Search

Chemodynamic therapy (CDT) is an emerging treatment strategy for cancer, but the low therapeutic efficacy and potential side effects still limit its applications. In this study, we report a semiconducting polymer nanocatalyst (PGFe) that can generate reactive oxygen species (ROS) only upon near-infrared (NIR) light-activation for photodynamic therapy (PDT)-synergized CDT. Such PGFe consists of a semiconducting polymer as a photosensitizer, iron oxide (Fe3O4) nanoparticles as CDT agents, and glucose oxidase (GOx), all of which are loaded into a singlet oxygen (1O2)-responsive nanocarrier. Under NIR laser irradiation, PGFe produces 1O2 through a photosensitizer-mediated PDT effect, and the produced 1O2 destroys the 1O2-responsive nanocarriers, leading to controlled releases of Fe3O4 nanoparticles and GOx. In a tumor microenvironment, GOx catalyzes glucose degradation to form hydrogen peroxide (H2O2), and thus the CDT effect of Fe3O4 nanoparticles is greatly improved. As such, an amplified ROS level in tumor cells is obtained by PGFe to induce cell death. PGFe can be utilized to treat subcutaneous 4T1 tumors, observably inhibiting the tumor growth and suppressing lung and liver metastasis. This study thus provides a NIR light-activated ROS generation strategy for precise and effective treatments of tumors. [ABSTRACT FROM AUTHOR]

Novel strategies for diagnosing triple-negative breast cancer (TNBC) are essential for effective clinical treatment. Vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) are potential targets for tumor imaging agents. We designed and synthesized [99mTc]Tc-labeled heptapeptide (A7R) and its D-type peptide (DA7R) with high affinity and specificity for VEGFR2 and NRP-1 as novel single-photon emission computed tomography (SPECT) probes for TNBC imaging. The specificities of A7R and DA7R were first evaluated in vitro using flow cytometry and confocal microscopy and ex vivo using fluorescence imaging. Subsequently, A7R and DA7R were labeled with [99mTc]Tc through 6-hydrazino nicotinamide (HYNIC), and their radiochemical purities (RCPs) and stability in vitro were assessed. The imaging performance and biodistribution of [99mTc]Tc-HYNIC-A7R and [99mTc]Tc-HYNIC-DA7R were evaluated in TNBC mouse models. A7R and DA7R exhibited good TNBC cell-targeting abilities and were readily labeled with [99mTc]Tc through HYNIC. Both [99mTc]Tc-HYNIC-A7R and [99mTc]Tc-HYNIC-DA7R had high RCPs and stability in vitro, and their accumulation in tumor tissues in the TNBC models was evident, with fast blood clearance and favorable biodistribution. More importantly, [99mTc]Tc-HYNIC-DA7R showed better tumor-to-muscle ratios and lower renal uptake than [99mTc]Tc-HYNIC-A7R. These results suggest that both [99mTc]Tc-HYNIC-DA7R and [99mTc]Tc-HYNIC-A7R have substantial potential as probes for targeted SPECT imaging of TNBC, and the former may be considered for future clinical translation owing to its superior tumor imaging performance. [ABSTRACT FROM AUTHOR]

The design and fabrication of nanoplatforms with both nuclear medical imaging and therapeutic functions remain challenging in current precision nanomedicine. Herein, we report the design of a novel nanoplatform based on glucose-modified dendrimer-entrapped gold nanoparticles (Au DENPs) labeled with radionuclide 68Ga and incorporated with cytosine-guanine (CpG) oligonucleotide for positron emission tomography (PET)/computed tomography (CT) dual-mode imaging and immunotherapy of tumors. In this study, generation 5 poly(amidoamine) (PAMAM) dendrimers were first modified to have 8.2 DOTA and 7.3 polyethylene glycol with the other end functionalized with 2-amino-2-deoxy- D -glucose (DG) for each dendrimer, entrapped with Au NPs, and then radiolabeled with 68Ga through the DOTA chelation. The synthesized DG-Au DENPs have good cytocompatibility, targeting specificity toward cancer cells expressing glucose transporters, and the ability to be labeled by 68Ga with great labeling efficiency (≥85%) and stability (≥95%). After being loaded with CpG, the formed DG-Au DENPs/CpG polyplexes were proven to be used for tumor dual-mode PET/CT imaging and immunotherapy by effectively maturing dendritic cells to initiate a T cell-based antitumor immune response in vivo. Compared with the DG-free polyplexes, the developed DG-Au DENPs/CpG polyplexes show a much more sensitive imaging effect and better inhibition effect of tumors. These findings demonstrate a unique design of 68Ga-labeled DG-Au DENPs, a promising theranostic nanoplatform that may be extended to tackle different tumor types. [ABSTRACT FROM AUTHOR]

