Drug Delivery: Cell-specific Targeted Therapeutics
Written by Prachi Gupta in the Thayumanavan group.
The field of drug delivery has been growing rapidly as it can provide clinical accessibility to a large number of potential drugs which are ineffective otherwise. Many drugs, including small molecules and biologics, fail in clinical trials because of poor bioavailability and safety profiles. Drug delivery strategies focus on modifying the existing form of the drug to give it a more desirable therapeutic window and better pharamacokinetics parameters. For example, it is a difficult task to accumulate large and charged biomolecule therapeutics at the target site without degrading them during circulation or inducing an immune response that could lead to adverse side effects. A key challenge, then, is to develop methods that can safely guide such therapeutics to the target site in their active form. Drug delivery vehicles have emerged as a promising technology to transport drugs safely to their target location – much like a UPS or FedEx delivery package. By the process of packing a drug inside a vehicle, the pharmacokinetic properties of a drug no longer decide its fate. Instead, the shield (vehicle) does, and can be fine-tuned to achieve the desired outcome.
A drug delivery vehicle must be non-toxic, highly stable in circulation, capable of homing in to the target site, and designed to release the drug efficiently. In the same way as multiple shipping companies exist to deliver an item, a variety of drug delivery vehicles have been explored over the last few decades, each of which has its own mechanism of action and advantages. The UMass Chemistry department has played a leading role in this field, with many contributions from research groups within the department. The department has particularly focused on polymer-based assemblies to deliver both small molecule drugs and macromolecular biologics. Here, a selection of examples are highlighted.
The Thayumanavan Group has developed highly tunable ‘Antibody Nanogel Conjugates’ (ANCs) for targeted delivery of small molecules and shown efficacy in vivo for delivery of a benchmark cancer therapeutic DM1 (mertansine). The group has also designed alternative strategies, including ‘shrink wrap’ and artificial vesicles, which can not only deliver proteins/antibodies but also reprogram cancer cell surfaces to activate an immune response. The launch of an early-stage startup company, Nalam Therapeutics, aims to translate these platforms to clinical use.
The Rotello group has designed self-assembled vehicles (polyplexes) for delivery of small interfering RNA (siRNA) and shown their efficacy in animal models of triple-negative breast cancer, Acute Respiratory Distress Syndrome (ARDS), and wound biofilm infections. Systems to deliver RNA-based cargoes are important for translating the RNA-design-based innovations in the department (see later in the article). The Rotello group has also developed a range of nanoemulsion systems for treating bacterial and fungal wound infections using essential oils and other antimicrobials.
Although a vehicle’s efficacy is undeniably an important parameter to assess its success, it is equally important to ask certain fundamental questions to enable clinical translation of the technology – 1) How do we know the route taken by the vehicle to reach the target? 2) Where exactly does most of it accumulate? 3) How do we study the vehicle in circulation when it might be surrounded by multiple serum proteins? 4) How does it interact with the cell membrane?
Just like we use an online tracking system to follow our packages, multiple strategies have been developed to track vehicles in circulation. The Vachet group has developed multimodal imaging tools that combine MALDI-MS imaging, laser ablation ICP-MS imaging, and microscopy which can reveal the location of vehicles, measure their quantities, and provide insight into their biochemical effects. Additionally, the group has established covalent labeling mass spectrometry (CL-MS) techniques for mapping the epitopes that are recognized by therapeutic proteins in living cells. These methods have enabled multiple research groups to accurately track their delivery systems.
