Polymeric nanoparticles encompass micelles and dendrimers. They are used for improving or controlling the action of the loaded therapy or imaging agent, including radionuclides. Some radionuclides ...possess properties appropriate for simultaneous imaging and therapy of a disease and are therefore called theranostic. The diversity in core materials and surface modification, as well as radiolabeling strategies, offers multiples possibilities for preparing polymeric nanoparticles using radionuclides. The present review describes different strategies in the preparation of such nanoparticles and their applications in nuclear nanomedicine.
The work describes the most suitable reported alternatives for the design and development of radiolabeled polymeric nanoparticles such as dendrimers and micelles, used to improve nuclear medicine. The diversity in core materials and surface modification, targeting strategies, radionuclides as well as radiolabeling strategies, offers multiples possibilities for molecular imaging, therapy, and theranostic tools.
Background
Manganese is a paramagnetic element suitable for magnetic resonance imaging (MRI) of neuronal function. However, high concentrations of Mn2 + can be neurotoxic. 52gMn may be a valid ...alternative as positron
emission tomography (PET) imaging agent, to obtain information similar to that delivered by MRI but using trace levels of Mn2 + , thus reducing its toxicity. Recently, the reaction nat$^{nat}$V(α,x)52gMn has been proposed as a possible alternative to the standard nat$^{nat}$Cr(p,x)52gMn one, but improvements in the modeling were needed to better compare the two production routes.
Purpose
This work focuses on the development of precise simulations and models to compare the 52gMn production from both reactions in terms of amount of activity and radionuclidic purity (RNP), as well as in terms of dose increase (DI) due to the co‐produced radioactive contaminants, versus pure 52gMnCl2.
Methods
The nuclear code Talys has been employed to optimize the nat$^{nat}$V(α,x)52gMn cross section by tuning the parameters of the microscopic level densities. Thick‐target yields have been calculated from the expression of the rates as energy convolution of cross sections and stopping powers, and finally integrating the time evolution of the relevant decay chains. Dosimetric assessments of xx$^{xx}$MnCl2 have been accomplished with OLINDA software 2.2.0 using female and male adult phantoms and biodistribution data for 52gMnCl2 in normal mice. At the end, the yield of xx$^{xx}$Mn radioisotopes estimated for the two production routes have been combined with the dosimetric results, to assess the DI at different times after the end of the irradiation.
Results
Good agreement was obtained between cross‐section calculations and measurements. The comparison of the two reaction channels suggests that nat$^{nat}$V(α,x)52gMn leads to higher yield and higher purity, resulting in more favorable radiation dosimetry for patients.
Conclusions
Both nat$^{nat}$V(α,x) and nat$^{nat}$Cr(p,x) production routes provide clinically acceptable 52gMnCl2 for PET imaging. However, the nat$^{nat}$V(α,x)52gMn reaction provides a DI systematically lower than the one obtainable with nat$^{nat}$Cr(p,x)52gMn and a longer time window in which it can be used clinically (RNP ≥ 99%).
Cu and
Cu radioisotopes have nuclear characteristics suitable for nuclear medicine applications. The production of
Cu is already well established. However, the production of
Cu in quantities suitable ...to conduct clinical trials is more challenging as it leads to the coproduction of other Cu isotopes, in particular
Cu. The aim of this study is to investigate the possibility of using a CuCl
solution with a mixture of
Cu radioisotopes for therapeutic purposes, providing an alternative solution for the cyclotron production problem.
Copper radioisotopes activities were calculated by considering proton beam irradiation of the following targets: (i)
Zn in the energy range 70-45 MeV; (ii)
Zn in the energy range 70-35 MeV; (iii) a combination of
Zn (70-55 MeV) and
Zn (55-35 MeV). The contribution of each copper radioisotope to the human-absorbed dose was estimated with OLINDA/EXM software using the biokinetic model for CuCl
published by ICRP 53. The total absorbed dose generated by the
CuCl
mixture, obtained through different production routes, was calculated at different times after the end of the bombardment (EOB). A simple spherical model was used to simulate tumors of different sizes containing uniformly distributed
Cu mixture and to calculate the absorbed dose of self-irradiation. The biological damage produced by
Cu and
Cu was also evaluated through cellular dosimetry and cell surviving fraction assessment using the MIRDcell code, considering two prostate cancer cell lines with different radiosensitivity.
The absorbed dose to healthy organs and the effective dose (ED) per unit of administered activity of
CuCl
are higher than those of
CuCl
. Absorbed dose values per unit of administered activity of
CuCl
mixture increase with time after the EOB because the amount of
Cu in the mixture increases. Survival data showed that the biological damage caused per each decay of
Cu is greater than that of
Cu, assuming that radionuclides remain accumulated in the cell cytoplasm. Sphere model calculations demonstrated that
Cu administered activity must be about five times higher than that of
Cu to obtain the same absorbed dose for tumor mass between 0.01 and 10 g and about 10 times higher for very small spheres. Consequently, the
CuCl
-absorbed dose to healthy organs will reach higher values than those of
CuCl
. The supplemental activity of the
CuCl
mixture, required to get the same tumor-absorbed dose produced by
CuCl
, triggers a dose increment (DI) in healthy organs. The waiting time post-EOB necessary to keep this DI below 10% (t
) depends on the irradiation methods employed for the production of the
CuCl
mixture.
