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Endosomolytic and Tumor-Penetrating Mesoporous Silica Nanoparticles for siRNA/miRNA Combination Cancer Therapy.
Wang Y, Xie Y, Kilchrist KV, Li J, Duvall CL, Oupický D
(2020) ACS Appl Mater Interfaces 12: 4308-4322
MeSH Terms: Animals, Breast Neoplasms, Drug Delivery Systems, Endosomes, Female, Genetic Therapy, Humans, Mice, MicroRNAs, Nanoparticles, RNA, Small Interfering, Silicon Dioxide
Show Abstract · Added March 19, 2020
Combination therapies consisting of multiple short therapeutic RNAs, such as small interfering RNA (siRNA) and microRNA (miRNA), have enormous potential in cancer treatment as they can precisely silence a specific set of oncogenes and target multiple disease-related pathways. However, clinical use of siRNA/miRNA combinations is limited by the availability of safe and efficient systemic delivery systems with sufficient tumor penetrating and endosomal escaping capabilities. This study reports on the development of multifunctional tumor-penetrating mesoporous silica nanoparticles (iMSNs) for simultaneous delivery of siRNA (siPlk1) and miRNA (miR-200c), using encapsulation of a photosensitizer indocyanine green (ICG) to facilitate endosomal escape and surface conjugation of the iRGD peptide to enable deep tumor penetration. Increased cell uptake of the nanoparticles was observed in both 3D tumor spheroids in vitro and in orthotopic MDA-MB-231 breast tumors in vivo. Using a galectin-8 recruitment assay, we showed that reactive oxygen species generated by ICG upon light irradiation functioned as an endosomolytic stimulus that caused release of the siRNA/miRNA combination from endosomes. Co-delivery of the therapeutic RNAs displayed combined cell killing activity in cancer cells. Systemic intravenous treatment of metastatic breast cancer with the iMSNs loaded with siPlk1 and miR-200c resulted in a significant suppression of the primary tumor growth and in marked reduction of metastasis upon short light irradiation of the primary tumor. This work demonstrates that siRNA-miRNA combination assisted by the photodynamic effect and tumor penetrating delivery system may provide a promising approach for metastatic cancer treatment.
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12 MeSH Terms
Light-activatable cannabinoid prodrug for combined and target-specific photodynamic and cannabinoid therapy.
Ling X, Zhang S, Liu Y, Bai M
(2018) J Biomed Opt 23: 1-9
MeSH Terms: Animals, Antineoplastic Agents, Cannabinoids, Cell Line, Tumor, Cell Survival, HEK293 Cells, Humans, Indoles, Mice, Organosilicon Compounds, Photochemotherapy, Photosensitizing Agents, Prodrugs, Reactive Oxygen Species
Show Abstract · Added April 2, 2019
Cannabinoids are emerging as promising antitumor drugs. However, complete tumor eradication solely by cannabinoid therapy remains challenging. In this study, we developed a far-red light activatable cannabinoid prodrug, which allows for tumor-specific and combinatory cannabinoid and photodynamic therapy. This prodrug consists of a phthalocyanine photosensitizer (PS), reactive oxygen species (ROS)-sensitive linker, and cannabinoid. It targets the type-2 cannabinoid receptor (CB2R) overexpressed in various types of cancers. Upon the 690-nm light irradiation, the PS produces cytotoxic ROS, which simultaneously cleaves the ROS-sensitive linker and subsequently releases the cannabinoid drug. We found that this unique multifunctional prodrug design offered dramatically improved therapeutic efficacy, and therefore provided a new strategy for targeted, controlled, and effective antitumor cannabinoid therapy.
(2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).
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14 MeSH Terms
Flow-Through Porous Silicon Membranes for Real-Time Label-Free Biosensing.
