labelled with radioactive holmium by adding holmium-166 to alginate microspheres, previously hardened with calcium (labelling efficiency 96%). The labelled microspheres had a high radiochemical stability (94% after 48 h incubation in human serum), allowing therapeutic applications for treatment of cancer. The potential in vivo application of the microspheres for a MR-guided renal embolization procedure was illustrated by selective administration of microspheres to the left kidney of a pig. Anatomic MR-imaging showed the presence of holmium-loaded microspheres in the kidney. In conclusion, this study demonstrates that the incorporation of holmium into alginate microspheres allows their visualisation with a gamma camera and MRI. Holmium-loaded alginate microspheres can be used therapeutically for embolization and, when radioactive, for local radiotherapy of tumours.
Article
The aim of this study was to get insight into the toxic effects of holmium-166-loaded poly(L-lactic acid) microspheres (Ho-PLLA-MS) which have very interesting features for treatment of liver malignancies. Acute, mid- and long-term effects were studied in healthy Wistar rats by evaluating clinical, biochemical and tissue response. Rats were divided into four treatment groups: sham, decayed neutron-irradiated Ho-PLLA-MS, non-irradiated Ho-PLLA-MS and PLLA-MS. After implantation of the microspheres into the liver of the rats, the animals were monitored (body weight, temperature and liver enzymes) for a period of 14-18 months. Some of the rats that received previously neutron-irradiated Ho-PLLA-MS were periodically scanned with magnetic resonance imaging (MRI) to see if holmium was released from the microspheres. After sacrifice, the liver tissue was histologically evaluated. Bone tissue was subjected to neutron-activation analysis in order to examine whether accumulation of released holmium in the bone had occurred. No measurable clinical and biochemical toxic effects were observed in any of the treatment groups. Furthermore, histological analyses of liver tissue samples only showed signs of a slight chronic inflammation and no significant differences in the tissue reaction between rats of the different treatment groups could be observed. The non-irradiated PLLA-MS and Ho-PLLA-MS stayed intact during the study. In contrast, 14 months after administration, the neutron-irradiated Ho-PLLA-MS was not completely spherical anymore, indicating that degradation had started. However, the holmium loading had not been released as was illustrated with MRI and affirmed by neutron-activation analysis of bone tissue. In conclusion, neutron-irradiated Ho-PLLA-MS does not provoke any toxic reaction and can be applied safely in vivo.
Article
Research on mesoporous materials for biomedical purposes has experienced an outstanding increase during recent years. Since 2001, when MCM-41 was first proposed as drug-delivery system, silica-based materials, such as SBA-15 or MCM-48, and some metal-organic frameworks have been discussed as drug carriers and controlled-release systems. Mesoporous materials are intended for both systemic-delivery systems and implantable local-delivery devices. The latter application provides very promising possibilities in the field of bone-tissue repair because of the excellent behavior of these materials as bioceramics. This Minireview deals with the advances in this field by the control of the textural parameters, surface functionalization, and the synthesis of sophisticated stimuli-response systems.
Article
We here measure the toxicity of MCM-41, a mesoporous silica nanomaterial, two of its functionalized analogs, AP-T, which has grafted aminopropyl groups and MP-T, which has grafted mercaptopropyl groups, and spherical silica nanoparticles (SiO(2)), toward human neuroblastoma (SK-N-SH) cells. Since the particles studied are not soluble in aqueous media, the metric used to report the cytotoxicity of these materials is a new quantity, Q(50), which is the number of particles required to inhibit normal cell growth by 50%. Determining the number of particles per gram of material applied to the cells required both the calculated and experimentally determined surface areas of these nanomaterials. This study shows that Q(50) increases in the order, MCM-41<MP-T<AP-T approximately SiO(2), showing that on a per particle basis, MCM-41 is the most cytotoxic material studied. For the three mesoporous silica materials in this study, cytotoxicity appears related to the adsorptive surface area of the particle, although the nature of the functional group cannot be ruled out. Silica nanospheres have the lowest surface area of the particles studied but since they exhibit a Q(50) value similar to that of AP-T, shape may also be important in the cytotoxicity of these materials.