Iron oxide nanoparticulate system as a cornerstone in the effective delivery of Tc-99 m radionuclide: a potential molecular imaging probe for tumor diagnosis.

BACKGROUND: The evolution of nanoparticles has gained prominence as platforms for developing diagnostic and/or therapeutic radiotracers. This study aims to develop a novel technique for fabricating a tumor diagnostic probe based on iron oxide nanoparticles excluding the utilization of chelating ligands. METHODS: Tc-99 m radionuclide was loaded into magnetic iron oxide nanoparticles platform (MIONPs) by sonication. 99mTc-encapsulated MIONPs were fully characterized concerning particles size, charge, radiochemical purity, encapsulation efficiency, in-vitro stability and cytotoxicity. These merits were biologically evaluated in normal and solid tumor bearing mice via different delivery approaches. RESULTS: 99mTc-encapsulated MIONPs probe was synthesized with average particle size 24.08 ± 7.9 nm, hydrodynamic size 52 nm, zeta potential -28 mV, radiolabeling yield 96 ± 0.83%, high in-vitro physiological stability, and appropriate cytotoxicity behavior. The in-vivo evaluation in solid tumor bearing mice revealed that the maximum tumor radioactivity accumulation (25.39 ± 0.57, 36.40 ± 0.59 and 72.61 ± 0.82%ID/g) was accomplished at 60, 60 and 30 min p.i. for intravenous, intravenous with physical magnet targeting and intratumoral delivery, respectively. The optimum T/NT ratios of 57.70, 65.00 and 87.48 were demonstrated at 60 min post I.V., I.V. with physical magnet targeting and I.T. delivery, respectively. These chemical and biological characteristics of our prepared nano-probe demonstrate highly advanced merits over the previously reported chelator mediated radiolabeled nano-formulations which reported maximum tumor uptakes in the scope of 3.65 ± 0.19 to 16.21 ± 2.56%ID/g. CONCLUSION: Stabilized encapsulation of 99mTc radionuclide into MIONPs elucidates a novel strategy for developing an advanced nano-sized radiopharmaceutical for tumor diagnosis. Graphical abstract 99mTc-encapsulated MIONPs nanosized-radiopharmaceutical as molecular imaging probe for tumor diagnosis.

Improved Targeting and Tumor Retention of a Newly Synthesized Antineoplaston A10 Derivative by Intratumoral Administration: Molecular Docking, Technetium 99m Radiolabeling, and In Vivo Biodistribution Studies.

BACKGROUND: Recently, the direct intratumoral (i.t.) injection of anticancer agents has been investigated. A newly synthesized Antineoplaston A10 analog 3-(4-methoxybenzoylamino)-2,6-piperidinedione (MPD) showed an antitumor activity in human breast cancer cell line. Unfortunately, MPD suffered from poor water solubility. MATERIALS AND METHODS: Pseudoternary phase diagram of oil (isopropyl myristate), surfactant (Tween 80), cosurfactant (ethanol), and water was plotted. MPD microemulsion (MPDME) was developed and characterized for particle size (PS), polydispersity index (PDI), zeta potential (ZP), and morphology (transmission electron microscopy). MPDME and MPD solution (MPDS) were radiolabeled with technetium 99m (99mTc) using stannous chloride dihydrate (SnCl2.2H2O). Molecular docking of MPD and 99mTc-MPD was performed to study the interaction with DNA. RESULTS: The impacts of intravenous (i.v.) and i.t. injections of 99mTc-MPDME and 99mTc-MPDS on biodistribution were studied. The developed MPDME showed spherical droplets with mean PS (74.00 ± 5.69 nm), PDI (0.25 ± 0.03), and ZP (33.90 ± 0.90 mV). Labeling yield of 99mTc-MPDME and 99mTc-MPDS was 97.00% ± 0.60% and 92.02% ± 0.45%, respectively. MPD and 99mTc-MPD showed almost same binding affinity with DNA binding site. Biodistribution results showed that i.t. injection of 99mTc-MPDME significantly enhanced tumor retention compared to i.v. route. CONCLUSIONS: Herein, the authors concluded that microemulsion could be used as i.t. injectable delivery vehicle to improve targeting and tumor retention of MPD.