An increasing number of studies show the diagnostic and therapeutic potential of scorpion venoms and toxins in cancer, including malignant glioma that represents the most fatal primary brain tumors. Chlorotoxin (CTX) and a CTX-like peptide Buthus martensii Karsch chlorotoxin (BmK CT) derived from scorpion venoms, have been identified as glioma-specific agents for imaging and therapy. In this study, we designed and manufactured a new BmK CT derivative (BmK CT-D) according to the amino acid sequences of native CTX and BmK CT and investigated the possibility of 99mTc-labeled BmK CT-D as a single-positron emission computed tomography (SPECT) imaging agent for glioma diagnosis. The data indicated that the BmK CT-D peptide had good cytocompatibility, improved cellular uptake compared to BmK CT, and could be readily radiolabeled by 99mTc via99mTc-tricarbonyl chemistry with high radiochemical yield and stability in vitro. Moreover, the formed 99mTc-BmK CT-D was able to be used as a probe for SPECT imaging of glioma cells in vitro and in tumor-bearing mice in vivo, indicating that the designed peptide is a promising targeting agent for tumor imaging. [ABSTRACT FROM AUTHOR]

Multifunctional 99mTc-labeled dendrimer-entrapped gold nanoparticles (99mTc-Au DENPs) were designed and synthesized. Our results show that the type of surface groups (acetyl or hydroxyl) significantly impact the biodistribution profile of the 99mTc-Au DENPs, thereby allowing for preferential SPECT/CT imaging of different organs. [ABSTRACT FROM AUTHOR]

The development of cost-effective targeted drug delivery systems for cancer chemotherapy still remains a great challenging task. Here, we describe the synthesis and characterization of multifunctional polyethylenimine (PEI) as an effective vehicle to load an anticancer drug doxorubicin (DOX) for in vivo targeted cancer therapy. In this study, PEI was sequentially conjugated with polyethylene glycol (PEG) monomethyl ether, PEGylated folic acid (FA), and fluorescein isothiocyanate (FI). This was followed by the acetylation of the remaining PEI surface amines. The formed FA-targeted multifunctional PEI (FA–mPEI) was used as a vehicle to encapsulate DOX. We show that the formed FA–mPEI/DOX complexes with each PEI encapsulating 6.9 DOX molecules are water dispersible and can sustainably release DOX in a pH-dependent manner, showing a higher release rate under acidic pH conditions than under physiological pH conditions. Furthermore, the complexes display specific therapeutic efficacy to cancer cells in vitro and a subcutaneous tumor model in vivo, and have good organ compatibility. The designed multifunctional PEI may be used as an effective vehicle for targeted cancer chemotherapy. [ABSTRACT FROM AUTHOR]

A multifunctional folic acid-targeted dendrimer-based nanoplatform was designed to have both Mn(ii) and 99mTc loaded via chelation. The formed nanoplatform displays good stability, cytocompatibility and hemocompatibility in a given concentration range, and can be used for targeted dual-mode single-photon emission computed tomography/magnetic resonance imaging of tumors. [ABSTRACT FROM AUTHOR]

Osteogenesis and angiogenesis that have interaction in vivo are two pivotal processes for implant osseointegration, so implant surfaces with both enhanced osteogenic and angiogenic activities are in need. Developing silicon (Si) doped TiO2 nanotube array (TNA-Si) coatings shall be a promising strategy to yield favorable implant osseointegration with the combined effects of TiO2 nanotube arrays (TNAs) and Si in the enhancement of both osteogenic and angiogenic activities. To achieve this purpose, TNA-Sis are fabricated through the unique strategy of anodization of magnetron-sputtered TiSi coatings. Under optimized conditions, a highly ordered nanotubular structure with even dispersion of Si throughout the nanotubes in the form of SiO2 can be obtained. Si incorporation has little influence on the nanotube length, but slightly decreases the diameter, thickens the nanotube wall, and increases the hydrophilicity. TNA-Sis show good cytocompatibility to both osteoblasts and endothelial cells (ECs). TNA-Sis show enhanced proliferation, spreading, alkaline phosphatase activity, collagen secretion, and matrix mineralization of osteoblasts. Meanwhile, TNA-Sis induce better EC proliferation, and the conditioned culture media from TNA-Sis generate better angiogenic ability, nitric oxide production, and vascular endothelial growth factor secretion from ECs. In particular, TNA-Si4.6 with the strongest osteogenic and angiogenic activities in the context of the present study is highly promising as the next-generation hard tissue implant coating. [ABSTRACT FROM AUTHOR]

