A glycan-stimulated and poly(3,4-ethylene-dioxythiophene)s (PEDOT)-based nanomaterial platform is fabricated to purify circulating tumor cells (CTCs) from blood samples of prostate cancer (PCa) patients. This new platform, phenylboronic acid (PBA)-grafted PEDOT NanoVelcro, combines the 3D PEDOT nanosubstrate, which greatly enhances CTC capturing efficiency, with a poly(EDOT-PBA-co-EDOT-EG3) interfacial layer, which not only provides high specificity for CTC capture upon antibody conjugation but also enables competitive binding of sorbitol to gently release the captured cells. CTCs purified by this PEDOT NanoVelcro chip provide well-preserved RNA transcripts for the analysis of the expression level of several PCa-specific RNA biomarkers, which may provide clinical insights into the disease.
In this study we immobilized gold nanoparticles (AuNPs) onto thiol-functionalized poly(3,4-ethylenedioxythiophene) (PEDOT) films as bioelectronic interfaces (BEIs) to be integrated into organic electrochemical transistors (OECTs) for effective detection of dopamine (DA) and also as surface-enhanced Raman scattering (SERS)—active substrates for the selective detection of p -cresol (PC) in the presence of multiple interferers. This novel PEDOT-based BEI device platform combined (i) an underlying layer of polystyrenesulfonate-doped PEDOT (PEDOT:PSS), which greatly enhanced the transconductance and sensitivity of OECTs for electrochemical sensing of DA in the presence of other ascorbic acid and uric acid metabolites, as well as amperometric response toward DA with a detection limit (S/N = 3) of 37 nM in the linear range from 50 nM to 100 μM; with (ii) a top interfacial layer of AuNP-immobilized three-dimensional (3D) thiol-functionalized PEDOT, which not only improved the performance of OECTs for detecting DA, due to the signal amplification effect of the AuNPs with high catalytic activity, but also enabled downstream analysis (SERS detection) of PC on the same chip. We demonstrate that PEDOT-based 3D OECT devices decorated with a high-density of AuNPs can display new versatility for the design of next-generation biosensors for point-of-care diagnostics.
To prevent nonspecific interactions with biomolecules (e.g., proteins), blood cells, and microorganisms (e.g., bacteria, viruses, fungi, parasites) that can exert severe side effects, several bio-inspired antifouling materials, including poly(ethylene glycol) and zwitterionic phosphocholine, sulfobetaine (SB), and carboxybetaine derivatives have been applied in biomedical electronic devices. In this paper, we report the development of an economical strategy for synthesizing ethylenedioxythiophene (EDOT)-SB and creating the corresponding highly antifouling polymer films though electrochemical polymerization. The poly(EDOT-SB) films inhibited 95% of the nonspecific binding of proteins from serum and prevented the adhesion of fibroblast cells. Moreover, the antifouling properties of the conducting film were maintained in both the oxidized and reduced states of PEDOT. Such zwitterionic, functionalized conducting polymer films appear to have great potential for application to bio-electronic implant devices.
Polyelectrolyte multilayers (PEMs) assembled layer-by-layer have emerged as functional polymer films that are both stable and capable of containing drug molecules for controlled release applications. Most of these applications concentrate on sustained release, where the concentration of the released molecules remains rather constant with time. However, high-efficiency delivery requires obtaining high local concentrations at the vicinity of the cells, which is achieved by triggered release. Here, we show that a nanopatterned PEM platform demonstrates superior properties with respect to drug retention and triggered delivery. A chemically modified block copolymer film was used as a template for the selective deposition of poly(ethylene imine) and a charged derivative of the electroactive poly(3,4-ethylenedioxythiophene) together with a drug molecule. This nanopatterned PEM shows the following advantages: (1) high drug loading; (2) enhanced retention of the bioactive molecule; (3) release triggered by an electrochemical stimulus; (4) high efficacy of drug delivery to cells adsorbed on the surface compared to the delivery efficacy of a similar concentration of drug to cells suspended in a solution.
In article number https://doi.org/10.1002/adhm.201700701, Hsiao‐hua Yu and co‐workers purified circulating tumor cells (CTCs) from blood samples of prostate cancer (PCa) patients. This platform not only captures CTCs with high efficiency and specificity, but also, released these cells gently by a competitive‐binding mechanism. The purified CTCs provide well‐preserved RNA transcripts for the analysis of the expression level of several PCa‐specific RNA biomarkers, which could provide clinical insights into the disease and valuable information for cancer diagnosis and therapeutics.
