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A safer and more effective strategy for siRNA delivery

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A safer and more effective strategy for siRNA delivery
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  ISSN 1743-588910.2217/17435889.4.1.7 © 2009 Future Medicine Ltd  Nanomedicine   (2009) 4(1), 7–10  7  N EWS  & V IEWS Research Highlights Highlights from the latest articles in nanomedicine Convergence of nanocrystal imaging and lipoprotein delivery  Evaluation of:  Cormode DP, Skajaa T, van Schooneveld MM et al. : Nanocrystal core high-density lipoproteins: a multimodality contrast agent platform. Nano Lett.  8(11), 3715–3723 (2008). Evaluation of: Kim BYS, Jiang W, Yip CM, Rutka JT, Chan WCW: Biodegradable quantum dot nanocomposites enable live cell labeling and imaging of cytoplasmic targets. Nano Lett.  8(11), 3887–3892 (2008). I Corbin 1 , B Scot 1,2  & G Zheng 1,2† †  Author for correspondence: 1 Division of Biophysics & Bioimaging, Ontario Cancer Instute, Toronto, ON, Canada E-mail: gzheng@uhnresearch.ca 2 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a  financial interest in or financial conflict with the sub- ject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or  patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. The use of nanocrystals, including quantum dots, gold and iron oxide nanoparticles, as highly effective imaging tools has enabled significant strides to be made in the nano-medicine field. Similarly, lipoproteins, owing to their intrinsic biocompatibility and versa-tile carrying capacity, are effective vehicles for ferrying imaging probes or toxic payloads. Both of these areas are being exploited inde-pendently to great avail, however, if a vehicle  was created that combines both the imag-ing power of nanocrystals with the natural targeting and biocompatibility properties of lipoproteins, it would be a considerable advancement in molecular imaging.In light of this, a high bar has been set in the recent article by Cormode and co  workers. The researchers have successfully created a family of high-density lipoprotein (HDL) nanoparticles encapsulating quan-tum dots, gold and iron oxide nanocrystals,  which are suitable for imaging macrophages and the detection of atherosclerotic plaques. These HDL nanocrystals are prepared using a generalized methodology and closely resemble the native HDL structure in terms of their size and morphology. More impor-tantly, the authors have demonstrated the atherosclerosis imaging ability (optical, MR and CT) of these multimodal nanoparticles both in vitro  and in vivo  by taking advantage of the macrophage-targeting specificity of HDL.This report represents the first instance of converging lipoprotein delivery with nanocrystal-based imaging. Although the mechanism of encapsulation of these different nanocrystals warrants further investigation, the results do demonstrate significant promise in the use of nanoc-rystal core-HDL nanoparticles as imaging tools and provide a platform from which to build on. Furthermore, it is foreseeable that the application range of these HDL nanocrystals can be greatly expanded by targeting a wide variety of disease mark-ers using customized lipoprotein rerouting strategies [1] . Reference Zheng G, Chen J, Li H, Glickson JD: Rerouting 1 lipoprotein nanoparticles to selected alternate receptors for the targeted delivery of cancer diagnostic and therapeutic agents. Proc. Natl  Acad. Sci. USA  102(49), 17757–17762 (2005). Subcellular targeting with cloaked quantum dots Current methods for interrogating sub-cellular structures rely on procedures that disrupt the plasma membrane or involve cell fixation. Although invasive and destructive, these methods do provide some valuable insight into cell biology. The capacity to perform similar studies in live cells would offer new opportunities to investigate  Nanomedicine  (2009) 4 (1) 8 future science group  N EWS  & V IEWS – Research Highlights molecular interactions and biological pro-cesses at a whole new level. Quantum dots hold great promise as a candidate contrast agent for such applications owing to their superior optics and multiplexing capabili-ties [1] . However, the inability of quantum dots to efficiently enter into the cytoplasm in large quantities hinders their use as tracers for cytoplasmic targets.Novel methods developed by Kim and coworkers formulate functionalized quan-tum dots within a biodegradable–biorespon-sive polymer coat that enhances vesicular internalization into cells without membrane-disruptive effects. Once inside the endolyso-somal compartment of the cell, the polymer coat of the nanocomposite is activated (by low pH) to sequester protons, which, in turn, destabilizes the vesicular membrane, thus permitting cytoplasmic escape. On entering the cytoplasm, the polymer coat is shed and the quantum dots decorated  with subcellular-targeting ligands are free to interrogate cytoplasmic structures. Furthermore, selectivity for identifying a distinct cell population for this ana lysis can be achieved by introducing homing mol-ecules to the surface of the polymer-coated quantum dot nanocomposite.The authors display the power of this technology by simultaneously imaging actin filaments and mitochondria in ErbB2-targeted breast cancer cells. Although the effect that these nanocomposites may have on the cellular machineries warrants further investigation, this work lays the foundation and provides the opportunity to simultane-ously monitor multiple subcellular struc-tures and interrogate intracellular processes  within live cells. Reference Michalet X, Pinaud FF, Bentolila LA 1 et al. : Quantum dots for live cells, in vivo  imaging and diagnostics. Science   307(5709), 538–544 (2005).  A safer and more effective strategy for siRNA delivery  Evaluation of: Yezhelyev MV, Qi L, O’Regan RM, Nie S, Gao X: Proton-sponge coated quantum dots for siRNA delivery and intracellular imaging.  