Although titanium (Ti) implants are already being broadly used, further improvement is still mandatory for improving its clinical performance. To this end, small interfering RNA (siRNA) biofunctionalization may present a novel strategy. In this study, siRNA biofunctionalization was realized on a titania nanotube array (TNT) on Ti by the cathodic electrodeposition (CED) of a chitosan (CS)/siRNA complex. The siRNA deposition amount was linearly correlated to the current density and the siRNA release profile was sensitive to the pH value of the surrounding solution. To confirm the activity of the cathodically electrodeposited siRNA, the siRNA targeting green fluorescent protein (siGFP) was introduced by CED, and the primary rat mesenchymal stem cells (rMSCs) encoding a GFP expression motif were seeded. High siRNA delivery efficiency and sustained target gene down-regulation were observed, which were much better than the conventional CS/siRNA nanoparticle delivery system and were related to the enhanced siRNA access into the cytoplasm. Simultaneously, good cytocompatibility was observed from the CS/siRNA biofunctionalization, as indicated by the good cell adhesion and viability. Finally, the siRNA targeting casein kinase-2 interacting protein-1 (siCkip-1), reported to have osteogenic potential, was introduced by CED to assess the potential of CS/siRNA biofunctionalization for application in bone implants. The CS/siCkip-1 biofunctionalization magnificently enhanced the osteogenic differentiation of rMSCs in terms of improved osteogenesis related gene expression, collagen secretion and calcium deposition, showing high promise for application in bone implants. The study demonstrates a new and convenient way to functionalize the biomedical metal implants with CS/siRNA for surface activation via local siRNA delivery. [ABSTRACT FROM AUTHOR]

The design and fabrication of nanoplatforms with both nuclear medical imaging and therapeutic functions remain challenging in current precision nanomedicine. Herein, we report the design of a novel nanoplatform based on glucose-modified dendrimer-entrapped gold nanoparticles (Au DENPs) labeled with radionuclide 68 Ga and incorporated with cytosine-guanine (CpG) oligonucleotide for positron emission tomography (PET)/computed tomography (CT) dual-mode imaging and immunotherapy of tumors. In this study, generation 5 poly(amidoamine) (PAMAM) dendrimers were first modified to have 8.2 DOTA and 7.3 polyethylene glycol with the other end functionalized with 2-amino-2-deoxy-D-glucose (DG) for each dendrimer, entrapped with Au NPs, and then radiolabeled with 68 Ga through the DOTA chelation. The synthesized DG-Au DENPs have good cytocompatibility, targeting specificity toward cancer cells expressing glucose transporters, and the ability to be labeled by 68 Ga with great labeling efficiency (≥85%) and stability (≥95%). After being loaded with CpG, the formed DG-Au DENPs/CpG polyplexes were proven to be used for tumor dual-mode PET/CT imaging and immunotherapy by effectively maturing dendritic cells to initiate a T cell-based antitumor immune response in vivo . Compared with the DG-free polyplexes, the developed DG-Au DENPs/CpG polyplexes show a much more sensitive imaging effect and better inhibition effect of tumors. These findings demonstrate a unique design of 68 Ga-labeled DG-Au DENPs, a promising theranostic nanoplatform that may be extended to tackle different tumor types.

