Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related deaths in Western civilization. Although localized prostate cancer can be treated ...effectively in different ways, almost all patients progress to the incurable metastatic castration-resistant prostate cancer. Due to the significant mortality and morbidity rate associated with the progression of this disease, there is an urgent need for new and targeted treatments. In this review, we summarize the recent advances in research on identification of prostate tissue-specific antigens for targeted therapy, generation of highly specific and selective molecules targeting these antigens, availability of therapeutic radionuclides for widespread medical applications, and recent achievements in the development of new-generation small-molecule inhibitors and antibody-based strategies for targeted prostate cancer therapy with alpha-, beta-, and Auger electron-emitting radionuclides.
The concept of nanoparticle-mediated radionuclide delivery in the cancer treatment has been widely discussed in the past decade. In particular, the use of inorganic and organic nanostructures in the ...development of radiopharmaceuticals enables the delivery of medically important radioisotopes for radionuclide therapy. In this review, we present the development of nanostructures for cancer therapy with Auger electron radionuclides. Following that, different types of nanoconstructs that can be used as carriers for Auger electron emitters, design principles, nanoparticle materials, and target vectors that overcame the main difficulties are described. In addition, systems in which high-Z element nanoparticles are used as radionuclide carriers, causing the emission of photoelectrons from the nanoparticle surface, are presented. Finally, future research opportunities in the field are discussed as well as issues that must be addressed before nanoparticle-based Auger electron radionuclide therapy can be transferred to clinical use.
A new group of arsenic(III) complexes with bidentate S,S-donor ligands, 1,2-benzenedithiol (Ph(SH)
) and toluene-3,4-dithiol (MePh(SH)
), were synthesized. The use of arsenic(III) iodide and bromide ...promoted the formation of neutral complexes (
-
) with the general formula AsX(LS
) (X = I or Br, L = MePh or Ph). The crystal structures of these compounds were determined using single-crystal X-ray diffraction (scXRD). Unlike other arsenic(III) complexes, AsBr(PhS
) complex (
) was found to crystallize with a rare 13 molecules in the asymmetric unit. The compounds were also characterized by conventional physico-chemical techniques (Fourier transform infrared (FT-IR) spectroscopy, ultraviolet-visible (UV-Vis) spectroscopy, nuclear magnetic resonance (NMR), high-performance liquid chromatography (HPLC), elemental analysis (EA) and electrospray ionization-mass spectrometry (ESI-MS)). The results from structural and spectroscopic studies were supported by DFT calculations using the B3LYP/LANL2DZ and (or) 6-31+G(d,p) approaches. The cytotoxicity of these complexes was estimated for human acute promyelocytic leukemia cell line (NB4). They exhibited remarkable cytotoxicities after 48 h of treatment with IC
equal to about 10 µM and 40 µM for complexes with 1,2-benzenedithiolato and toluene-3,4-dithiolato ligand, respectively. Their toxicity was lower than that of commonly used chemotherapeutic As
O
(IC
= 1.4 µM).
Recently, targeted nanoparticles (NPs) have attracted much attention in cancer treatment due to their high potential as carriers for drug delivery. In this article, we present a novel bioconjugate ...(DOX-AuNPs-Tmab) consisting of gold nanoparticles (AuNPs, 30 nm) attached to chemotherapeutic agent doxorubicin (DOX) and a monoclonal antibody, trastuzumab (Tmab), which exhibited specific binding to HER2 receptors. The size and shape of synthesized AuNPs, as well as their surface modification, were analyzed by the TEM (transmission electron microscopy) and DLS (dynamic light scattering) methods. Biological studies were performed on the SKOV-3 cell line (HER2+) and showed high specificity of binding to the receptors and internalization capabilities, whereas MDA-MB-231 cells (HER2-) did not. Cytotoxicity experiments revealed a decrease in the metabolic activity of cancer cells and surface area reduction of spheroids treated with DOX-AuNPs-Tmab. The bioconjugate induced mainly cell cycle G2/M-phase arrest and late apoptosis. Our results suggest that DOX-AuNPs-Tmab has great potential for targeted therapy of HER2-positive tumors.
