Site-Specific 111In-Radiolabeling of Dual-PEGylated Porous Silicon Nanoparticles and Their In Vivo Evaluation in Murine 4T1 Breast Cancer Model

Polyethylene glycol (PEG) has been successfully used for improving circulation time of several nanomaterials but prolonging the circulation of porous silicon nanoparticles (PSi NPs) has remained challenging. Here, we report a site specific radiolabeling of dual-PEGylated thermally oxidized porous silicon (DPEG-TOPSi) NPs and investigation of influence of the PEGylation on blood circulation time of TOPSi NPs. Trans-cyclooctene conjugated DPEG-TOPSi NPs were radiolabeled through a click reaction with [111In]In-DOTA-PEG4-tetrazine (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and the particle behavior was evaluated in vivo in Balb/c mice bearing 4T1 murine breast cancer allografts. The dual-PEGylation significantly prolonged circulation of [111In]In-DPEG-TOPSi particles when compared to non-PEGylated control particles, yielding 10.8 ± 1.7% of the injected activity/g in blood at 15 min for [111In]In-DPEG-TOPSi NPs. The improved circulation time will be beneficial for the accumulation of targeted DPEG-TOPSi to tumors

Site-Specific 111In-Radiolabeling of Dual-PEGylated Porous Silicon Nanoparticles and Their In Vivo Evaluation in Murine 4T1 Breast Cancer Model

Polyethylene glycol (PEG) has been successfully used for improving circulation time of several nanomaterials but prolonging the circulation of porous silicon nanoparticles (PSi NPs) has remained challenging. Here, we report a site specific radiolabeling of dual-PEGylated thermally oxidized porous silicon (DPEG-TOPSi) NPs and investigation of influence of the PEGylation on blood circulation time of TOPSi NPs. Trans-cyclooctene conjugated DPEG-TOPSi NPs were radiolabeled through a click reaction with [111In]In-DOTA-PEG4-tetrazine (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and the particle behavior was evaluated in vivo in Balb/c mice bearing 4T1 murine breast cancer allografts. The dual-PEGylation significantly prolonged circulation of [111In]In-DPEG-TOPSi particles when compared to non-PEGylated control particles, yielding 10.8 ± 1.7% of the injected activity/g in blood at 15 min for [111In]In-DPEG-TOPSi NPs. The improved circulation time will be beneficial for the accumulation of targeted DPEG-TOPSi to tumors

Black porous silicon as a photothermal agent and immunoadjuvant for efficient antitumor immunotherapy

Photothermal therapy (PTT) in combination with other treatment modalities has shown great potential to activate immunotherapy against tumor metastasis. However, the nanoparticles (NPs) that generate PTT have served as the photothermal agent only. Moreover, researchers have widely utilized highly immuno-genic tumor models to evaluate the immune response of these NPs thus giving over-optimistic results. In the present study black porous silicon (BPSi) NPs were developed to serve as both the photothermal agent and the adjuvant for PTT-based antitumor immunotherapy. We found that the poorly immunogenic tumor models such as B16 are more valid to evaluate NP-based immunotherapy than the widely used im-munogenic models such as CT26. Based on the B16 cancer model, a cocktail regimen was developed that combined BPSi-based PTT with doxorubicin (DOX) and cytosine-phosphate-guanosine (CpG). BPSi-based PTT was an important trigger to activate the specific immunotherapy to inhibit tumor growth by featuring the selective upregulation of TNF-alpha. Either by adding a low dose DOX or by prolonging the laser heating time, a similar efficacy of immunotherapy was evoked to inhibit tumor growth. Moreover, BPSi acted as a co-adjuvant for CpG to significantly boost the immunotherapy. The present study demonstrates that the BPSi-based regimen is a potent and safe antitumor immunotherapy modality. Moreover, our study high-lighted that tuning the laser heating parameters of PTT is an alternative to the toxic cytostatic to evoke immunotherapy, paving the way to optimize the PTT-based combination therapy for enhanced efficacy and decreased side effects.Peer reviewe