Introduction and Objective: Circulating tumor cells (CTCs) are being used in efforts to identify important transcriptomic features such as androgen receptor (AR) splicing variants in prostate cancer (PCa) and other malignancies. The low abundance of CTCs and the fragility of the genetic materials create a need for tools that obtain high-quality signals with great efficiency. Poly(3,4-ethylenedioxythiophene) (PEDOT) is a stimulation-responsive nanomaterial which allows for rapid and gentle cell purification through the use of bio-competition between pheylboronic acid and carbohydrates. We hypothesized that a combination of PEDOT with the NanoVelcro cell affinity assay (NanoVelcro-PBA Chip) would yield a tool that could minimize contamination from white blood cells and maximize cell viably and molecular intactness. In this study, we benchmarked the efficiency of this platform for purification of CTCs from blood specimens and the feasibility of using this approach for detection of PCa-related RNA signatures from purified CTCs. Methods: The capture and release efficiency of NanoVelcro-PBA Chip was tested using PCa cell lines (LNCaP, PC3, 22Rv1) and artificial blood samples with PCa cells mixed with healthy donor blood. Variations on operating conditions were tested including the capturing antibodies on the NanoVelcro substrate, incubation time, sorbitol concentration, and bio-competition time. Impact was measured on process efficacy and cell viability. Blood specimens from 17 PCa patients were processed using NanoVelcro-PBA chip. Analysis focused detection of full length AR (AR-FL), AR splicing variant 7 (AR-V7), KLK3 (prostate-specific antigen, PSA), FOLH1 (prostate-specific membrane antigen, PSMA), and long-noncoding RNA SChLAP1 (second chromosome locus associated with prostate-1) using quantitative RT-PCR method. Results: The combination of NanoVelcro substrate, PEDOT nanomaterial, and capturing antibody exhibits the highest cell capture efficiency (up to 80%). The highest cell release efficiency and viability was achieved by bio-competition with 100 μmol/200μL sorbitol solution for 30 minutes. PCa-related RNA signals were detected in 16/17 CTC(+) PCa patients, and was detected more frequently in patients with metastatic disease and with higher expression level. Conclusions: We have developed a novel CTC purification platform, NanoVelcro-PBA Chip. This platform is capable of purifying CTCs with high efficiency and while retaining cell viability and molecular integrity. This in turn allows for detection of disease-relevant RNA signals. Further this new tool is being moved into clinical studies that will validate its performance in CTC purification and subsequent RNA detection. Citation Format: Jie-Fu Chen, Mo-Yuan Shen, Chun-Hao Luo, Shirley Cheng, Sangjun Lee, Shuang Hou, Edwin M. Posadas, Hsian-Rong Tseng, Hsiao-Hua Yu. Bio-competition-based smart NanoVelcro Chip for isolation and gene expression analysis of circulating tumor cells from prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3780. doi:10.1158/1538-7445.AM2017-3780
Efficiently delivering liposomal content to cells in a relatively uniform dose and patterned fashion, especially bypassing the degradative endocytosis pathway, is an important technology in cell culture and potentially to tissue engineering that still remains challenging. We developed a "nano-on-nano" platform technology that consists of the following three material features: (1) high density silicon nanopillars to create a pseudo-3dimensional nanoenvironment for cell culturing, (2) thermoresponsive polymer grafted onto silicon nanopillars to form a responsive nanosubstrate, and (3) immobilized liposomes using a biotin-streptavidin-biotin conjugation. The working principle is that the liposomes are detached for cellular uptake upon thermal stimulation and high local liposome concentration between the cells and substrates drives the cellular uptake with nonendocytic pathways. Cryo-EM images confirms that liposomes are attached to form liposome-warped nanopillars. Upon thermal stimulation, an 8 times higher increase in the liposomal fluorescence intensity is observed compared to the conventional solution-phase liposome delivery, indicating that high local concentration drives liposome uptake with greater efficiency. Moreover, preliminary mechanistic studies reveal that these liposomes are taken up by nonendocytic pathways. The ability of our nano-on-nano delivery system that achieves efficient dose-uniform cellular delivery can open a unique era in cell and tissue engineering by controlling cell behaviors with the delivery of bioactive ingredient-loaded liposomes.
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