Overcoming the limitations for efficient and selective drug delivery is one of the most challenging obstacles for newly designed anticancer agents. In this study, we present two types of ...platinum-based nanoparticles (NP), ultrasmall 2 nm PtNPs and core-shell 30 nm Au@Pt, which can be highly cytotoxic in an oxidative environment and remain biologically inactive in cells with lower oxidative status. Our research highlighted the differences in platinum nanoparticle-induced chemotoxicity and is the first study examining its mechanism as a substantial aspect of Au@Pt/PtNPs biological activity. Selectively induced oxidative stress was found to be a primary trigger of NPs' toxicity. Significant differences between Au@Pt and PtNPs were observed especially during 24 h treatment, due to successful intranuclear PtNPs location (~13% of internalized fraction). Reactive oxygen species (ROS)-level induced from both NPs types were similar, while reduction of reduced glutathione (GSH) intracellular content was stronger after treatment with PtNPs. Any biological activity was found in HER2+ breast cancer cells, which have only slightly increased oxidative status. Platinum-containing nanoparticles are an interesting tool for the improvement of selectivity in anticancer therapies against hepatocellular carcinoma (HCC). Due to intranuclear uptake, 2 nm PtNPs seems to be more promising for further research for HCC therapy.
Prostate cancer is the second most frequent malignancy in men worldwide. Unfortunately, current therapies often lead to the onset of metastatic castration-resistant prostate cancer (mCRPC), causing ...significant mortality. Therefore, there is an urgent need for new and targeted therapies that are advantageous over the current ones. Recently, the PSMA-targeted radioligand therapy of mCRPC has shown very promising results. In line with this, we described the synthesis of a new radioimmunoconjugate, 223RaA-silane-PEG-D2B, for targeted mCRPC therapy. The new compound consists of a NaA zeolite nanocarrier loaded with the α-particle emitting Ra-223 radionuclide, functionalized with the anti-PSMA D2B antibody. Physicochemical properties of the synthesized compound were characterized by standard methods (HR-SEM, TEM, XRD, FTIR, EDS, NTA, DLS, BET, TGA). The targeting selectivity, the extent of internalization, and cytotoxicity were determined in LNCaP C4-2 (PSMA+) and DU-145 (PSMA-) cells. Our results supported the 223RaA-silane-PEG-D2B synthesis and revealed that the final product had a diameter ca. 120 nm and specific activity 0.65 MBq/1mg. The product was characterized by a high yield of stability (>95% up to 12 days). The conjugation reaction resulted in approximately 50 antibodies/nanoparticle. The obtained radioimmunoconjugate bound specifically and internalized into PSMA-expressing LNCaP C4-2 cells, but not into PSMA-negative DU-145 cells. 223RaA-silane-PEG-D2B demonstrated also potent cytotoxicity in LNCaP C4-2 cells. These promising results require further in vivo evaluation of 223RaA-silane-PEG-D2B with regard to its toxicity and therapeutic efficacy.
This study was performed to synthesize a radiopharmaceutical designed for multimodal hepatocellular carcinoma (HCC) treatment involving radionuclide therapy and magnetic hyperthermia. To achieve this ...goal, the superparamagnetic iron oxide (magnetite) nanoparticles (SPIONs) were covered with a layer of radioactive gold (198Au) creating core–shell nanoparticles (SPION@Au). The synthesized SPION@Au nanoparticles exhibited superparamagnetic properties with a saturation magnetization of 50 emu/g, which is lower than reported for uncoated SPIONs (83 emu/g). Nevertheless, the SPION@Au core–shell nanoparticles showed a sufficiently high saturation magnetization value which allows them to reach a temperature of 43 °C at a magnetic field frequency of 386 kHz. The cytotoxic effect of nonradioactive and radioactive SPION@Au–polyethylene glycol (PEG) bioconjugates was carried out by treating HepG2 cells with various concentrations (1.25–100.00 µg/mL) of the compound and radioactivity in range of 1.25–20 MBq/mL. The moderate cytotoxic effect of nonradioactive SPION@Au-PEG bioconjugates on HepG2 was observed. The cytotoxic effect associated with the β− radiation emitted by 198Au was much greater and already reaches a cell survival fraction below 8% for 2.5 MBq/mL of radioactivity after 72 h. Thus, the killing of HepG2 cells in HCC therapy should be possible due to the combination of the heat-generating properties of the SPION-198Au–PEG conjugates and the radiotoxicity of the radiation emitted by 198Au.