Design and development of microemulsion systems of a new antineoplaston A10 analog for enhanced intravenous antitumor activity: In vitro characterization, molecular docking, 125I-radiolabeling and in vivo biodistribution studies.

A10, (3-phenylacetylamino-2,6-piperidinedione), is a natural peptide with broad antineoplastic activity. Recently, in vitro antitumor effect of a new A10 analog [3-(4-methoxybenzoylamino)-2,6-piperidinedione] (MPD) has been verified. However, poor aqueous solubility represents an obstacle towards intravenous formulation of MPD and impedes successful in vivo antitumor activity. To surmount such limitation, MPD microemulsion (MPDME) was developed. A 3122 full factorial design using Design-Expert® software was adopted to study the influence of different parameters and select the optimum formulation (MPDME1). Transmission electron microscopy (TEM) displayed spherical droplets of MPDME1. The cytotoxicity of MPDME1 in Michigan Cancer Foundation 7 (MCF-7) breast cancer cell line exceeded that of MPD solution (MPDS) and tamoxifen. Compatibility with injectable diluents, in vitro hemolytic studies and in vivo histopathological examination confirmed the safety of parenteral application of MPDME1. Molecular docking results showed almost same binding affinity of A10, MPD and 125I-MPD with histone deacetylase 8 (HDAC8) receptor. Accordingly, radioiodination of MPDME1 and MPDS was done via direct electrophilic substitution reaction. Biodistribution of 125I-MPDME1 and 125I-MPDS in normal and tumor (ascites and solid) bearing mice showed high accumulation of 125I-MPDME1 in tumor tissues. Overall, the results proved that MPDME represents promising parenteral delivery system capable of improving antineoplastic activity of MPD.

Laser-responsive liposome for selective tumor targeting of nitazoxanide nanoparticles.

Nitazoxanide [2-(Acetyloxy)-N-(5-nitro-2-thiazolyl)benzamide], usually referred as NTZ, is an antiparasites drug with a potential anti-cancer reactivity. However, the bioavailability of nitazoxanide is limited due to its poor water solubility. In this study, nitazoxanide could be successfully incorporated in a stable biocompatible liposome (NTZ-LP) using a modified thin film hydration technique. Further, a novel lipophilic phthalocyanine star polymer R4PcZn was prepared as photosensitizer and in situ incorporated with NTZ in the liposome formulation affording a laser-responsive liposome (NTZ-ZnPc-LP). Both (NTZ-LP) and (NTZ-ZnPc-LP) showed high entrapment efficiency (EE) and high in vitro drug release rates. Transmission electron microscope (TEM) images and dynamic light scattering (DLS) measurements of (NTZ-LP) and (NTZ-ZnPc-LP) showed unilamellar vesicles of mean diameter 192.2 and 87.4nm, respectively. In addition, NTZ nanoparticles (NTZ NPs) were prepared via membrane extrusion method using DMF and water as solvents. All formulations were similarly prepared using radiolabeled nitazoxanide 125I-NTZ. After induction of solid tumor in mices using Ehrlich Ascites Carcinoma, the prepared formulations were injected in the tail vein of the mices. Tumor sites of the animal injected with (125I-NTZ-ZnPc-LP) were illuminated with a HeNe laser (λ=630nm). Afterwards, the biodistriburtion of 125I-NTZ was tagged using γ counter. Results showed that the light-responsive formulation (125I-NTZ-ZnPc-LP) affords a higher accumulation of 125I NTZ in the tumor sites after illumination. This can be attributed to the rupture of liposome lipid bilayer as a result of the photosensitization process and the singlet oxygen species resulted thereof. Despite (NTZ NPs) formulation showed a rapid accumulation of NTZ in tumor, it showed unfavoured rapid blood clearance rate.