a future in graphic design?

The latest Accounts of Chemical Research is a special issue on Gene Silencing and Delivery. We were fortunate to have been invited to contribute to the volume, while also having the issue adorned with cover art developed by our very own Mike Smith.

Click the image for a higher resolution version. We should also thank Hiro for alerting us to the program used to create the artwork, Shade. There is a bit of a steep learning curve on it, but they tell me it is fantastic once you get going. Anyway, enjoy the issue – there are some tremendous contributions spanning a huge range of research – definitely a must-read.

the importance of being self-critical

In laboratory science-based fields, we are accustomed to performing research using the principles of the scientific method. To summarize, we form a hypothesis, conduct an experiment, collect data, analyze and interpret the data, and then draw conclusions that may or may not be aligned with the initial hypothesis. We then cycle back with a revised hypothesis and repeat the method. For this process to work, the experiments being performed must be designed to limit the number of possible conclusions, hence the need for appropriate controls. Finally, we try to use Occam’s Razor when drawing conclusions; the simplest, most assumption-free interpretation of the data should be explored first, before moving on to more complex explanations.

Recently I have been reading literature from various disciplines associated with obesity and heart disease, and the relationship between diet and those maladies. To be blunt, I have been amazed at what folks can get away with in the supposedly peer-reviewed literature. In my opinion, coming at it as an experimentalist, some of what I present below crosses the line from being poorly done to just plain irresponsible. For the sake of brevity, I will present these examples by linking to writers who have already gone through the process of dissecting the primary literature. I don’t think it is necessary for me to re-do analyses that have already been ably done. However, I want to make it clear that some of these writers have economic interest in the whole argument – they are selling books, are on lecture circuits, etc. By linking to those articles, I am not endorsing their products – I do however find some of what they have to say quite useful.

Continue reading “the importance of being self-critical”

wow…someone would really do this?

Thought I would share the following post from Retraction Watch:

Elsevier parasitology journal retracts paper after finding author made up peer reviewer email addresses

So, the main point is this: the author apparently submitted the paper and suggested reviewers for the paper, as is required by most (all?) journals these days. However, the editors of the journal discovered that the emails were bogus. For example, some of the addresses suggested went to a domain in China, despite the fact that the reviewers allegedly associated with those emails WERE NOT from China. The implication here is that the author was abusing the review system in order to obtain a favorable review (i.e., perhaps the author was on the other end of those addresses?). I guess I am just a bit sheltered – just shocks me that someone would actually go to these lengths.

good luck to Alicia!

This coming Friday is Alicia’s last day with the group. We have been very fortunate to work with her – she brought a fantastic attitude to a job that probably got a bit frustrating at times. Hopefully we made her job a bit easier by being a generally friendly and low-maintenance group!

Soon she will be moving back to Michigan where she won’t have to deal with our lovely triple-digit temperatures here in Atlanta. To wish her a fond farewell, we went to lunch at The Real Chow Baby (turning into a group favorite). The pix after the jump are evidence of our gluttony.

Continue reading “good luck to Alicia!”

the interplay of normalized tumor vasculature and nanoparticles

It’s been a while since the last post – busy times around here. However, I finally found a few spare moments to read some papers. One that popped out at me is a recent pub in Nature Nanotechnology entitled “Normalization of tumor blood vessels improves the delivery of nanomedicines in a size-dependent manner“. Rakesh Jain from Massachusetts General Hospital is the corresponding author, with contributions from a bunch of other folks, including Moungi Bawendi from MIT. The paper points out one of the main conundrums associated with delivery of therapeutics deep into a solid tumor (regardless of whether they are “nano” or not). Whereas the leaky vasculature, and the associated “enhanced permeability and retention” (EPR) effect can in principle increase the deposition of nanomedicines at the tumor, leaky vessels also lead to an increased interstitial fluid pressure within tumors, which hinders penetration through the tumor. Clearly, poor tumor distribution, and the associated gradients in drug concentration, are not conducive to good clinical outcomes.

However, it has been shown that vascular normalization, which reduces the leakiness of the vessels, can improve clinical outcomes (for traditional chemotherapies) in a number of cancer types, presumably due to better drug delivery and tumor distribution. Jain and co-workers sought to investigate whether this might be true for nanomedicines, which are typically thought to rely upon vascular leakiness for deposition. Would a decrease in the vessel pore size (via normalization with VEGF receptor blocking antibodies) decrease the penetration of nanoparticles?

