A novel gold-polymer-antibody conjugate for targeted (radio-photothermal) treatment of HepG2 cells.

Localization of the near-infrared (NIR) plasmonic nanoparticles at the tumor sites is essential for safe and efficient photothermal therapy of cancer. In this work, two biocompatible polymers: modified poly(ethylene glycol) (PEG) and branched polyethyleneimine (bPEI) were used to bind plasmonic hollow gold nanospheres (HAuNS) to the tumor-specific antibody, atezolizumab (ATZ). The photo-immunoconjugate (HAuNS-PEI-PEG-ATZ) was prepared via a simple and cost-effective procedure. The conjugate was also prepared with the radioiodinated antibody (ATZ-131I) to combine the targeted radio- and photothermal cytotoxic actions against human hepatoma (HepG2) cells. In vitro study revealed that attachment to the antibody and the use of cellular internalizing polymers enhanced the cellular localization of both gold and the radiotherapeutic Iodine-131. Compared to bare gold nanoparticles, (HAuNS-PEI-PEG-ATZ) conjugate exhibited a significantly enhanced photothermal ablation of HepG2 cells after laser irradiation (0.4 W cm-2, 5 min). Laser irradiation of the cells treated with the radiolabeled conjugate (HAuNS-PEI-PEG-ATZ-131I) exhibited the highest cytotoxicity against HepG2 cells due to the combinatorial cytotoxic effects.

Pyrazole derivatives as potent EGFR inhibitors: synthesis, biological evaluation and in silico and biodistribution study.

Aim: Synthesis of pyrazole derivatives as EGFR inhibitors. Materials & methods: Cytotoxicity and EGFR inhibitory effect were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and EGFR kits, respectively. The biodistribution of radioiodinated compound nanoparticles in tumor-bearing mice was studied. Results: The IC50 values of compound 4a against HepG2 cells and EGFR were 0.15 ± 0.03 and 0.31 ± 0.008 µM, respectively, while those of erlotinib were 0.73 ± 0.04 and 0.11 ± 0.008 µM, respectively. The binding scores of compound 4a and erlotinib to EGFR were -9.52 and -10.23 Kcal/mol, respectively. The maximum tumor uptake of radioiodinated compound after intravenous nanoparticle injection was 6.7 ± 0.3% radioactivity/g. Conclusion: Compound 4a is a promising antitumor agent with a potential EGFR inhibitory effect.

Biocompatible mucoadhesive nanoparticles for brain targeting of ropinirole hydrochloride: Formulations, radiolabeling and biodistribution.

Two nanoformulations with mucoadhesive properties and brain-targeting mechanisms were designed to deliver the anti-Parkinson's drug, ropinirole hydrochloride (RH). In the first formulation, RH and the amphiphilic block copolymer methoxy poly(ethylene glycol)-b-poly(caprolactone) were assembled in a core-shell morphology followed by coating with a mucoadhesive chitosan outer layer producing a multilayer vehicle (MLV). In the second formulation, RH was encapsulated during the polyelectrolyte complexation of two natural polymers, chitosan and alginate producing RH-loaded chitosan-alginate polyelectrolyte (PEC) nanocomplex. Conditions of each formulation were adopted for optimal drug loading. Physico-chemical characterization of the prepared formulations (particle size, polydispersity index and zeta-potential) exhibited stable monodispersed nanoparticles. RH was radiolabeled by I-131 radiotracer in a high-radiochemical yield. Biodistribution and brain targeting of RH from the prepared formulations were studied after administration of 131 I-RH-loaded nanoparticles to albino mice via intranasal and intravenous routs. Elevated brain radioactivity was detected post IN administration of (131 I-RH/PCL-PEG/CS) nanoparticles and (131 I-RH/CS-ALG) nanoparticles comparing with the IN administrated RH solutions (Cmax  = 2.8 ± 0.3, 2 ± 0.3, 0.93 ± 0.03% radioactivity/g, 1 h post administration, respectively). This demonstrated that a relatively high-brain targeting could be achieved via intranasal route of administration of RH-loaded nanoparticles. The proposed models are further potential for application to deliver many other brain-targeting therapeutics.

99mTc radiolabeling of polyethylenimine capped carbon dots for tumor targeting: synthesis, characterization and biodistribution.

PURPOSE: Due to the favorable physicochemical properties and the biocompatibility, carbon dots (CDs) have gained a great attention as a tumor targeting agent. This study investigates polyethylenimine capped CDs (PEI capped CDs) as a prospective nanocarrier of technetium-99m (99mTc) for tumor targeting. Technetium-labeled CDs could be introduced as a promising candidate for single photon emission tomography (SPECT) imaging. MATERIALS AND METHODS: Polyethylenimine capped CDs were prepared by hydrothermal method using hyperbranched PEI and citric acid. For a purpose of comparison, citrate capped CDs were also prepared by microwave irradiation. Both types of CDs were characterized and radiolabeled with 99mTc using sodium borohydride (NaBH4) as a reducing agent. Biodistribution and tumor targeting efficiency of the produced radiolabeled CDs have been studied in Earlich ascites tumor mice model. RESULTS: Citrate capped CDs and PEI capped CDs have been synthesized successfully and characterized. High radiochemical yield of 99mTc-citrate capped CDs 99mTc-PEI capped CDs was obtained (97 ± 0.7 and 90 ± 0.2, respectively). Biodistribution studies of 99mTc-labeled PEI capped CDs have shown a potential tumor uptake (10 ± 0.5% Radioactivity/gram tumor) with high target to non-target ratio (T/NT) around 7 at 1-h post injection. 99mTc-citrate capped CDs have achieved a lower tumor uptake level (3.8 ± 0.3% Radioactivity/gram tumor 1 h post injection). CONCLUSION: This study introduces PEI capped CDs as a promising nanocarrier of 99mTc for efficient tumor targeting. Technetium-labeled PEI capped CDs could be utilized as a potential SPECT tumor imaging agent.

