Progress in Aptamer-Mediated Drug Delivery Vehicles for Cancer Targeting and Its Implications in Addressing Chemotherapeutic Challenges

Aptamers are novel oligonucleotides with flexible three-dimensional configurations that recognize and bind to their cognate targets, including tumor surface receptors, in a high-affinity and highly specific manner. Because of their unique intrinsic properties, a variety of aptamer-mediated nanovehicles have been developed to directionally transport anti-cancer drugs to tumor sites to minimize systemic cytotoxicity and to enhance permeation by these tumoricidal agents. Despite advances in the selection and synthesis of aptamers and in the conjugation and self-assembly of nanotechnologies, current chemotherapy and drug delivery systems face great challenges. These challenges are due to the limitations of aptamers and vehicles and because of complicated tumor mechanisms, including heterogeneity, anti-cancer drug resistance, and hypoxia-induced aberrances. In this review, we will summarize current approaches utilizing tumor surface hallmarks and aptamers and their roles and mechanisms in therapeutic nanovehicles targeting tumors. Delivery forms include nanoparticles, nanotubes, nanogels, aptamer-drug conjugates, and novel molecular trains. Moreover, the obstacles posed by the aforementioned issues will be highlighted, and possible solutions will be acknowledged. Furthermore, future perspectives will be presented, including cutting-edge integration with RNA interference nanotechnology and personalized chemotherapy, which will facilitate innovative approaches to aptamer-based therapeutics

Chemokine CXCL12 and its receptor CXCR4 expression are associated with perineural invasion of prostate cancer

<p>Abstract</p> <p>Objective</p> <p>To identify the roles of CXCL12 and CXCR4 and the associated mechanism involved in perineural invasion of prostate cancer.</p> <p>Methods</p> <p>The distribution and expression of CXCL12, CXCR4, MMP-2 and MMP-9 in human prostate cancer and in tumor cells invading nerve tissue were studied with immunohistochemical staining. The effects of exogenous CXCL12 and CXCR4 antagonist AMD3100 on PC3 prostate cancer cells invasiveness were assessed in vitro and in vivo.</p> <p>Results</p> <p>The expression of CXCL12, CXCR4, MMP-2, and MMP-9 in human prostate cancer were higher than those in hyperplastic prostate tissues (<it>P </it>< 0.05). In vitro CXCL12 could stimulate the PC3 cells invasiveness (<it>P </it>< 0.05) while AMD3100 could inhibit invasiveness. In vivo, the number of nerves around the tumor tissue in the group treated with CXCL12 was significantly higher than that found in the control group (<it>P </it>< 0.05). Both the control group and the CXCL12-treated group had more nerves number near the tumor tissue than it found in the AMD3100-treated group. The positive cell number of CXCL12, CXCR4, MMP-2, MMP-9, and NGF expression ranked from highest to lowest, were the CXCL12-treated, the control, and the AMD3100-treated group(<it>P </it>< 0.05).</p> <p>Conclusion</p> <p>CXCL12 and its receptor CXCR4 along with MMP-2 and MMP-9 are related with prostate cancer perineural invasion.</p

Fibroblast growth factor 3 promotes spontaneous mammary tumorigenesis in Tientsin albino 2 mice via the FGF3/FGFR1/STAT3 pathway

IntroductionTientsin albino 2 (TA2) mice can develop spontaneous breast cancer (SBC), which is associated with multiple pregnancies and infection with the mouse mammary tumor virus (MMTV). In this study, we sought to elucidate the molecular mechanisms underlying the development of SBC in TA2 mice induced by MMTV.MethodsThe integration site of MMTV in TA2 SBC was identified using whole-genome sequencing. The expression of fibroblast growth factor 3 (FGF3) in SBCs and normal breast tissues was compared. The primary cell line, TA-1106, derived from SBC, was cultured. The proliferation, cell cycle, migration, invasion, and tumorigenicity abilities, as well as the expression of epithelial-mesenchymal transition-related proteins, phosphorylated STAT3, and phosphorylated Akt, were assessed in MA-891cell line from TA2 and TA-1106 cells after FGF3 knockdown. The binding of FGF3 to FGF receptor 1 (FGFR1) was determined by co-immunoprecipitation. Additionally, the relationship between STAT3 and Akt phosphorylation was investigated using a small molecule inhibitor and STAT3 knockdown.ResultsMMTV integrated upstream of the FGF3 gene, and the FGF3 protein was highly expressed in TA2 SBCs. FGF3 knockdown in MA-891 and TA-1106 decreased their proliferation, migration, and invasion abilities, affected the cell cycle and expression of epithelial-mesenchymal transition-related proteins, and inhibited the growth of animal xenografts. FGF3 binds to FGFR1, and either FGF3 or FGFR1 knockdown decreases STAT3 and Akt phosphorylation levels. Inhibition of phosphorylation or expression of STAT3 resulted in decreased Akt phosphorylation levels. Inhibition of Akt phosphorylation also resulted in decreased STAT3 phosphorylation levels. Furthermore, treatment of MA-891 and TA-1106 cells with Wortmannin or Stattic caused FGFR1 upregulation in addition to inhibiting Akt or STAT3 phosphorylation.ConclusionThe results of this study demonstrate that FGF3 plays a significant role in the development of SBC through the FGF3/FGFR1/STAT3 signaling pathway. There is a reciprocal activation between STAT3 and Akt. Inhibition of STAT3 or Akt phosphorylation promoted the expression of FGFR1. Validating the conclusions obtained in this study in human breast cancer (HBC) may contribute to targeted therapy and it is worth exploring whether the homologous sequences of MMTV in HBC have a similar oncogenic effect