Zhao Y, Gaur G, Retterer ST, Laibinis PE, Weiss SM
(2016) Anal Chem 88: 10940-10948
MeSH Terms: Biosensing Techniques, Microfluidic Analytical Techniques, Particle Size, Porosity, Silicon, Surface Properties, Time Factors
Show Abstract · Added April 27, 2017
A flow-through sensing platform based on open-ended porous silicon (PSi) microcavity membranes that are compatible with integration in on-chip sensor arrays is demonstrated. Because of the high aspect ratio of PSi nanopores, the performance of closed-ended PSi sensors is limited by infiltration challenges and slow sensor responses when detecting large molecules such as proteins and nucleic acids. In order to improve molecule transport efficiency and reduce sensor response time, open-ended PSi nanopore membranes were used in a flow-through sensing scheme, allowing analyte solutions to pass through the nanopores. The molecular binding kinetics in these PSi membranes were compared through experiments and simulation with those from closed-ended PSi films of comparable thickness in a conventional flow-over sensing scheme. The flow-through PSi membrane resulted in a 6-fold improvement in sensor response time when detecting a high molecular weight analyte (streptavidin) versus in the flow-over PSi approach. This work demonstrates the possibility of integrating multiple flow-through PSi sensor membranes within parallel microarrays for rapid and multiplexed label-free biosensing.
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7 MeSH Terms
Porous Silicon and Polymer Nanocomposites for Delivery of Peptide Nucleic Acids as Anti-MicroRNA Therapies.
Beavers KR, Werfel TA, Shen T, Kavanaugh TE, Kilchrist KV, Mares JW, Fain JS, Wiese CB, Vickers KC, Weiss SM, Duvall CL
(2016) Adv Mater 28: 7984-7992
MeSH Terms: Animals, Cell Line, Tumor, Colloids, Female, Humans, Mice, MicroRNAs, Nanocomposites, Peptide Nucleic Acids, Polymers, Porosity, RNAi Therapeutics, Silicon
Show Abstract · Added April 27, 2017
Self-assembled polymer/porous silicon nanocomposites overcome intracellular and systemic barriers for in vivo application of peptide nucleic acid (PNA) anti-microRNA therapeutics. Porous silicon (PSi) is leveraged as a biodegradable scaffold with high drug-cargo-loading capacity. Functionalization with a diblock polymer improves PSi nanoparticle colloidal stability, in vivo pharmacokinetics, and intracellular bioavailability through endosomal escape, enabling PNA to inhibit miR-122 in vivo.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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13 MeSH Terms
First Implantation of Silicon Nanopore Membrane Hemofilters.
Kensinger C, Karp S, Kant R, Chui BW, Goldman K, Yeager T, Gould ER, Buck A, Laneve DC, Groszek JJ, Roy S, Fissell WH
(2016) ASAIO J 62: 491-5
MeSH Terms: Animals, Dogs, Hemofiltration, Humans, Membranes, Artificial, Nanopores, Pilot Projects, Silicon, Thrombosis
Show Abstract · Added April 11, 2016
An implantable hemofilter for the treatment of kidney failure depends critically on the transport characteristics of the membrane and the biocompatibility of the membrane, cartridge, and blood conduits. A novel membrane with slit-shaped pores optimizes the trade-off between permeability and selectivity, enabling implanted therapy. Sustained (3-8) day function of an implanted parallel-plate hemofilter with minimal anticoagulation was achieved by considering biocompatibility at the subnanometer scale of chemical interactions and the millimeter scale of blood fluid dynamics. A total of 400 nm-thick polysilicon flat sheet membranes with 5-8 nm × 2 micron slit-shaped pores were surface-modified with polyethylene glycol. Hemofilter cartridge geometries were refined based on computational fluid dynamics models of blood flow. In an uncontrolled pilot study, silicon filters were implanted in six class A dogs. Cartridges were connected to the cardiovascular system by anastamoses to the aorta and inferior vena cava and filtrate was drained to collection pouches positioned in the peritoneum. Pain medicine and acetylsalicylic acid were administered twice daily until the hemofilters were harvested on postoperative days 3 (n = 2), 4 (n = 2), 5 (n = 1), and 8 (n = 1). No hemofilters were thrombosed. Animals treated for 5 and 8 days had microscopic fractures in the silicon nanopore membranes and 20-50 ml of transudative (albumin sieving coefficient θalb ~ 0.5 - 0.7) fluid in the collection pouches at the time of explant. Shorter experimental durations (3-4 days) resulted in filtration volumes similar to predictions based on mean arterial pressures and membrane hydraulic permeability and (θalb ~ 0.2 - 0.3), similar to preimplantation measurements. In conclusion, a detailed mechanistic and materials science attention to blood-material interactions allows implanted hemofilters to resist thrombosis. Additional testing is needed to determine optimal membrane characteristics and identify limiting factors in long-term implantation.