The Wu group has been actively working on establishing molecular tools to track spatio-temporal dynamics of RNA and to probe cellular signaling events. Moreover, the group is currently creating new approaches to control the life cycle of RNA in living cells; such insights can drastically improve the design parameters of RNA-carriers. During circulation, vehicles encounter a variety of serum proteins and potentially develop a layer of proteins (called protein corona) which can drastically alter the original properties of the vehicles. The Kaltashov group has pioneered powerful approaches to characterize protein
aggregates, biopharmaceuticals, and protein conjugates. These tools are highly relevant in drug delivery as they can provide a step-by-step guide to characterize protein corona, which can provide substantial information about the fate of the vehicle. It is estimated that only <0.1% of vehicles overcome biological barriers and reach the target site. Therefore, it is of paramount importance to predict the behavior of vehicles in the biological milieu. Once the nanoparticles reach the target site, they rely on various mechanisms to get access to the cytosol; however, all the pathways have one common interaction—between the nanoparticles and lipid membranes of the cellular surface. This intricate interaction decides whether the particles will be allowed inside the target cells or not. Studying these miniscule and delicate interactions are possible with computational modeling. The Jianhan Chen and Thayumanavan groups have utilized molecular modeling to study complex peptide-based amphiphilic polymer interactions and elucidated stepwise disassembly of supramolecular assemblies upon specific binding to a target protein. Such modeling provides fundamental understanding of how nanoparticles might interact with and respond to the presence of the target protein to release the encapsulated cargo.
The success of fabricating a suitable vehicle depends heavily on understanding the characteristics of the therapeutic. For example, a vehicle that is designed to carry hydrophobic molecules will not be applicable for highly charged, water soluble therapeutics. Research on investigating new therapeutics can facilitate the progress of delivery strategies. The Hardy lab has worked collaboratively with the Thayumanavan, Rotello, and Forbes (Chem Eng) labs to deliver caspase proteases for therapeutic purposes. Due to their ability to induce programmed cell death, caspases make an ideal cargo for targeting cancer cells. This group’s investigations have demonstrated that both the catalytic efficiency of the caspase impact its killing potential and the suite of anti-cell death factors that target each particular caspase, which are expressed in various cell types, dictate which caspase is most effective in treating and killing different cancer cells. In addition, the Thompson group utilizes biophysical techniques to study bacterial chemotaxis receptors in depth. Their findings reveal that changes in protein order and stability play a key role in the signaling mechanism. This work may enable the development of novel antibiotics targeting chemotaxis proteins and the ability to engineer bacteria for bioremediation and drug delivery.
Another example of therapeutic personalization is the foundational research done on RNA by the Martin group. The group has innovated a novel technology which can not only synthesize ultra-pure RNA, but also reduce the cost by many-fold. Startup company Waterfall Scientific is a remarkable step in providing high quality RNA to a broad swath of researchers who are developing effective RNA therapeutics. In addition to being a highly scalable platform, it is ideal for the expanding field of personalized therapeutics.
The department has also made a huge contribution in exploring alternative delivery strategies to minimize side effects and enhance efficacy. The You group focuses on creating synthetic DNA- and RNA-based tools for analytical and biomedical applications. The group has applied the nucleic acid-based tools to generate force-responsive delivery of anticancer drugs by designing a DNA mechanical nano-vehicle. Such a strategy opens the door to a plethora of applications in both drug delivery and membrane customization. The Farkas group has contributed to generating macrophage based novel delivery systems where the chemical modification of macrophages is utilized to create imaging and delivery tools. Macrophage ‘re-education’ is another emerging technique to target cancer cells being investigated by the group. Another exciting platform which departs from traditional delivery strategies is the fundamental research in membrane pore-forming proteins led by the Min Chen group. Such a technology can be extended to developing tailored delivery vehicles which can potentially reprogram cellular membranes and induce cytotoxicity to the target cells.
The chemistry department at UMass Amherst has been pioneering the development of advanced delivery methods which have the potential to enhance therapeutic efficacy and minimize side effects. These efforts are also enabled by the Center for Bioactive Delivery at the Institute for Applied Life Sciences. The Center, which brings all these departmental researchers together with complementary researchers from other departments in UMass, focuses on enabling translation of fundamental research findings in the delivery arena to the clinic. These collective efforts have given rise to the development of remarkable delivery platforms which point towards a bright future of drug delivery at UMass Amherst.