A mixture of cyclotron produced
Cu radioisotopes proved to be an alternative solution for the therapeutic use of CuCl
with minimal DI to healthy organs compared with pure
Cu. Irradiation of a
Zn+
Zn target in the 70-35 MeV proton energy range for 185 h appears to be the best option from among all the production routes investigated, as it gives the maximum amount of activity, the shortest t
(10 h), and less than 1% of
Cu and
Cu impurities.
Previously, we demonstrated that the 177Lu-labeled single-chain variable fragment of an anti-prostate-specific membrane antigen (PSMA) IgG D2B antibody (scFvD2B) showed higher prostate cancer (PCa) ...cell uptake and tumor radiation doses compared to 177Lu-labeled Glu-ureide-based PSMA inhibitory peptides. To obtain a 99mTc-/177Lu-scFvD2B theranostic pair, this research aimed to synthesize and biochemically characterize a novel 99mTc-scFvD2B radiotracer. The scFvD2B-Tag and scFvD2B antibody fragments were produced and purified. Then, two HYNIC derivatives, HYNIC-Gly-Gly-Cys-NH2 (HYNIC-GGC) and succinimidyl-HYNIC (S-HYNIC), were used to conjugate the scFvD2B-Tag and scFvD2B isoforms, respectively. Subsequently, chemical characterization, immunoreactivity tests (affinity and specificity), radiochemical purity tests, stability tests in human serum, cellular uptake and internalization in LNCaP(+), PC3-PIP(++) or PC3(−) PCa cells of the resulting unlabeled HYNIC-scFvD2B conjugates (HscFv) and 99mTc-HscFv agents were performed. The results showed that incorporating HYNIC as a chelator did not affect the affinity, specificity or stability of scFvD2B. After purification, the radiochemical purity of 99mTc-HscFv radiotracers was greater than 95%. A two-sample t-test of 99mTc-HscFv1 and 99mTc-HscFv1 uptake in PC3-PIP vs. PC3 showed a p-value < 0.001, indicating that the PSMA receptor interaction of 99mTc-HscFv agents was statistically significantly higher in PSMA-positive cells than in the negative controls. In conclusion, the results of this research warrant further preclinical studies to determine whether the in vivo pharmacokinetics and tumor uptake of 99mTc-HscFv still offer sufficient advantages over HYNIC-conjugated peptides to be considered for SPECT/PSMA imaging.
Protein interactions are the basis for the biological functioning of human beings. However, many of these interactions are also responsible for diseases, including cancer. Synthetic inhibitors of ...protein interactions based on small molecules are widely investigated in medicinal chemistry. The development of radiolabeled protein-inhibitor peptides for molecular imaging and targeted therapy with quickstep towards clinical translation is an interesting and active research field in the radiopharmaceutical sciences. In this article, recent achievements concerning the design, translational research and theranostic applications of structurally-modified small radiopeptides, such as prostate-specific membrane antigen (PSMA) inhibitors, fibroblast activation protein (FAP) inhibitors and antagonists of chemokine-4 receptor ligands (CXCR-4-L), with high affinity for cancer-associated target proteins, are reviewed and discussed.
In order to establish the potential of 51/52MnCl2 as safe PET brain tracers, the radiation effective dose (ED) of 51Mn- and 52Mn-chloride has been assessed by using biokinetic models in ...anthropomorphic phantoms. Results showed that 52Mn-chloride releases one hundred thirty times more radiation dose (ED = 1.35 mSv/MBq) than 51Mn-chloride (ED = 1.02E-02 mSv/MBq). Although the maximum positron energy of 52Mn allows a PET image resolution similar to that of 18F, activities below 15 MBq should be administered.
•51Mn-chloride is a safe PET brain agent due to its low radiation effective dose.•52Mn-chloride produces effective doses one hundred-fold greater than 18F (e.g., 18FFDG).•52Mn-chloride produces effective doses 2.7-fold greater than 89Zr (e.g., 89ZrTrastuzumab).
: The
TcTc(N)(PNP) system, where PNP is a bisphosphinoamine, is an interesting platform for the development of tumor '
' agents. Here, we compared the reactivity and impact of three Tc(N)(PNP) ...frameworks on the stability, receptor targeting properties, biodistribution, and metabolism of the corresponding
TcTc(N)(PNP)-tagged cRGDfK peptide to determine the best performing agent and to select the framework useful for the preparation of
TcTc(N)(PNP)-housing molecular targeting agents.
cRGDfK pentapeptide was conjugated to Cys and labeled with each Tc(N)(PNP) framework. Radioconjugates were assessed for their lipophilicity, stability, in vitro and in vivo targeting properties, and performance.