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9 MeSH Terms
Preliminary Diffusive Clearance of Silicon Nanopore Membranes in a Parallel Plate Configuration for Renal Replacement Therapy.
Kim S, Heller J, Iqbal Z, Kant R, Kim EJ, Durack J, Saeed M, Do L, Hetts S, Wilson M, Brakeman P, Fissell WH, Roy S
(2016) ASAIO J 62: 169-75
MeSH Terms: Animals, Equipment Design, Membranes, Artificial, Nanopores, Renal Dialysis, Silicon, Swine
Show Abstract · Added February 22, 2016
Silicon nanopore membranes (SNMs) with compact geometry and uniform pore size distribution have demonstrated a remarkable capacity for hemofiltration. These advantages could potentially be used for hemodialysis. Here, we present an initial evaluation of the SNM's mechanical robustness, diffusive clearance, and hemocompatibility in a parallel plate configuration. Mechanical robustness of the SNM was demonstrated by exposing membranes to high flows (200 ml/min) and pressures (1,448 mm Hg). Diffusive clearance was performed in an albumin solution and whole blood with blood and dialysate flow rates of 25 ml/min. Hemocompatibility was evaluated using scanning electron microscopy and immunohistochemistry after 4 hours in an extracorporeal porcine model. The pressure drop across the flow cell was 4.6 mm Hg at 200 ml/min. Mechanical testing showed that SNM could withstand up to 775.7 mm Hg without fracture. Urea clearance did not show an appreciable decline in blood versus albumin solution. Extracorporeal studies showed blood was successfully driven via the arterial-venous pressure differential without thrombus formation. Bare silicon showed increased cell adhesion with a 4.1-fold increase and 1.8-fold increase over polyethylene glycol (PEG)-coated surfaces for tissue plasminogen factor (t-PA) and platelet adhesion (CD41), respectively. These initial results warrant further design and development of a fully scaled SNM-based parallel plate dialyzer for renal replacement therapy.
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7 MeSH Terms
Shape-engineered multifunctional porous silicon nanoparticles by direct imprinting.
Mares JW, Fain JS, Beavers KR, Duvall CL, Weiss SM
(2015) Nanotechnology 26: 271001
MeSH Terms: Drug Carriers, Equipment Design, Models, Chemical, Molecular Imprinting, Nanoparticles, Nanotechnology, Peptide Nucleic Acids, Porosity, Silicon
Show Abstract · Added April 27, 2017
A versatile and scalable method for fabricating shape-engineered nano- and micrometer scale particles from mesoporous silicon (PSi) thin films is presented. This approach, based on the direct imprinting of porous substrates (DIPS) technique, facilitates the generation of particles with arbitrary shape, ranging in minimum dimension from approximately 100 nm to several micrometers, by carrying out high-pressure (>200 MPa) direct imprintation, followed by electrochemical etching of a sub-surface perforation layer and ultrasonication. PSi particles (PSPs) with a variety of geometries have been produced in quantities sufficient for biomedical applications (≫10 μg). Because the stamps can be reused over 150 times, this process is substantially more economical and efficient than the use of electron beam lithography and reactive ion etching for the fabrication of nanometer-scale PSPs directly. The versatility of this fabrication method is demonstrated by loading the DIPS-imprinted PSPs with a therapeutic peptide nucleic acid drug molecule, and by vapor deposition of an Au coating to facilitate the use of PSPs as a photothermal contrast agent.
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2 Members
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9 MeSH Terms
Effect of DNA-induced corrosion on passivated porous silicon biosensors.
