pH-Sensitive doxorubicin delivery using zinc oxide nanoparticles as a rectified theranostic platform: in vitro anti-proliferative, apoptotic, cell cycle arrest and in vivo radio-distribution studies.

Despite enormous advancements in its management, cancer is the world's primary cause of mortality. Therefore, tremendous strides were made to produce intelligent theranostics with mitigated side effects and improved specificity and efficiency. Thus, we developed a pH-sensitive theranostic platform composed of dextran immobilized zinc oxide nanoparticles, loaded with doxorubicin and radiolabeled with the technetium-99m radionuclide (99mTc-labelled DOX-loaded ZnO@dextran). The platform measured 11.5 nm in diameter with -12 mV zeta potential, 88% DOX loading efficiency and 98.5% radiolabeling efficiency. It showed DOX release in a pH-responsive manner, releasing 93.1% cumulatively at pH 5 but just 7% at pH 7.4. It showed improved intracellular uptake, which resulted in a high growth suppressive effect against MCF-7 cancer cells as compared to the free DOX. It boasted a 4 times lower IC50 than DOX, indicating its significant anti-proliferative potential (0.14 and 0.55 µg ml-1, respectively). The in vitro biological evaluation revealed that its molecular mode of anti-proliferative action included downregulating Cdk-2, which provoked G1/S cell cycle arrest, and upregulating both the intracellular ROS level and caspase-3, which induced apoptosis and necrosis. The in vivo experiments in Ehrlich-ascites carcinoma bearing mice demonstrated that DOX-loaded ZnO@dextran showed a considerable 4-fold increase in anti-tumor efficacy compared to DOX. Moreover, by utilizing the diagnostic radionuclide (99mTc), the radiolabeled platform (99mTc-labelled DOX-loaded ZnO@dextran) was in vivo monitored in tumor-bearing mice, revealing high tumor accumulation (14% ID g-1 at 1 h p.i.) and reduced uptake in non-target organs with a 17.5 T/NT ratio at 1 h p.i. Hence, 99mTc-labelled DOX-loaded ZnO@dextran could be recommended as a rectified tumor-targeted theranostic platform.

Cod liver oil nano-structured lipid carriers (Cod-NLCs) as a promising platform for nose to brain delivery: Preparation, in vitro optimization, ex vivo cytotoxicity & in vivo biodistribution utilizing radioiodinated zopiclone.

Nano-structured lipid carriers containing zopiclone were prepared as a targeted drug delivery system to convey zopiclone directly to brain via nasal route. Nano-structured lipid carriers were constructed adopting hot emulsification-ultrasonication method using palmitic acid in place of the solid lipid, cod liver oil as liquid lipid, and poloxamer 407 as a surfactant. A three-factor three-level central composite face-centered design was used to optimize the formulated nano-structured lipid carriers. The independent factors were lipid amount (X1), surfactant amount (X2), and sonication time (X3). The examined responses were entrapment efficiency (EE,Y1,%), particle size (PS,Y2,nm), zeta potential(mV), polydispersity index(PDI,Y3), in vitro release(Q8h,Y4,%) and dissolution efficiency (DE,Y5,%). The optimum formula showed high entrapment efficiency of 94.31% ± 2.44, in vitro drug release of 83.89% ± 1.77 with dissolution efficiency equals 88.63% ± 2.01, small particle size of 71.27 nm ± 13.57 and low polydispersity index 0.097 ± 0.15. In vivo biodistribution in mice was evaluated by a radiobiological technique using radioiodinated zopiclone([131I]iodo-ZP). Results revealed the superiority of the intranasal route to deliver zopiclone directly to brain faster and higher brain uptake (6.9 ± 1.02%ID/g at 5 min post-administration). The current study confirmed that intranasal administration of nano-structured lipid carriers had great potential as an effective tool for targeted brain zopiclone delivery for insomnia treatment.

New frontier radioiodinated probe based on in silico resveratrol repositioning for microtubules dynamic targeting.

