DISPERSAL AND DELIVERY

Publication Details

Aerosols and Aerobiology – Chad Roy, Tulane National Primate Research Center, USA

Dr. Chad Roy began the session by discussing infectious disease aerobiology. Although he noted that naturally-acquired infections tend to be characterized by more heterogeneous aerosol size, particle distribution, and temporal patterns than experimentally controlled studies, he pointed out that understanding factors such as environmental susceptibility, aerosol size and distribution, deposition, and interactions in the respiratory system are key to understanding airborne disease processes, whether in natural or experimental contexts (Roy and Milton, 2004). He noted that it is very difficult to study the complex, dynamic system of disease progression through empirical studies alone, and that experimental work is required. Dr. Roy also presented several examples demonstrating that microbial viability in aerosols differed significantly among strains and species, as well as with varying aerosol particle sizes. All of these factors (the physical characteristics of the aerosol, the biological characteristics of the pathogen, the susceptibility of a given individual or population, etc.) play significant roles in determining the eventual progress of the disease.

Dr. Roy described the ways in which deposition within the respiratory tract is affected by the aerodynamic particle size, a characteristic that takes into account particle density. In humans, particles with an aerodynamic diameter of 10–30 micrometers generally deposit in the mouth and nose, particles of 2–10 micrometers deposit in the trachea and bronchi, and particles of less than 2 micrometers reach the alveoli. Particular areas of the respiratory tract can thus be targeted by exposure to differently sized particles, while the tissue susceptibility of different respiratory tract regions to a particular disease agent is also likely to vary. Clearance mechanisms such as exhalation and mucociliary clearance also determine the duration the body is in contact with the agent, affecting the disease pathology.

Dr. Roy led into a discussion of how research on aerobiology has contributed to the development of alternative, inhalation-based methods of drug and vaccine delivery. Inhaled vaccines seek to elicit protective immunity at both the mucosal surface, where exposure to the disease agent would naturally occur, and systemically through the generation of serum antibody titers. Dr. Roy pointed out that research on inhalation delivery is not new, and noted studies on aerosol vaccination against agents of both public health and biodefense significance from the 1950s to 2000s (including Cohn et al., 1958; Tseng et al., 1995; and Sepúlveda-Amor et al., 2002). However, he noted that early efforts suffered from vaccine reactogenicity, lack of suitable mucosal adjuvants, and limited availability of individual inhalation devices. However, Dr. Roy concluded by presenting data from several recent studies in which advances in the production of subunit vaccines and alternative formulations to prolong residence time have been able to achieve improved efficacy of inhalable biologics.

Nanostructured Delivery Systems for Drugs, Proteins and Cells – Jackie Ying, Institute of Bioengineering and Nanotechnology, Singapore

Dr. Jackie Ying, of the Institute of Bioengineering and Nanotechnology, continued the session by describing some of the components of the “nano tool box” and discussing ways in which nanomaterials with unique properties may be designed to serve purposes such as targeted drug delivery and tissue regeneration.

Dr. Ying reported that formulation into nanoparticles may help protect a protein or drug from systemic degradation and may also reduce side effects by reducing the dosage required and promoting site-specific uptake. Nanosystems may include conjugated molecules designed to bind cell-surface receptors. Temperature-responsive, pH-responsive, and stimuli-responsive systems may also be created through the use of varying polymer subunits and chemical groups. Dr. Ying presented several examples of such engineered polymeric nanosystems, including nanorods designed to release the chemotherapeutic drug Paclitaxel only when exposed to the slightly acidic pH within cancer cells and not when at neutral physiologic pH (Zaman et al., 2010). She also described glucose-sensitive systems in which insulin is released as glucose concentration rises and the free glucose disrupts polymer cross-linking. This system can be designed to be reversible, enabling multiple cycles of polymer dissolution and insulin release, followed by re-formation, as glucose concentration rises and falls, which would allow for much finer control of blood sugar levels than existing treatments.