Zhao Y, Lawrie JL, Beavers KR, Laibinis PE, Weiss SM
(2014) ACS Appl Mater Interfaces 6: 13510-9
MeSH Terms: Biosensing Techniques, Corrosion, DNA, DNA Probes, Magnesium, Optical Phenomena, Peptide Nucleic Acids, Porosity, Silanes, Silicon, Spectroscopy, Fourier Transform Infrared
Show Abstract · Added April 27, 2017
This work examines the influence of charge density and surface passivation on the DNA-induced corrosion of porous silicon (PSi) waveguides in order to improve PSi biosensor sensitivity, reliability, and reproducibility when exposed to negatively charged DNA molecules. Increasing the concentration of either DNA probes or targets enhances the corrosion process and masks binding events. While passivation of the PSi surface by oxidation and silanization is shown to diminish the corrosion rate and lead to a saturation in the changes by corrosion after about 2 h, complete mitigation can be achieved by replacing the DNA probe molecules with charge-neutral PNA probe molecules. A model to explain the DNA-induced corrosion behavior, consistent with experimental characterization of the PSi through Fourier transform infrared spectroscopy and prism coupling optical measurements, is also introduced.
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11 MeSH Terms
In situ synthesis of peptide nucleic acids in porous silicon for drug delivery and biosensing.
Beavers KR, Mares JW, Swartz CM, Zhao Y, Weiss SM, Duvall CL
(2014) Bioconjug Chem 25: 1192-7
MeSH Terms: Biosensing Techniques, Carcinoma, Hepatocellular, DNA, Drug Delivery Systems, Humans, Liver Neoplasms, Mass Spectrometry, MicroRNAs, Nanoparticles, Nucleic Acid Hybridization, Peptide Nucleic Acids, Porosity, Propylamines, Silanes, Silicon, Tumor Cells, Cultured
Show Abstract · Added April 27, 2017
Peptide nucleic acids (PNA) are a unique class of synthetic molecules that have a peptide backbone and can hybridize with nucleic acids. Here, a versatile method has been developed for the automated, in situ synthesis of PNA from a porous silicon (PSi) substrate for applications in gene therapy and biosensing. Nondestructive optical measurements were performed to monitor single base additions of PNA initiated from (3-aminopropyl)triethoxysilane attached to the surface of PSi films, and mass spectrometry was conducted to verify synthesis of the desired sequence. Comparison of in situ synthesis to postsynthesis surface conjugation of the full PNA molecules showed that surface mediated, in situ PNA synthesis increased loading 8-fold. For therapeutic proof-of-concept, controlled PNA release from PSi films was characterized in phosphate buffered saline, and PSi nanoparticles fabricated from PSi films containing in situ grown PNA complementary to micro-RNA (miR) 122 generated significant anti-miR activity in a Huh7 psiCHECK-miR122 cell line. The applicability of this platform for biosensing was also demonstrated using optical measurements that indicated selective hybridization of complementary DNA target molecules to PNA synthesized in situ on PSi films. These collective data confirm that we have established a novel PNA-PSi platform with broad utility in drug delivery and biosensing.
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16 MeSH Terms
Cannabinoid CB2 receptor as a new phototherapy target for the inhibition of tumor growth.
Jia N, Zhang S, Shao P, Bagia C, Janjic JM, Ding Y, Bai M
(2014) Mol Pharm 11: 1919-29
MeSH Terms: Animals, Cell Death, Cell Line, Tumor, Indoles, Mice, Neoplasms, Organosilicon Compounds, Photosensitizing Agents, Phototherapy, Receptor, Cannabinoid, CB2
Show Abstract · Added April 2, 2019
The success of targeted cancer therapy largely relies upon the selection of target and the development of efficient therapeutic agents that specifically bind to the target. In the current study, we chose a cannabinoid CB2 receptor (CB2R) as a new target and used a CB2R-targeted photosensitizer, IR700DX-mbc94, for phototherapy treatment. IR700DX-mbc94 was prepared by conjugating a photosensitizer, IR700DX, to mbc94, whose binding specificity to CB2R has been previously demonstrated. We found that phototherapy treatment using IR700DX-mbc94 greatly inhibited the growth of CB2R positive tumors but not CB2R negative tumors. In addition, phototherapy treatment with nontargeted IR700DX did not show significant therapeutic effect. Similarly, treatment with IR700DX-mbc94 without light irradiation or light irradiation without the photosensitizer showed no tumor-inhibitory effect. Taken together, IR700DX-mbc94 is a promising phototherapy agent with high target-specificity. Moreover, CB2R appears to have great potential as a phototherapeutic target for cancer treatment.
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MeSH Terms