A Real-time Non-contact Localization Method for Faulty Electric Energy Storage Components using Highly Sensitive Magnetometers

With the wide application of electric energy storage component arrays, such as battery arrays, capacitor arrays, inductor arrays, their potential safety risks have gradually drawn the public attention. However, existing technologies cannot meet the needs of non-contact and real-time diagnosis for faulty components inside these massive arrays. To solve this problem, this paper proposes a new method based on the beamforming spatial filtering algorithm to precisely locate the faulty components within the arrays in real-time. The method uses highly sensitive magnetometers to collect the magnetic signals from energy storage component arrays, without damaging or even contacting any component. The experimental results demonstrate the potential of the proposed method in securing energy storage component arrays. Within an imaging area of 80 mm $\times$ 80 mm, the one faulty component out of nine total components can be localized with an accuracy of 0.72 mm for capacitor arrays and 1.60 mm for battery arrays

Development of magnetorheological elastomers-based tuned mass damper for building protection from seismic events

This study investigated and evaluated a semi-active tuned mass damper which incorporated four multi-layered structures fabricated using magnetorheological elastomers. The four magnetorheological elastomer structures formed a square and provided the tuned mass damper variable stiffness used to track the excitation frequencies. This design not only increases the stability of the tuned mass damper but more importantly eliminates the magnetic circuit gap in a design which we used in the past because all four of the magnetic circuits used to control the magnetorheological elastomer isolators are closed circuits. In order to verify the capability of the magnetorheological elastomer-based tuned mass damper to protect a building from earthquake, extensive simulation and experimental testing were conducted. The swept sinusoidal signal and the scaled 1940 El Centro earthquake record were used to excite a scaled three-story building. Both simulation and experiment have verified that the magnetorheological elastomer-based tuned mass damper outperformed all other passive tuned mass dampers under either swept sinusoidal or seismic conditions

Path Integral Treatment of Proton Transport Processes in BaZrO3

Nuclear quantum effects on proton transfer and reorientation in BaZrO3 is investigated theoretically using the ab initio path-integral molecular-dynamics simulation technique. The result demonstrates that adding quantum fluctuations has a large effect on, in particular, the transfer barrier. The corresponding rates and diffusion coefficient are evaluated using the path-centroid transition state theory. In contrast with what is found assuming classical mechanics for the nuclear motion, the reorientation step becomes rate limiting below 600 K

Differential expression of decorin, EGFR and cyclin D1 during mammary gland carcinogenesis in TA2 mice with spontaneous breast cancer

<p>Abstract</p> <p>Background</p> <p>The Tientsin Albino 2 (TA2) mouse is an inbred strain originating from the Kunming strain. It has a high incidence of spontaneous breast cancer without the need for external inducers or carcinogens. Until now, the mechanism of carcinogenesis has remained unclear. In this study, we investigate differential gene expression, especially the expression of decorin, EGFR and cyclin D1, during mammary gland epithelial cell carcinogenesis in TA2 mice.</p> <p>Methods</p> <p>Gene expression profiles of spontaneous breast cancer and matched normal mammary gland tissues in TA2 mice were ascertained using an Affymetrix Mouse 430 2.0 array. Twelve mammary tissue samples from five month-old female TA2 mice (Group A), as well as 28 samples from mammary (Group B) and cancer tissues (Group C) of spontaneous breast cancer-bearing TA2 mice, were subsequently used to detect the expression of decorin, EGFR and cyclin D1 by real-time PCR and immunohistochemical methods.</p> <p>Results</p> <p>Several imprinted genes, oncogenes and tumor suppressor genes were differentially expressed between normal mammary gland tissues and breast cancer tissues of TA2 mice. The imprinted gene decorin and the oncogene EGFR were down-regulated in tumor tissues, while the oncogene cyclin D1 was up-regulated. Immunohistochemistry showed that samples in Group A showed high decorin expression more frequently than those in Group B (<it>P </it>< 0.05). More tissue samples in Group B than Group A were positive for nuclear EGFR, and tissue samples in Group B more frequently showed high nuclear EGFR expression than those in Group A or Group C (<it>P </it>< 0.05). The labeling index for cyclin D1 in Group C was significantly higher than in Group B. Mammary tissues of Group A expressed the highest level of decorin mRNA (<it>P </it>< 0.05), and mammary tissues of Group B expressed the highest level of EGFR mRNA (<it>P </it>< 0.05), while cancer tissues expressed the highest level of cyclin D1 mRNA (<it>P </it>< 0.05).</p> <p>Conclusions</p> <p>The expression of decorin, EGFR and cyclin D1 in mammary epithelial cells changes with increasing age. The abnormal expression of them may partly contribute to the genesis of spontaneous breast cancer in TA2 mice.</p

A Magnetically and Thermally Controlled Liquid Metal Variable Stiffness Material

Smart materials that can actively tune their stiffness are of great interest to many fields, including the construction industry, medical devices, industrial machines, and soft robotics. However, developing a material that can offer a large range of stiffness change and rapid tuning remains a challenge. Herein, a liquid metal variable stiffness material (LMVSM) that can actively and rapidly tune its stiffness by applying an external magnetic field or by changing the temperature is developed. The LMVSM is composed of three layers: a gallium–iron magnetorheological fluid (Ga–Fe MRF) layer for providing variable stiffness, a nickel–chromium wire layer for Joule heating, and a soft heat dissipation layer for accelerating heating and rapid cooling. The stiffness can be rapidly increased by 4 times upon the application of a magnetic field or 10 times by solidifying the Ga–Fe MRF. Finally, the LMVSM is attached to a pneumatically controlled soft robotic gripper to actively tune its load capacity, demonstrating its potential to be further developed into smart components that can be widely adopted by smart devices