Dr. Ying next discussed several examples of the use of polymeric scaffolds for tissue regeneration. She presented an example of a nanocomposite constructed of inorganic, bone-like mineral apatite complexed to a bone morphogenic protein, along with the polymer poly(lactic-co-glycolic acid) (PLGA), which releases acidic degradation products. In this system, acidic byproducts from PLGA degradation gradually dissolve the apatite and provide sustained release of the protein, promoting healing in bone defect models. Fibrous polymer scaffolds can also be constructed to help promote the attachment and proliferation of seeded cells for soft tissue regeneration applications (Wan et al., 2006; Tai et al., 2010). Dr. Ying concluded by again noting that nanostructured delivery systems can be engineered to meet the unique needs of various applications.

Remarks: Implications Stemming From Advances in Dual-Use Targeted Delivery Systems – Kathryn Nixdorff, Darmstadt University of Technology, Germany

Dr. Kathryn Nixdorff closed the session by providing commentary on potential implications arising from advances in targeted delivery systems. Dr. Nixdorff noted that targeted delivery systems include both viral and non-viral systems, and she highlighted the fact that systems designed to deliver a biological agent such as DNA or protein effectively to target cells and tissues have many important applications in vaccines, cancer treatment, and other therapies.

Dr. Nixdorff reported that multiple viruses have been explored for use as delivery vectors, including adenoviruses, adeno-associated viruses, vaccinia virus, and lentiviruses. Work on such viral vector systems has led to improvements in targeting to specific tissues, gene transfer and expression levels in those tissues, and vector stabilization from environmental degradation (Liu et al., 2007; Mok et al., 2007; Chalikonda et al., 2008). In addition, several studies have successfully demonstrated viral vector administration through aerosols. Advances in aerosol delivery may lead to improved absorption through the respiratory tract and across the blood-brain barrier along with improved protection of the delivered agents or drugs from environmental stress and other detrimental factors (Medina et al., 2003; Hwang et al., 2007; Suri et al., 2007). Dr. Nixdorff pointed out that nanomaterials such as those described by Dr. Ying can serve as “artificial viruses” (Douglas, 2008) to provide targeted delivery of DNA, proteins, and drugs to cells and tissues. These non-viral systems can help overcome some of the safety, manufacturing and immunogenicity issues associated with viral vectors, although transfection efficiency from non-viral systems remains lower than from viral delivery systems.

Targeted delivery may also be employed to deliver bioregulatory molecules such as fentanyl (Wax et al., 2003), insulin (Gunter and Dhand, 2007), oxytocin (Kosfeld et al., 2005) or orexin (Deadwyler et al., 2007), which can alter the functions of physiologic systems and have previously been delivered in aerosols. Given the complexity of biological systems, however, Dr. Nixdorff noted that it was not always possible to predict the effects of such regulators. She pointed to a passage from the 2006 NRC report Globalization, Biosecurity, and the Future of the Life Sciences, which observed that dissemination of bioregulators may be more feasible than in the past due to delivery system advances (NRC, 2006).

Dr. Nixdorff concluded by commenting that the ability to exploit advances in delivery technologies appears most relevant to potential state-sponsored programs due to the need for expertise, funding, and laboratories equipped to design and develop these systems. She noted that States Parties to the BWC and CWC have a responsibility to continue to consider the biosecurity implications of advances in science and technology and highlighted that the scientists developing targeted delivery systems also have a responsibility to consider potential implications of their work. As a result, Dr. Nixdorff expressed concern that education about dual-use issues has not been widely implemented in the life sciences. A great deal of effort by professional organizations and individuals working from the bottom up has been put into drafting and promoting codes of conduct and education programs with the aim of awareness-raising among life scientists about dual-use issues. However, only governments can require and implement education programs through regulations. Therefore, pressure for successful implementation of these programs would be most effective coming from the top as well as from the bottom.

Discussion

Issues raised during the discussion session included the relative barriers to misuse provided by the importance of tacit knowledge in the application of fields such as aerobiology, and the potential window of opportunity, during the current phase of development of these technologies, for the community to consider effectively their potential implications before the relevant knowledge and skills became more widely available.