Assessment of the Relaxation-Enhancing Properties of a Nitroxide-Based Contrast Agent TEEPO-Glc with In Vivo Magnetic Resonance Imaging

Magnetic resonance imaging examinations are frequently carried out using contrast agents to improve the image quality. Practically all clinically used contrast agents are based on paramagnetic metals and lack in selectivity and specificity. A group of stable organic radicals, nitroxides, has raised interest as new metal-free contrast agents for MRI. Their structures can easily be modified to incorporate different functionalities. In the present study, a stable nitroxide TEEPO (2,2,6,6-tetraethylpiperidin-1-oxyl) was linked to a glucose moiety (Glc) to construct a water-soluble, potentially tumor-targeting compound with contrast-enhancing ability. The ability was assessed with in vivo MRI experiments. The constructed TEEPO-Glc agent proved to shorten the T-1 relaxation time in tumor, while the T-1 time in healthy brain tissue remained the same. The results indicate the potential of TEEPO-Glc as a valuable addition to the growing field of metal-free contrast enhancement in MRI-based diagnostics.Peer reviewe

Low-Load Metal-Assisted Catalytic Etching Produces Scalable Porosity in Si Powders

The recently discovered low-load metal-assisted catalytic etching (LL-MACE) creates nanostructured Si with controllable and variable characteristics that distinguish this technique from the conventional high-load variant. LL-MACE employs 150 times less metal catalyst and produces porous Si instead of Si nanowires. In this work, we demonstrate that some of the features of LL-MACE cannot be explained by the present understanding of MACE. With mechanistic insight derived from extensive experimentation, it is demonstrated that (1) the method allows the use of not only Ag, Pd, Pt, and Au as metal catalysts but also Cu and (2) judicious combinations of process parameters such as the type of metal, Si doping levels, and etching temperatures facilitate control over yield (0.065−88%), pore size (3−100 nm), specific surface area (20−310 m2·g−1), and specific pore volume (0.05−1.05 cm3·g−1). The porous structure of the product depends on the space-charge layer, which is controlled by the Si doping and the chemical identity of the deposited metal. The porous structure was also dependent on the dynamic structure of the deposited metal. A distinctive comet-like structure of metal nanoparticles was observed after etching with Cu, Ag, Pd, and, in some cases, Pt; this structure consisted of 10−50 nm main particles surrounded by smaller (\u3c5 nm) nanoparticles. With good scalability and precise control of structural properties, LL-MACE facilitates Si applications in photovoltaics, energy storage, biomedicine, and water purification

Biocompatibility of Thermally Hydrocarbonized Porous Silicon Nanoparticles and their Biodistribution in Rats

Peer reviewe

Site-Specific In-111-Radiolabeling of Dual-PEGylated Porous Silicon Nanoparticles and Their In Vivo Evaluation in Murine 4T1 Breast Cancer Model

Polyethylene glycol (PEG) has been successfully used for improving circulation time of several nanomaterials but prolonging the circulation of porous silicon nanoparticles (PSi NPs) has remained challenging. Here, we report a site specific radiolabeling of dual-PEGylated thermally oxidized porous silicon (DPEG-TOPSi) NPs and investigation of influence of the PEGylation on blood circulation time of TOPSi NPs. Trans-cyclooctene conjugated DPEG-TOPSi NPs were radiolabeled through a click reaction with [In-111]In-DOTA-PEG(4)-tetrazine (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and the particle behavior was evaluated in vivo in Balb/c mice bearing 4T1 murine breast cancer allografts. The dual-PEGylation significantly prolonged circulation of [In-111]In-DPEG-TOPSi particles when compared to non-PEGylated control particles, yielding 10.8 +/- 1.7% of the injected activity/g in blood at 15 min for [In-111]In-DPEG-TOPSi NPs. The improved circulation time will be beneficial for the accumulation of targeted DPEG-TOPSi to tumors