PURPOSE: As the 'de novo' drug discovery faces a highly attrition rates, drug repositioning procures a heighten concern in identifying novel uses for existing medications. This study aimed to fabricate radioiodinated resveratrol as a potent microtubules interfering agent for cancer theragnosis. METHODS: Resveratrol was radiolabeled with radioactive iodine where the radioiodination efficiency was enlightened and the computational approaches were employed to investigate the affinity and specificity with tubulins. Furthermore, the in-vivo distribution and pharmacokinetic studies in normal and tumor induced mice were investigated. RESULTS: The maximum radioiodination yield (94.6 ± 1.66) was achieved at optimum preparation parameters stated as 100 µg/mL of oxidizing agent, 100 µg/ml of resveratrol, reaction time of 30 min and reaction pH 5. The in silico studies showed that di-iodinated resveratrol (compound 6) exhibited the best binding score (-34.46) and interaction with the ß-tubulin binding site. The in vivo distribution in tumor models revealed a significant accumulation (4.02% ID/g) in tumor lesion at 60 min p.i. The rate of drug elimination demonstrated a mono-exponential decline of radioactivity versus time in the blood. CONCLUSION: Radioiodinated resveratrol revealed good microtubules targeting which render it as a novel theranostic probe for cancer management.

99mTc-doxorubicin-loaded gallic acid-gold nanoparticles (99mTc-DOX-loaded GA-Au NPs) as a multifunctional theranostic agent.

The development of cancer theranostic nanomedicines is recommended to concurrently achieve and evaluate the therapeutic benefit and progress. The current work aims to develop gallic acid-gold nanoparticles (GA-Au NPs) as a theranostic probe for 99mTc-Doxorubicin (99mTc-DOX) based on the spatiotemporal release pattern induced intra-tumoral (IT) delivery. DOX-loaded GA-Au NPs were developed and identified via UV-Vis spectroscopy. The system was characterized for drug loading efficiency%, particle size, zeta potential, topography, in vitro DOX release and anti-proliferative activity against the MCF-7 cell-line. The factors influencing radiolabeling efficiency of DOX with 99mTc (DOX concentration, stannous chloride concentration, reaction time and pH) were optimized. The in vitro stability in mice serum and in vivo distribution studies in mice of 99mTc-DOX-loaded GA-Au NPs were investigated following IV and IT administration. Dox-loaded GA-Au NPs had a loading efficiency of 91%, a small particle size (≈50 nm), a promising zeta potential (-20 mV) and a sustained drug release profile at pH 5.3. GA-Au NPs exhibited increased anti-proliferative activity, with approximately a four-fold lower IC50 value (0.15 µg/ml) than free DOX. The optimized radiolabeling efficiency of 99mTc-DOX was ≈93%. It showed good physiological stability in mice serum for at least 8 h. The IT delivery of 99mTc-DOX-loaded GA-Au NPs in tumor-induced mice showed dramatic tumor accumulation. A maximum magnitude of 86.73%ID/g was achieved, at 15 min post-injection, with a target/non-target ratio of ≈56. 99mTc-DOX-loaded GA-Au NPs could be used for the selective IT delivery of a chemotherapeutic agent and an imaging agent to a target organ.

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.

I-131 doping of silver nanoparticles platform for tumor theranosis guided drug delivery.

Nanotechnology may be applied in medicine where the utilization of nanoparticles (≤100 nm) for the delivery and targeting of theranostic agents is at the forefront of projects in cancer nano-science. This study points a novel one step synthesis approach to build up polyethylene glycol capped silver nanoparticles doped with I-131 radionuclide (131I-doped Ag-PEG NPs). The formula was prepared with average hydrodynamic size 21 nm, zeta potential - 25 mV, radiolabeling yield 98 ±â€¯0.76%, and showed good in-vitro stability in saline and mice serum. The in-vitro cytotoxicity study of cold Ag-PEG NPs formula as a drug carrier vehicle showed no cytotoxic effect on normal cells (WI-38 cells) at a concentration below 3 µL/104 cells. The in-vivo biodistribution pattern of 131I-doped Ag-PEG NPs in solid tumor bearing mice showed high radioactivity accumulation in tumor tissues with maximum uptake of 35.43 ±â€¯1.12 and 63.8 ±â€¯1.3% ID/g at 60 and 15 min post intravenous (I.V.) and intratumoral injection (I.T.), respectively. Great potential of T/NT ratios were obtained throughout the experimental time points with maximum ratios 45.23 ±â€¯0.65 and 92.46 ±â€¯1.02 at 60 and 15 min post I.V. and I.T. injection, respectively. Thus, 131I-doped Ag-PEG NPs formulation could be displayed as a great potential tumor nano-sized theranostic probe.