The Mitragotri group is engaged in the research field of drug delivery and biomaterials. Our research has advanced fundamental understanding of transport processes in biological systems and has led to the development of new materials as well as technologies for diagnosis and treatment of various ailments including diabetes, cardiovascular diseases and infectious diseases.
Our research has made particular impact on the following areas:
- Transdermal drug delivery: Drug delivery by placement of patches on the skin is a simple and painless alternative to needles. However, delivery of drugs across the skin is very challenging. We have developed novel technologies to increase skin permeability and deliver drugs into and across the skin. Our technologies include the use of ultrasound, penetration enhancers, liquid microjets and peptides to enable delivery of proteins, peptides and siRNA.
- Oral drug delivery: Pills offer a non-invasive and patient-compliant way of delivering drugs. This route, however, cannot be used for proteins and peptides since they are degraded in the stomach and possess low absorption across the intestine. We have developed novel polymer devices to protect the drug in the stomach and promote their adhesion on the intestine, which enhances oral bioavailability. Our lab has also developed the use of small organic molecules to enhance drug permeability across the intestine.
- Targeted drug delivery: Polymer particles allow encapsulation and targeting of drugs to diseased tissues. Our lab explores the effect of shape and deformability on performance of nanoparticles. We have shown that both shape and deformability impact various processes including circulation, adhesion and targeting, which we exploit for enhanced targeting.
- Biomimetic and bio-hybrid drug delivery systems: Our lab has developed synthetic particles using proteins and polymers that mimic the structural properties of red blood cells and platelets. We are exploring the use of these particles for various biomedical applications. We have also developed hybrid systems that utilize synthetic particles hitchhiking on cells for targeted drug delivery.
The Science behind Drug Delivery
Drug delivery can be broadly defined as the science and engineering of converting potent drugs into beneficial therapies. Successful drug delivery methods facilitate one or more processes including drug administration, absorption and targeting. At a fundamental level, the challenge in drug delivery reflects the fact that achieving the desired biodistribution of drugs in the body is limited by body’s natural metabolic processes and transport barriers. Our research aims at developing a fundamental understanding of these transport barriers. Research on biological barriers in our laboratory includes:
- Skin: Human skin offers an excellent barrier against the entry of foreign molecules. The primary contributor to skin’s barrier properties is its topmost layer, stratum corneum (SC). Our research aims at the use of experimental and theoretical tools to understand structural-permeation relationships of skin’s barrier properties. We also study transdermal transport of molecules under the influence of physical and chemical enhancers including ultrasound, liquid jet injectors, penetration enhancers and peptides. Our studies have described the interactions of ultrasound with skin and its impact on drug transport. We have also developed biomechanical models to understand the penetration of liquid jets into skin and its impact on drug delivery. Our studies have also focused on developing molecular-level understanding of the impact of penetration enhancers on skin lipids and proteins and their correlations with permeability and toxicity.
- Intestinal Mucosal Membrane: Uptake of macromolecular drugs across the intestine is very low due to low permeability of the mucosal membrane and susceptibility of drugs to enzymatic degradation. We aim to understand the barrier properties of the intestine to drug transport using in vitro models. In particular, we study, using experimental and theoretical tools, the effect of chemical penetration enhancers on drug transport across the intestine.
- Cellular Membranes: We study internalization of drugs and drug-carrying nanoparticles into target as well as immune cells. In particular, we focus on understanding the role of particle morphology on internalization. Our studies have shown that particle morphology makes a dramatic impact on the likelihood and rate of internalization by cells. Our research also focuses on understanding the mechanism by which physical forces such as ultrasound enhance the permeability of cell membranes and allow entry of drugs into the cytoplasm.
- Vascular Flow: The ability of nanoparticles to flow in the vascular compartment and adhere to the endothelium plays a major role in targeting nanomedcine to various diseased tissues, especially the endothelium. Using synthetic microvascular networks, we study the flow and adhesion of particles. Our studies showed that particle shape makes a profound impact on margination and vascular adhesion of nanoparticles.
- Intracellular Trafficking: We are investigating intracellular trafficking of nanoparticles in cells. Current understanding of intracellular trafficking of carriers is largely based on experimental data collected either at the population level, as the macroscopic end point of the therapy, e.g. cell death or gene expression; or at the single-cell single-particle level, in the form of detailed information about the transport steps, e.g. intracellular mobility of the carrier. We study the multi-scale nature of transport properties of particles within the cells. At the heart of the problem is the transport of particles on microtubules which is mediated by molecular proteins kinesins and dyneins. Through a combination of experiments and stochastic simulations, our group is establishing the governing equations of motor-driven transport.