Tumor microenvironment targeted nanotherapeutics for cancer therapy and diagnosis: A review

Polyacrylic acid (PAA) is a non-toxic, biocompatible, and biodegradable polymer that gained lots of interest in recent years. PAA nano-derivatives can be obtained by chemical modification of carboxyl groups with superior chemical properties in comparison to unmodified PAA. For example, nano-particles produced from PAA derivatives can be used to deliver drugs due to their stability and biocompatibility. PAA and its nanoconjugates could also be regarded as stimuli-responsive platforms that make them ideal for drug delivery and antimicrobial applications. These properties make PAA a good candidate for conventional and novel drug carrier systems. Here, we started with synthesis approaches, structure characteristics, and other architectures of PAA nanoplatforms. Then, different conjugations of PAA/nanostructures and their potential in various fields of nanomedicine such as antimicrobial, anticancer, imaging, biosensor, and tissue engineering were discussed. Finally, biocompatibility and challenges of PAA nanoplatforms were highlighted. This review will provide fundamental knowledge and current information connected to the PAA nanoplatforms and their applications in biological fields for a broad audience of researchers, engineers, and newcomers. In this light, PAA nanoplatforms could have great potential for the research and development of new nano vaccines and nano drugs in the future.

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Polyacrylic Acid Nanoplatforms: Antimicrobial, Tissue Engineering, and Cancer Theranostic Applications

The idea that in vivo intravoxel incoherent motion magnetic resonance signal is influenced by blood motion in the microvasculature is exciting, because it suggests that local and quantitative perfusion information can be obtained in a simple and elegant way from a few diffusion-weighted images, without contrast injection. When the method was proposed in the late 1980s some doubts appeared as to its feasibility, and, probably because the signal to noise and image quality at the time was not sufficient, no obvious experimental evidence could be produced to alleviate them. Helped by the tremendous improvements seen in the last three decades in MR hardware, pulse design, and post-processing capabilities, an increasing number of encouraging reports on the value of intravoxel incoherent motion perfusion imaging have emerged. The aim of this article is to review the current published evidence on the feasibility of in vivo perfusion imaging with intravoxel incoherent motion MRI.

Intravoxel incoherent motion MRI as a means to measure in vivo perfusion: A review of the evidence

In recent days, vanadium complexes and nanoparticles have received sustainable attention owing to their vast applications in different fields. In the present study, we report a facile approach for the synthesis of irregular dumbbell shaped vanadium pentoxide nanoparticles (V2O5 NPs: 30-60 nm) via the polyol-induced microwave irradiation process along with calcination. The as-synthesized nanoparticles were characterized using various physico-chemical techniques (e.g. XRD, TEM, FT-IR, DLS and XPS). The cell viability assay showed that V2O5 NPs could efficiently inhibit the proliferation of different cancer cells (B16F10, A549, and PANC1), depicting their anti-proliferative activity. However, V2O5 NPs did not exert significant cytotoxicity to the normal cells (CHO, HEK-293 and NRK-49F), suggesting their biocompatible nature. Interestingly, these nanoparticles inhibited the proliferation and migration of the endothelial cells (HUVECs and EA.hy926) and disrupted the blood vasculature in a chick embryo model, indicating their anti-angiogenic properties. The mechanistic study revealed that the effective internalization of V2O5 NPs generated intracellular reactive oxygen species (ROS) which in turn up-regulated p53 protein and down-regulated survivin protein in cancer cells, leading to the apoptosis process. Furthermore, the administration of V2O5 NPs to melanoma bearing C57BL6/J mice significantly increased their survivability as compared to the control untreated tumor bearing mice, exhibiting the therapeutic potential of the nanoparticles against melanoma. Additionally, the in vivo toxicity study demonstrated no toxic effect in mice upon sub-chronic exposure to V2O5 NPs. Altogether, we strongly believe that V2O5 NPs could intrinsically provide a new direction for alternative therapeutic treatment strategies for melanoma and other cancers by employing their anti-angiogenic properties in the future.

Anti-angiogenic vanadium pentoxide nanoparticles for the treatment of melanoma and their in vivo toxicity study.

Intravoxel incoherent motion MRI in neurological and cerebrovascular diseases.

To evaluate the expression level of integrin αvβ3 on activated hepatic stellate cells (HSCs) at different stages of liver fibrosis induced by carbon tetrachloride (CCl4) in rat model and the feasibility to stage liver fibrosis by using molecular magnetic resonance imaging (MRI) with arginine-glycine-aspartic acid (RGD) peptide modified ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) specifically targeting integrin αvβ3.All experiments received approval from our Institutional Animal Care and Use Committee. Thirty-six rats were randomly divided into three groups of 12 subjects each, and intraperitoneally injected with CCl4 for either 3, 6, or 9 weeks. Controls (n=10) received pure olive oil. The change in T2* relaxation rate (ΔR2*) pre- and postintravenous administration of RGD-USPIO or naked USPIO was measured by 3.0T clinical MRI and compared by one-way analysis of variance or the Student's t-test. The relationship between expression level of integrin αvβ3 and liver fibrotic degree was evaluated by Spearman's ranked correlation.Activated HSCs were confirmed to be the main cell types expressing integrin αvβ3 during liver fibrogenesis. The protein level of integrin αv and β3 subunit expressed on activated HSCs was upregulated and correlated well with the progression of liver fibrosis (r=0.954, P<0.001; r=0.931, P<0.001, respectively). After injection of RGD-USPIO, there is significant difference in ΔR2* among rats treated with 0, 3, 6, and 9 weeks of CCl4 (P<0.001). The accumulation of iron particles in fibrotic liver specimen is significantly greater for RGD-USPIO than naked USPIO after being injected with equal dose of iron.Molecular MRI of integrin αvβ3 expressed on activated HSCs by using RGD-USPIO may distinguish different liver fibrotic stages in CCl4 rat model and shows promising to noninvasively monitor the progression of the liver fibrosis and therapeutic response to antifibrotic treatment.