Systematic design of cell membrane coating to improve tumor targeting of nanoparticles

Cell membrane (CM) coating technology is increasingly being applied in nanomedicine, but the entire coating procedure including adsorption, rupture, and fusion is not completely understood. Previously, we showed that the majority of biomimetic nanoparticles (NPs) were only partially coated, but the mechanism underlying this partial coating remains unclear, which hinders the further improvement of the coating technique. Here, we show that partial coating is an intermediate state due to the adsorption of CM fragments or CM vesicles, the latter of which could eventually be ruptured under external force. Such partial coating is difficult to self-repair to achieve full coating due to the limited membrane fluidity. Building on our understanding of the detailed coating process, we develop a general approach for fixing the partial CM coating: external phospholipid is introduced as a helper to increase CM fluidity, promoting the final fusion of lipid patches. The NPs coated with this approach have a high ratio of full coating (similar to 23%) and exhibit enhanced tumor targeting ability in comparison to the NPs coated traditionally (full coating ratio of similar to 6%). Our results provide a mechanistic basis for fixing partial CM coating towards enhancing tumor accumulation.Peer reviewe

Colonic Delivery of α-Linolenic Acid by an Advanced Nutrient Delivery System Prolongs Glucagon-Like Peptide-1 Secretion and Inhibits Food Intake in Mice

ScopeNutrients stimulate the secretion of glucagon-like peptide-1 (GLP-1), an incretin hormone, secreted from enteroendocrine L-cells which decreases food intake. Thus, GLP-1 analogs are approved for the treatment of obesity, yet cost and side effects limit their use. L-cells are mainly localized in the distal ileum and colon, which hinders the utilization of nutrients targeting GLP-1 secretion. This study proposes a controlled delivery system for nutrients, inducing a prolonged endogenous GLP-1 release which results in a decrease food intake.Methods and Resultsα-Linolenic acid (αLA) was loaded into thermally hydrocarbonized porous silicon (THCPSi) particles. In vitro characterization and in vivo effects of αLA loaded particles on GLP-1 secretion and food intake were studied in mice. A total of 40.4 ± 3.2% of loaded αLA is released from particles into biorelevant buffer over 24 h, and αLA loaded THCPSi significantly increased in vitro GLP-1 secretion. Single-dose orally given αLA loaded mesoporous particles increased plasma active GLP-1 levels at 3 and 4 h and significantly reduced the area under the curve of 24 h food intake in mice.ConclusionsαLA loaded THCPSi particles could be used to endogenously stimulate sustain gastrointestinal hormone release and reduce food intake.</p

Triple Contrast CT Method Enables Simultaneous Evaluation of Articular Cartilage Composition and Segmentation

Early degenerative changes of articular cartilage are detected using contrast-enhanced computed tomography (CT) with a cationic contrast agent (CA). However, cationic CA diffusion into degenerated cartilage decreases with proteoglycan depletion and increases with elevated water content, thus hampering tissue evaluation at early diffusion time points. Furthermore, the contrast at synovial fluid-cartilage interface diminishes as a function of diffusion time hindering accurate cartilage segmentation. For the first time, we employ quantitative dual-energy CT (QDECT) imaging utilizing a mixture of three CAs (cationic CA4+ and non-ionic gadoteridol which are sensitive to proteoglycan and water contents, respectively, and bismuth nanoparticles which highlight the cartilage surface) to simultaneously segment the articulating surfaces and determine of the cartilage condition. Intact healthy, proteoglycan-depleted, and mechanically injured bovine cartilage samples (n = 27) were halved and imaged with synchrotron microCT 2-h post immersion in triple CA or in dual CA (CA4+ and gadoteridol). CA4+ and gadoteridol partitions were determined using QDECT, and pairwise evaluation of these partitions was conducted for samples immersed in dual and triple CAs. In conclusion, the triple CA method is sensitive to proteoglycan depletion while maintaining sufficient contrast at the articular surface to enable detection of cartilage lesions caused by mechanical impact