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On Target

Targeted drug delivery has been recognised as a novel approach for delivering medication to specific organs without the need to increase the concentration of the medication (1). In traditional drug delivery systems, such as oral ingestion or intravascular injection, the medication is distributed throughout the body through systemic blood circulation. Consequently, only a small portion of the medication reaches the target organ. However, the ability to increase the concentration of the dose is limited by peripheral toxicity related to the systemic administration of compounds. In contrast, targeted drug delivery is able to concentrate the medication in the tissues of interest without increasing the relative concentration of the medication in the remaining tissues, thus reducing side effects. Targeted drug delivery can be used to treat many diseases, such as cardiovascular diseases, diabetes and cancerous tumours (2). Synthetic targeted drug delivery vehicles, including antibodies, peptides, proteins and vitamins, can enhance the selective uptake of drugs by target tissues or cells (1). However, developing synthetic vehicles can be a cost- and time-intensive process. The ability to monitor the structures of these drug delivery vehicles during and after the manufacturing process could be vital to avoid dead-end development paths and wasted resources.

 

No technology, so far, can help the drug delivery field to monitor the structure of individual drug delivery vehicles during production, since current technologies, such as x-ray crystallography, nuclear magnetic resonance (NMR) and smallangle scattering, have a common problem that particles need to be relatively homogeneous in order to obtain their structure. However, many vehicles are structurally dynamic and heterogeneous, such as antibodies and lipoproteins. Thus, producing vehicles without monitoring their structures is like taking a stab in the dark. Many vehicle failures are related to structural changes within the vehicles.

 

A new method in electron microscopy electron microscopy (EM) called individual particle electron tomography (IPET) overcomes this obstacle by discerning the structure of individual protein particles, allowing for examination of highly heterogeneous, dynamic or flexible proteins. IPET technology allows users to perform a computed tomography (CT) by EM on individual vehicles, and then to build up the three-dimensional (3D) density map of each individual vehicle (3,4) via a focused electron tomographic reconstruction algorithm (5). The map would be critically important for examining the structural changes during the production of vehicles by different production protocols, and for troubleshooting vehicles that lose functionality after modification.

 

DETERMINATION OF THE DYNAMIC PROTEIN STRUCTURE BY IPET

 

Protein structure determination by EM has been widely used for decades, the mainstay of which is the single-particle reconstruction method (6). In examining proteins by EM, the particles can either be imaged after negative staining (NS) them, or in their frozen, hydrated state by electron cryo-microscopy (cryoEM). Each method has its pros and cons: negative staining offers good contrast but can cause artifacts or alter protein conformation, while cryoEM allows for native-state observation but has low contrast and poor signal-tonoise ratio. Single-particle reconstruction of cryoEM gets around these limitations by grouping similar images and averaging them into 2D classes, which are then used to back-project to a 3D density map (6,7). However, for highly heterogeneous or dynamic proteins such as lipoproteins or antibodies, this averaging can be devastating to fine detail, and can drastically reduce reconstruction resolution.

 


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James Song is a research specialist in the Dr renís research lab at the Department of Biochemistry and Biophysics at the University of California, San Francisco. He assists with the 3D reconstruction algorithms improvement for determining the structure of small proteins by using electron tomography. Prior to that, James received his Bachelor degree in Computer Science at University of California, Berkeley. Email: jimsong@msg.ucsf.edu

Lei Zhang is a PhD student in Dr Renís research lab at the University of California, San Francisco. He focuses on the 3D reconstruction algorithms development for determining the structure of small proteins by using electron tomography. Prior to that, he received his Masters degree in Theoretical Physics at Xiían Jiaotong University, China. Email: lei.zhang@ucsf.edu

Gang (Gary) Ren, PhD, is a principal investigator in the Department of Biochemistry and Biophysics at the University of California, San Francisco. Garyís research lab is focused on studying the structure and function of dynamic proteins, including lipoproteins and antibodies. He got his postdoctoral training at the Scripps Research Institute, where he solved the first atomic resolution structure of transmembrane protein by cryoEM in the US, the structure of aquaporin 1 water channel. Prior to that, Gary obtained his MS degree in theoretical physics and PhD degree in Material Physics. His previous calculated electron scattering factors have been collected by the international table of crystallography, volume D since 2004. Email: gren@msg.ucsf.edu

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James Song
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Lei Zhang
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Gang (Gary) Ren
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