193mPt and 195mPt radionuclides are therapeutically attractive Auger electron emitters with notably high Auger electron yield per decay. The present paper summarizes the first step of research on the ...applications of core-shell (Au@Pt) nanoparticles for electron Auger therapy of HER2+ (human epidermal growth factor receptor 2) breast cancer and hepatocellular carcinoma. Gold nanoparticles (30 nm) were synthesized covered with a platinum shell at high efficiency (>80%) and were further evaluated for in vitro studies such as binding affinity, internalization and cytotoxicity. To find the mechanism(s) responsible for platinum cytotoxicity in HepG2 cells, the platinum concentration in isolated cell nuclei and cytoplasm was determined using ICP-MS (inductively coupled plasma mass spectrometry). Lack of platinum in cell nuclei suggests that the cytotoxic effect is associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Studies carried out on the SKOV-3 cell line with the use of a synthesized targeting bioconjugate (Au@Pt-PEG-trastuzumab) revealed a high affinity of this preparation to HER2+ cells, its internalization, its placement in the perinuclear area and partial intranuclear location. The specific binding for HER2 negative cells, MDA-MB-231, was negligible and Au@Pt-PEG-trastuzumab did not enter these cells. The results obtained are promising and warrant future investigation of Auger electron therapy using 193mPt and 195mPt based radiopharmaceuticals.
A semi-automated purification module for the cyclic separation of
99m
Tc was designed for production of
99m
TcTcO
4
–
from γ irradiated
100
Mo target. The separation process was carried out by using ...a 3-column purification system and the final product,
99m
TcTcO
4
–
, was obtained in a total volume of 7 mL. To confirm proper separation achieved for
99m
Tc, a radio-labeling procedure using DTPA chelator was performed. The radiochemical purity was higher than 95%, which meets the strict radiopharmaceutical requirements. The yielded
99m
Tc can be separated with high efficiency from Mo in a quick and repeated way. Loss of
99m
Tc radioactivity during such a three-column separation process was not larger than 10%.
Iron oxide nanoparticles are commonly used in many medical applications as they can be easily modified, have a high surface-to-volume ratio, and are biocompatible and biodegradable. This study was ...performed to synthesize nanoparticles designed for multimodal HER2-positive cancer treatment involving radionuclide therapy and magnetic hyperthermia. The magnetic core (Fe3O4) was coated with a gold-198 layer creating so-called core-shell nanoparticles. These were then further modified with a bifunctional PEG linker and monoclonal antibody to achieve the targeted therapy. Monoclonal antibody—trastuzumab was used to target specific breast and nipple HER2-positive cancer cells. The nanoparticles measured by transmission electron microscopy were as small as 9 nm. The bioconjugation of trastuzumab was confirmed by two separate methods: thermogravimetric analysis and iodine-131 labeling. Synthesized nanoparticles showed that they are good heat mediators in an alternating magnetic field and exhibit great specific binding and internalization capabilities towards the SKOV-3 (HER2 positive) cancer cell line. Radioactive nanoparticles also exhibit capabilities regarding spheroid degradation without and with the application of magnetic hyperthermia with a greater impact in the case of the latter. Designed radiobioconjugate shows great promise and has great potential for in vivo studies regarding magnetic hyperthermia and radionuclide combined therapy.
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