J. Am. Chem. Soc.  130, 9006–9012 (2008). The incredible ability of short sequences of synthetic RNA to interfere with messenger RNA and thereby silence the activity of specific gene products has the capacity to revolutionize the way we view and treat diseases. The biggest challenge for this technology is the problem surrounding the safe and effective delivery of siRNA [1] . Not only do these compounds have to be delivered efficiently to the right cell type but they must also be delivered to the right subcellular location for effective therapeu-tic activity. Although general nanoparticle-targeting strategies are developed to address the former issue, they fail to resolve the latter because these macromolecule carri-ers are typically internalized by receptor-mediated pathways that deposit and trap the siRNA into endosomal–lyzosomal compartments.In a recent article in the  J. Am. Chem. Soc. , Yezhelyev and colleagues address this key issue by engineering a polymer–encapsulated quantum dot nanoparticle capable of ferrying siRNA into the cell and subsequently facilitating its endo-somal release in a safe and effective man-ner. By titrating precisely the amounts of carboxylic acid and tertiary amine groups introduced to the surface of the quantum dot, the authors optimize the capacity of the nanoparticle to bind and release siRNA, enter into cells and escape endosomal–lyso somal compartments by proton-sponge mechanisms. The ingenious balancing of these surface functionalities enhanced gene silencing activity by 10- to 20-fold and simultaneously reduced the cellular toxicity by five- to sixfold in vari-ous cancer cell lines relative to conventional siRNA-delivery agents.  www.futuremedicine.com  9 future science group  N EWS  & V IEWS Research Highlights – The salient strategies for siRNA deliv-ery and release outlined in this work are not limited to quantum dots only but can be applied to other carrier systems and thus should have a broad appeal to many in the drug-delivery field. In fact, the authors speculate that, for future in vivo  applications, alternate nanoparticle-based systems, such as iron oxide or polymeric scaffolds, may be used to deliver siRNA  with these methods. This promising new delivery strategy may take us one step closer to making systemic siRNA delivery a reality. Reference Blow N: Small RNAs: delivering the future. 1 Nature   450(7172), 1117–1120 (2007). ‘Click’ nanoparticles for in vivo  applications ‘Click’ chemistry has been used as a selective and robust chemical tool in the development of numerous devices [1] . One interesting trend in nanomedicine is that click chemistry has been adopted toward generating targeting nano-particles because they can be formed under unusually mild conditions and in a highly quantitative manner. However, efforts of using these click nanopar-ticles for in vivo  applications have been hampered by the limited knowledge of their in vivo  stability.Recently, a significant step forward has been made by von Maltzahn and cowork-ers who have applied click chemistry to synthesize fluorescent, superparamagnetic iron oxide nanoparticles. Initially, the particles are stabilized with azido-PEG groups that undergo click reactions with an alkyne-functionalized homing peptide (LyP-1) sequence to yield a tumor-target-ing nanodevice. The authors found that these nanoparticles are able to stably circu-late for hours (>5 h) following intravenous administration, extravasate into tumors and penetrate the tumor interstitium to bind specifically to tumor cells.This study has validated the use of click nanoparticles for in vivo  applications and  will undoubtedly broaden the impact of using this new chemical tool in the field of targeted nanoparticle development. Furthermore, one can even speculate that there might be significant potential for click reactions to occur in vivo  and thus opens a new doorway into future pathways for in vivo  assembly of targeted nanodevices. Reference Kolb HC, Finn MG, Sharpless KB: 1 Click chemistry: diverse chemical function from a few good reactions.  Angew. Chem. Int. Ed. Engl.  40(11), 2004–2021 (2001). Evaluation of: Von Maltzahn G, Ren Y, Park J-H et al. : In vivo  cell targeting with ‘click’ nanoparticles. Bioconjugate Chem.  19, 1570–1578 (2008). Evaluation of: Bennett KM, Zhou H, Summer JP et al. : MRI of the basement membrane using charged nanoparticles as contrast agents. Mag. Res. Med.  60, 564–574 (2008).  A new way of looking at the basement membrane in living subjects The basement membrane is a composite matrix of proteins and proteoglycans that forms a lining and functional barrier for overlying endothelial and epithelial cells. Loss or compromise to the integrity of this structure is a hallmark feature of many important biological processes, ranging from tissue development to metastatic dissemination of cancer cells. The central role of this structure in health and disease highlights the need for suitable methods to evaluate the basement membrane in situ . Current methods of evaluating the base-ment membrane are invasive, requiring biopsy samples and subsequent immuno-histochemistry or electron microscopy. These methods are limited in their scope and practicality for monitoring progres-sive alterations in basement membrane structure in human and animal subjects.In the recent seminal work of Bennett and coworkers, simple yet compelling MRI methods were developed using charged ferritin-based nanoparticles (13 nm) to noninvasively assess the integrity of the glomerular basement membrane in the kidneys of healthy rats and those with chemical-induced renal failure. Cationic ferritin nanoparticles accumulated selec-tively throughout the renal cortex in a uniform punctuate pattern reflective of the location of individual glomeruli. The authors suggest that the cationic ferritin particles localize to the glomerular base-ment membrane as a result of electrostatic interactions between the cationic nano-particle and the high density of anionic proteglycan moieties within the basement  Nanomedicine  (2009) 4 (1) 10 future science group  N EWS  & V IEWS – Research Highlights membrane matrix. Furthermore, the pro-file of the MRI findings change with renal disease and the loss of glomerular integ-rity because less ferritin particles accu-mulate at the glomeruli and more diffuse signal reduction is detected within the kidney tubules.The landmark finding of this present study demonstrates the feasibility of noninvasive imaging of the basement membrane in animal models and human subjects. The use of cationic ferritin contrast agents may alleviate the need to acquire biopsy samples to assess base-ment membrane integrity and provide new opportunities to study developmen-tal and disease processes in an entirely new light.
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