The basic findings are perhaps not surprising, but are nonetheless very important. Nanoparticles (quantum dots, in this case) around 12-nm in diameter display much better tumor penetration than larger particles (following normalization of the vessels). The authors pointed out that this size is about the smallest that can benefit from the EPR effect, making the absolute particle size an important design consideration in the development of nanomedicines. Larger materials will always suffer from poor vascular escape and tumor penetration, while smaller particles may localize in healthy organs simply by virtue of the size cutoff associated with normal vessels in those organs. In our group, these things are obviously very important, and we are further interested in how particle modulus might change these design rules – hopefully we will have some answers in the near future.

delivering siRNA and cleaving cross-links

A couple of new papers from the group have appeared online. Jeff has written up his very nice work on disulfide containing microgels – the manuscript recently appeared online in Macromolecules. In this paper, we demonstrate the ability to synthesize redox-sensitive microgels using a low temperature synthesis approach originally developed in the group by Xiaobo Hu. The erosion properties of these particles were studied in collaboration with Mike using A4F/MALS. Additionallly, John Hyatt from Alberto Fernandez-Nieves’ group in the School of Physics helped out with rheology studies of disulfide based inter-microgel cross-linking. Together, the results illustrate our ability make well-defined microgels with controllable porosities and erosion properties using disulfide-based cross-linkers. We are currently employing these strategies in some controlled-release applications.

In the second paper, Mike has written up an Accounts of Chemical Research article on siRNA delivery. This manuscript mainly highlights our work with the McDonald group in the School of Biology in which we use peptide-based targeting strategies to deliver siRNA to ovarian cancer cells. Additionally, the manuscript describes our “synthetic toolbox” for the construction of complex core/shell microgel architectures, which we have been developing for the last 13 years. Our hope is to translate this toolbox into the development of truly functional vehicles…stay tuned.

proteins in microgels

A new paper from the group just appeared in Macromolecules ASAP.  “Tunable Encapsulation of Proteins within Charged Microgels” describes some light scattering studies by Mike Smith wherein he used the Calypso coupled to MALS and dRI detection to study the loading of cytochrome C within pNIPAm-AAc microgels. The take-home message here is that for the case of cationic protein encapsulation within anionic microgels, the increase in capacity is not a simple linear function of anion density. For example, a ~10-fold increase in protein loading is obtained by increasing the AAc content from 20 mol% to 30 mol%. Additionally, the loading is extremely sensitive to ionic strength, with very tight protein binding being observed at ~20 mM salt. Nearly quantitative release is then obtained upon raising the ionic strength to physiological levels (~140 mM), suggesting a mechanism for triggering the release in vivo. We hope to use the analytical methods presented in this paper to perform detailed, quantitative studies of protein-microgel affinity for a variety of proteins that are of interest in pharma applications.

self-replication is cool

A clever little paper just came out as an Advance Online Publication in Nature Chemistry (Self-reproduction of supramolecular giant vesicles combined with the amplification of encapsulated DNA). Tadashi Sugawara from the University of Tokyo shows in this work that when you fabricate a vesicle containing an amphiphilic imidazolium catalyst, you can actually cause the vesicle to self-replicate when a membrane precursor is placed in solution. Furthermore, the vesicle can be used to encapsulate DNA and PCR reagents, thereby creating self-replicating vesicles that contain replicated DNA. Perhaps the coolest thing about this from a “biosimilar” point of view is that the giant vesicle division is accelerated by the encapsulation of DNA within the vesicle membrane. Thus, only the DNA containing vesicles are actually capable of rapid division and replication. The similarity of this work to actual “synthetic cell” fabrication makes me think that the popular press could have a field day with this…stay tuned.

A tight sqeeze

A new paper from the group is out today that has arisen out of our collaboration with Henry White at U. of Utah and his student Deric Holden. The basic idea is this:  Grant Hendrickson from our group previously observed, using a simple filtration set-up, that microgels could pass through pores that were nearly 10-times smaller than the equilibrium diameter of the spheres. Continue reading “A tight sqeeze”

Microgels as (poor) crowders

Here is an interesting paper that has arisen out of a collaboration with Gary Pielak’s group at UNC-CH.  “An upper limit for macromolecular crowding effects“, just published in BMC Biophysics, basically illustrates that even at very high microgel concentrations, there is little change in the observed stability of solvated proteins. In other words, microgels are pretty crummy macromolecular crowders. The proteins appear to localize in the aqueous space between the microgels, and perhaps within large pores in the microgels, thereby not “feeling” any macromolecular crowding effects.

Continue reading “Microgels as (poor) crowders”