Targeted photoimmunotherapy based on photosensitizer-antibody conjugates for multiple myeloma treatment.

Despite the high in vitro efficacy of photodynamic therapeutics, lack of tumor targeting significantly reduces their in vivo efficacy and thus limits their clinical use. Photoimmunotherapy (PIT) is a new synthetic strategy to target and treat cancer by photodynamic therapy (PDT). In this study, we describe design and synthesis of a third-generation photosensitizer comprising a PEGylated-phthalocyanine star-polymer photosensitizer that covalently bound to a myeloma tumor-selective antibody (MAb) via the carbodiimide chemistry. The free photosensitizer demonstrated a minimum dark toxicity when tested in mammalian myeloma cell line (SP2/OR); and a moderate phototoxicity after irradiation with non thermal laser red light as a result of light-induced production of cytotoxic singlet oxygen species. Covalent attachment of the photosensitizer (Pc) to the MAb resulted in a significantly enhanced phototoxicity. This is mainly ascribed to the fact that internalization enhances phototoxicity of Pc-MAb bioconjugates. The radioactivated photoimmuno-conjugates 131I(PcMAb) demonstrated the highest phototoxicity to myeloma cells. The suggested bioconjugates are promising candidates as multiple therapeutic models for in vivo treatment of myeloma.

Gold nanorod-loaded (PLGA-PEG) nanocapsules as near-infrared controlled release model of anticancer therapeutics.

Despite of high in vitro anticancer efficacy of many chemotherapeutics, their in vivo use is limited due to lack of biocompatibility and tumor targeting. Near-infrared (NIR) photothermally induced phase transition of PLGA-PEG regime was utilized for developing highly efficient photoresponsive drug delivery systems. Co-encapsulation of plasmonic gold nanorods (GNRs), as NIR-trigger, with the novel and highly efficient anticancer drug N'-(2-Methoxybenzylidene)-3-methyl-1-phenyl-H-Thieno[2,3-c]Pyrazole-5-Carbohyd-razide (MTPC) produced NIR-responsive biodegradable polymeric (PLGA-b-PEG) nanocapsules. This remotely controllable drug release significantly enhanced both biodistribution and pharmacokinetics of the hydrophobic drug. Intravenous (IV) injection of the prepared nanocapsules (MTPC/GNRs@PLGA-PEG) to tumor-bearing mice followed by extracorporeal exposure of the tumor to NIR light resulted in highly selective drug accumulation at the tumor sites. In vivo biodistribution and pharmacokinetics utilizing iodine-131 drug-radiolabelling technique revealed a maximum target to non-target ratio (T/NT) of 5.8, 4 h post-injection with maximum drug level in the tumor (6.3 ± 0.6% of the injected dose). Graphical abstract.

Penetration enhancer-containing spanlastics (PECSs) for transdermal delivery of haloperidol: in vitro characterization, ex vivo permeation and in vivo biodistribution studies.

Haloperidol (Hal) is one of the widely used antipsychotic drugs. When orally administered, it suffers from low bioavailability due to hepatic first pass metabolism. This study aimed at developing Hal-loaded penetration enhancer-containing spanlastics (PECSs) to increase transdermal permeation of Hal with sustained release. PECSs were successfully prepared using ethanol injection method showing reasonable values of percentage entrapment efficiency, particle size, polydispersity index and zeta potential. The statistical analysis of the ex vivo permeation parameters led to the choice of F1L - made of Span® 60 and Tween® 80 at the weight ratio of 4:1 along with 1% w/v Labrasol® - as the selected formula (SF). SF was formulated into a hydrogel by using 2.5% w/v of HPMC K4M. The hydrogel exhibited good in vitro characteristics. Also, it retained its physical and chemical stability for one month in the refrigerator. The radiolabeling of SF showed a maximum yield by mixing of 100 µl of diluted formula with 50 µl saline having 200 MBq of 99mTc and containing 13.6 mg of reducing agent (NaBH4) and volume completed to 300 µl by saline at pH 10 for 10 min as reaction time. The biodistribution study showed that the transdermal 99mTc-SF hydrogel exhibited a more sustained release pattern and longer circulation duration with pulsatile behavior in the blood and higher brain levels than the oral 99mTc-SF dispersion. So, transdermal hydrogel of SF may be considered a promising sustained release formula for Hal maintenance therapy with reduced dose size and less frequent administration than oral formula.

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.