Mobilizing Biomolecular Therapeutics in the Body

The design of drug targeting strategies to enable delivery of therapeutic agents to areas of the body requiring intervention is an active research field. Therapeutic targets are often confined to specific regions or tissues in the body, where proper access requires active transport (e.g. from the gastrointestinal tract into the circulation, from the circulation into the underlining tissue, etc.). In addition, once within the tissue or body compartment of interest, most therapeutics need to access within selected sub-cellular environments, further requiring strategies of active transport. This is particularly troublesome for biological macromolecules given their relatively large size and chemical features, which cannot be altered to accommodate these premises as is common for classical chemical drugs.

While most efforts in the field are aimed to design new drugs and drug-carrier formulations, IBBR investigators additionally focus on deciphering the biological cues regulating transport through body tissues and cells. This is of outmost importance because the mechanisms involved in this transport are poorly understood, particularly for novel nanomedicines: How do cells and tissues sense and react to artificial materials? How do they inter-communicate to regulate transport and does this transport differ from that of natural substances? Which design parameters and physiological parameters determine which cellular mechanisms are employed that increase or prevent drug delivery? None of these aspects are known. The interface between molecular-cell biology and nanomedicine-pharmaceutics represents a unique opportunity toward deciphering this. Appreciating both sides of these global healthcare problems, IBBR acts as a catalyst developing new interdisciplinary science that integrates these fields.

The approach is to characterize and co-opt natural transport mechanisms rather than trying to overwhelm them. Current strategies overwhelm biological systems because they compete against natural molecules continuously mobilized in the body using the same cellular machinery. Instead, IBBR focuses on pathways that do not continuously transport body molecules, so that their biological machinery is available for drug delivery. In addition, most targeting strategies are designed to achieve specific binding to a cell receptor, but they rely on the signaling and transport processes with which the bound receptor naturally associates. Alternatively, IBBR researchers impart the drug carrier control over these signaling events, so that the transport mechanisms, kinetics, and destinations associated with these receptors can be modulated and even bypassed on command. These approaches are characterized and optimized through parallel examination using cell cultures and in vivo in laboratory animals, showing great promise to improve aspects such as oral delivery of biotherapeutics, delivery of these agents into the brain, or transport into selected sub-cellular compartments, which represent major unmet goals in the quest for better therapeutics.