Drug Delivery

Conventional drug administration often requires high dosages or repeated administration to stimulate a therapeutic effect, which can lower overall efficacy and patient compliance, and result in severe side effects and even toxicity. Oral administration, which is the most common approach for delivering pharmaceuticals, is frequently limited by poor targeting and short circulation times. Protein and nucleotide-based drugs often have short serum half-lives of only minutes to hours. To address these issues, controlled drug delivery systems, including membranes, nanoparticles, liposomes and hydrogels have been a major focus in recent decades. We are developing new drug delivery strategies to provide highly precise spatiotemporal availability of both small and large drug molecules to address these challenges.

We focus on a multiscale design of drug delivery systems, to provide versatile platforms to meet specific application-based requirements. The macroscopic design largely determines the routes by which hydrogels can be delivered into the human body. Micropores, if present, will dramatically affect the overall physical properties, while allowing for convective drug transport. On the several-nanometre scale, a cross-linked polymeric network surrounds the water contained in hydrogel networks. Such networks contain open spaces, the size of which is referred to as the mesh size of the network. Importantly, the mesh size governs how drugs diffuse inside the hydrogel network. Finally, at the molecular and atomistic scale, various chemical interactions may occur between the drugs and the polymer chains. The features at the mesh scale and the molecular and atomistic scale are essential for controlled drug release. Because they are decoupled from the macroscopic properties of the hydrogel, desirable features at each length scale can often be designed independently of the other.

We are interested in the development of different polymer systems (i.e., hydrogels) that allow for minimally invasive delivery (injectable systems) or implantable systems for various applications in musculoskeletal, skin and oral/craniofacial regeneration, and cancer therapy (Fig. 1). These systems, which deliver therapeutic agents (e.g., cells, protein growth factors, chemoattractants, antibodies, genetic material, etc.) are being tested in a variety of small/large animal models, and human clinical trials for various applications.

Li et al Nat Rev Mater 2016

Figure 1. Drug-laden polymeric hydrogels of varying size can be delivered to the body in a minimally-invasive manner for therapeutic applications. Image taken from (Li, J. et al., Nature Reviews Materials, 2016).

Reloading of delivery devices in situ, and dynamic, real-time control over delivery are of major interest. For many therapeutic applications, an invasive procedure is needed to inject or implant a drug-eluting device, and these devices cannot be refilled or replaced without another invasive surgery. We have proposed a new paradigm in drug delivery, the refilling of a delivery device in vivo in a minimally invasive manner, via targeting with fresh drug payloads through the blood. In this paradigm, the injectable delivery device is modified to bind refills infused into the blood or taken orally. Drug delivery to the diseased heart in particular, in the form of cells, macromolecules and small molecules, has faced multiple hurdles to clinical translation. Motivated by the potential advantages of localized, repeatable delivery of therapy, we are developing new systems that enable direct, repeated administration of therapy via a polymer-based reservoir connected to a subcutaneous port.

As many biological cues are present for specific and short time periods, we have also developed a variety of active scaffolds that can be remotely actuated by ultrasound, electric fields and magnetic fields to deliver factors and cells on demand. In these applications, the microenvironment of the target cells may dramatically impact their ability to respond to the drug, and this is also an active area of investigation. 

Overall, our research provides novel therapeutic opportunities for the targeting and treatment of various diseases by controlling spatial arrangement and temporal release of therapeutic agents.

 

Relevant review articles in this area

  1. Li J, Mooney DJ. Designing hydrogels for controlled drug delivery. Nat Rev Mater. 2016;1(12):16071. doi:10.1038/natrevmats.2016.71.
  2. Kearney CJ, Mooney DJ. Macroscale delivery systems for molecular and cellular payloads. Nat Mater. 2013;12(11):1004-1017. doi:10.1038/nmat3758.

Representative research publications area

  1. Shea LD, Smiley E, Bonadio J, Mooney DJ. DNA delivery from polymer matrices for tissue engineering. Nat Biotechnol. 1999;17(6):551-554. doi:10.1038/9853.
  2. Richardson TP, Peters MC, Ennett AB, Mooney DJ. Polymeric system for dual growth factor delivery. Nat Biotechnol. 2001;19(11):1029-1034. doi:10.1038/nbt1101-1029.
  3. Chen RR, Silva EA, Yuen WW, et al. Integrated approach to designing growth factor delivery systems. FASEB J. 2007;21(14):3896-3903. doi:10.1096/fj.06-7873com.
  4. Mooney DJ, Lee KY, Peters MC, Anderson KW. Controlled growth factor release from synthetic extracellular matrices. Nature. 2000;408(6815):998-1000. doi:10.1038/35050141.
  5. Brudno Y, Silva EA, Kearney CJ, et al. Refilling drug delivery depots through the blood. Proc Natl Acad Sci. 2014;111(35):12722-12727. doi:10.1073/pnas.1413027111.
  6. Huebsch N, Kearney CJ, Zhao X, et al. Ultrasound-triggered disruption and self-healing of reversibly cross-linked hydrogels for drug delivery and enhanced chemotherapy. Proc Natl Acad Sci. 2014;111(27):9762-9767. doi:10.1073/pnas.1405469111.