/pdf/molecular-magnetic-resonance-imaging-of-activated-hepatic-4q5x9d4ry0.pdf

Molecular magnetic resonance imaging of activated hepatic stellate cells with ultrasmall superparamagnetic iron oxide targeting integrin αvβ3 for staging liver fibrosis in rat model

Early therapeutic effects of anti-angiogenic agent ZD6474 upon nasopharyngeal carcinoma (NPC) in nude mouse were monitored by using intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI). Mice bearing NPC underwent IVIM DWI at baseline and after 1, 3, and 7 days of treatment with ZD6474 or vehicle (n = 12 per group). Parameters of apparent diffusion coefficient (ADC), true diffusion coefficient (D), perfusion fraction (f), and blood pseudodiffusion coefficient (D*) at different time points were compared between the two groups or within the treated group. In the treated group, the perfusion-related parameters f and D* of the tumors decreased significantly on day 1 while the diffusion-related parameters ADC and D were significantly higher beginning on day 3 compared with the control group. The decreases in f on day 1 and D* on day 3 were moderately correlated with the smaller tumor size change on day 7. Moderate correlations were established between MVD and f and D* as well as between increased TUNEL or decreased Ki-67 index and ADC and D. This study supports that IVIM DWI is sensitive to detect the ZD6474-induced changes in NPC in nude mouse and the f parameter could predict early response to anti-angiogenic treatment.

/pdf/intravoxel-incoherent-motion-diffusion-weighted-magnetic-5fg69f85mw.pdf

Intravoxel Incoherent Motion Diffusion-weighted Magnetic Resonance Imaging for Monitoring the Early Response to ZD6474 from Nasopharyngeal Carcinoma in Nude Mouse.

Purpose Arginine-glycine-aspartic acid (RGD)-based nanoprobes allow specific imaging of integrin αvβ3, a protein overexpressed during angiogenesis. Therefore, this study applied a novel RGD-coupled, polyacrylic acid (PAA)-coated ultrasmall superparamagnetic iron oxide (USPIO) (referred to as RGD-PAA-USPIO) in order to detect tumor angiogenesis and assess the early response to antiangiogenic treatment in human nasopharyngeal carcinoma (NPC) xenograft model by magnetic resonance imaging (MRI). Materials and methods The binding specificity of RGD-PAA-USPIO with human umbilical vein endothelial cells (HUVECs) was confirmed by Prussian blue staining and transmission electron microscopy in vitro. The tumor targeting of RGD-PAA-USPIO was evaluated in the NPC xenograft model. Later, mice bearing NPC underwent MRI at baseline and after 4 and 14 days of consecutive treatment with Endostar or phosphate-buffered saline (n=10 per group). Results The specific uptake of the RGD-PAA-USPIO nanoparticles was mainly dependent on the interaction between RGD and integrin αvβ3 of HUVECs. The tumor targeting of RGD-PAA-USPIO was observed in the NPC xenograft model. Moreover, the T2 relaxation time of mice in the Endostar-treated group decreased significantly compared with those in the control group both on days 4 and 14, consistent with the immunofluorescence results of CD31 and CD61 (P Conclusion This study demonstrated that the magnetic resonance molecular nanoprobes, RGD-PAA-USPIOs, allow noninvasive in vivo imaging of tumor angiogenesis and assessment of the early response to antiangiogenic treatment in NPC xenograft model, favoring its potential clinical translation.

https://www.dovepress.com/getfile.php?fileID=33611

Noninvasive monitoring of early antiangiogenic therapy response in human nasopharyngeal carcinoma xenograft model using MRI with RGD-conjugated ultrasmall superparamagnetic iron oxide nanoparticles.

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Molecular magnetic resonance imaging of activated hepatic stellate cells with ultrasmall superparamagnetic iron oxide targeting integrin αvβ3 for staging liver fibrosis in rat model

Intravoxel Incoherent Motion Diffusion-weighted Magnetic Resonance Imaging for Monitoring the Early Response to ZD6474 from Nasopharyngeal Carcinoma in Nude Mouse.

Noninvasive monitoring of early antiangiogenic therapy response in human nasopharyngeal carcinoma xenograft model using MRI with RGD-conjugated ultrasmall superparamagnetic iron oxide nanoparticles.