All compounds were equally synthetically accessible and easy to purify (RCY ≥ 95%). The main influences of the synthon on the targeting peptide were observed in in vitro cell binding and in vivo.
The variation in the substituents on the phosphorus atoms of the PNP enables a fine tuning of the biological features of the radioconjugates.
TcTc(N)(PNP3OH)- and
TcTc(N)(PNP3)- are better performing synthons in terms of labeling efficiency and in vivo performance than the
TcTc(N)(PNP43) framework and are therefore more suitable for further radiopharmaceutical purposes. Furthermore, the good labeling properties of the
TcTc(N)(PNP3OH)- framework can be exploited to extend this technology to the labeling of temperature-sensitive biomolecules suitable for SPECT imaging.
The zinc dithiocarbamates functionalized with folic acid
and
were synthesized with a simple straightforward method, using an appropriated folic acid derivative and a functionalized zinc ...dithiocarbamate (
). Zinc complexes
and
show very low solubilities in water, making them useful for preparing Tc-99m radiopharmaceuticals with a potentially high molar activity. Thus, the transmetallation reaction in water medium between the zinc complexes
or
and the cation
-
Tc(H
O)
(CO)
, in the presence of the monodentate ligand TPPTS, leads to the formation of the 2 + 1 complexes
-
Tc(CO)
(SS)(P) bioconjugated to folic acid (
and
). In spite of the low solubility of
and
in water, the reaction yield is higher than 95%, and the excess zinc reagent is easily removed by centrifugation. The Tc-99m complexes were characterized by comparing their HPLC with those of the homologous rhenium complexes (
and
) previously synthesized and characterized by standard methods. Preliminary in vivo studies with
and
indicate low specific binding to folate receptors. In summary, Tc-99m folates
and
were prepared in high yields, using a one-pot transmetallation reaction with low soluble zinc dithiocarbamates (>1 ppm), at moderate temperature, without needing a subsequent purification step.
This study was designed to evaluate the pharmacologic and biological properties of a paclitaxel-hyaluronan bioconjugate (ONCOFID-P) against IGROV-1 and OVCAR-3 human ovarian cancer xenografts ...following i.p. administration.
In vitro tumor sensitivity to ONCOFID-P was analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, whereas bioconjugate interaction with cells was studied cytofluorimetrically and by confocal microscopy. In vivo toxicity was assessed by a single-dose maximum-tolerated dose, peripheral blood cell count determination and by histologic analysis. Biodistribution of the compound was evaluated with a small animal-dedicated scintigraphy gamma camera following injection of 99mTc-labeled ONCOFID-P. Pharmacokinetic analysis was also carried out. Female severe combined immunodeficiency mice implanted with ovarian cancer cells underwent treatment with ONCOFID-P or free paclitaxel starting from day 7 or 14 after tumor injection, and survivals were compared.
ONCOFID-P interacted with CD44, entered cells through a receptor-mediated mechanism, and exerted a concentration-dependent inhibitory effect against tumor cell growth. After i.p. administration, the bioconjugate distributed quite uniformly within the peritoneal cavity, was well-tolerated, and was not associated with local histologic toxicity. Pharmacokinetic studies revealed that blood levels of bioconjugate-derived paclitaxel were much higher and persisted longer than those obtained with the unconjugated free drug. Intraperitoneal treatment of tumor-bearing mice with the bioconjugate revealed that ONCOFID-P exerted a relevant increase in therapeutic activity compared with free drug.
ONCOFID-P significantly improved results obtained with conventional paclitaxel, in terms of in vivo tolerability and therapeutic efficacy; these data strongly support its development for locoregional treatment of ovarian cancer.
Abstract
The clinical translation of theranostic
177
Lu-radiopharmaceuticals based on inhibitors of the prostate-specific membrane antigen (PSMA) has demonstrated positive clinical responses in ...patients with advanced prostate cancer (PCa). However, challenges still remain, particularly regarding their pharmacokinetic and dosimetric properties. We developed a potential PSMA-immunotheranostic agent by conjugation of a single-chain variable fragment of the IgGD2B antibody (scFvD2B) to DOTA, to obtain a
177
Lu-labelled agent with a better pharmacokinetic profile than those previously reported. The labelled conjugated
177
Lu-scFvD2B was obtained in high yield and stability.
In vitro
,
177
Lu-scFvD2B disclosed a higher binding and internalization in LNCaP (PSMA-positive) compared to PC3 (negative control) human PCa cells.
In vivo
studies in healthy nude mice revealed that
177
Lu-scFvD2B present a favorable biokinetic profile, characterized by a rapid clearance from non-target tissues and minimal liver accumulation, but a slow wash-out from kidneys. Micro-SPECT/CT imaging of mice bearing pulmonary microtumors evidenced a slow uptake by LNCaP tumors, which steadily rose up to a maximum value of 3.6 SUV at 192 h. This high and prolonged tumor uptake suggests that
177
Lu-scFvD2B has great potential in delivering ablative radiation doses to PSMA-expressing tumors, and warrants further studies to evaluate its preclinical therapeutic efficacy.
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