Novel theranostic nanosystems demonstrate great potential to achieve timely diagnosis and effective therapy at the same time. However, due to the relatively low accumulation of theranostic nanosystems at the tumor site, the theranostic efficiency is limited. In this study, a novel theranostic nanosystem with a pH-responsive charge conversion property was constructed to improve the cellular uptake towards cancer cells for enhanced single photon emission computed tomography (SPECT)/computed tomography (CT) dual mode imaging and radiotherapy of tumors. In detail, polyethylenimine (PEI) was utilized as a nanoplatform to link with polyethylene glycol (PEG) monomethyl ether with one end of N-hydroxylsuccinimide (mPEG-NHS), PEG with ends of maleimide and succinimidyl valerate (MAL-PEG-SVA), alkoxyphenyl acylsulfonamide (APAS), 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO), and fluorescein isothiocyanate (FI), successively. The formed functionalized PEI was then utilized to entrap gold nanoparticles, acetylate the remaining amines of PEI and label with radioactive iodine-131 ( 131 I) to build theranostic nanosystems. The result demonstrated that the theranostic nanosystem has a 3.8 nm Au core and showed excellent colloidal stability. On account of the charge conversion property of APAS, the APAS linked PEI entrapped gold nanoparticles could switch from neutral to positive in a slightly acidic microenvironment, which induced improved cellular uptake. Above all, after 131 I labeling, the generated theranostic nanosystem could achieve enhanced SPECT/CT dual mode imaging and radiotherapy of cancer cells in vitro and a xenograft tumor model in vivo. The constructed APAS-linked PEI nanosystem has great potential to be used as a model for SPECT/CT imaging and radiotherapy of various types of cancer.

Multifunctional 99m Tc-labeled dendrimer-entrapped gold nanoparticles ( 99m Tc-Au DENPs) were designed and synthesized. Our results show that the type of surface groups (acetyl or hydroxyl) significantly impact the biodistribution profile of the 99m Tc-Au DENPs, thereby allowing for preferential SPECT/CT imaging of different organs.

Osteogenesis and angiogenesis that have interaction in vivo are two pivotal processes for implant osseointegration, so implant surfaces with both enhanced osteogenic and angiogenic activities are in need. Developing silicon (Si) doped TiO 2 nanotube array (TNA-Si) coatings shall be a promising strategy to yield favorable implant osseointegration with the combined effects of TiO 2 nanotube arrays (TNAs) and Si in the enhancement of both osteogenic and angiogenic activities. To achieve this purpose, TNA-Sis are fabricated through the unique strategy of anodization of magnetron-sputtered TiSi coatings. Under optimized conditions, a highly ordered nanotubular structure with even dispersion of Si throughout the nanotubes in the form of SiO 2 can be obtained. Si incorporation has little influence on the nanotube length, but slightly decreases the diameter, thickens the nanotube wall, and increases the hydrophilicity. TNA-Sis show good cytocompatibility to both osteoblasts and endothelial cells (ECs). TNA-Sis show enhanced proliferation, spreading, alkaline phosphatase activity, collagen secretion, and matrix mineralization of osteoblasts. Meanwhile, TNA-Sis induce better EC proliferation, and the conditioned culture media from TNA-Sis generate better angiogenic ability, nitric oxide production, and vascular endothelial growth factor secretion from ECs. In particular, TNA-Si4.6 with the strongest osteogenic and angiogenic activities in the context of the present study is highly promising as the next-generation hard tissue implant coating.

[(99m)Tc(CO)(3)](+)-6-[N-(2-dipicolyl)amino]hexanoic acid (1a) and [(99m)Tc(CO)(3)](+)-11-[N-(2-dipicolyl)amino]undecanoic acid (1b) were prepared by incorporating [(99m)Tc-(CO)(3)](+) into 6-[N-(2-dipicolyl)amino]hexanoic acid and 11-[N-(2-dipicolyl)amino]undecanoic acid, respectively. The overall radiochemical yield of 1a and 1b was from 79.7% to 91.3% and radiochemical purity after HPLC purification was more than 94%. The resulting complexes were found to be chemically stable when incubated in SD rat serum for 3 h at 37 °C. Tissue distribution studies in normal mice showed that high initial uptake of Tc-99m complexes were observed, followed by slow clearance from the heart. The maximum heart-to-blood ratio of 1a was 1.46 at 60 min, but 1b showed a poor heart-to-blood ratio. By estimating the tissue distribution and the computing result of the molar volume and the solvation free energy of Tc-99m chelating groups, a small-size and monocationic Tc-99m core is very important to enhance the myocardial accumulation and low liver uptake for the fatty acid tracers.