UCL - Pulmonary Drug Delivery

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Medical Sector

LOUVAIN DRUG RESEARCH INSTITUTE (LDRI)

> UCL > SECTORS > Medical Sector > Louvain Drug Research Institute > Research Groups > Advanced Drug Delivery and Biomaterials

(ADDB) > Research themes and objectives > Pulmonary Drug Delivery

Pulmonary Drug Delivery

The research aims at improving the treatment or prophylaxis of severe respiratory diseases by delivering locally therapeutic
proteins, small molecular weight drugs and vaccines as well as by developing formulation strategies to enhance their local
efficacy. Our approaches include i) the formulation of dry powder aerosols with good aerosolization properties, ii) the use of
particular excipients or adjuvants, iii) the understanding of the fate of pulmonary delivered molecules.
Dry powder aerosols have been prepared by spray-drying using excipients that are either approved for inhalation as lactose
and mannitol or, endogenous to the lungs as dipalmitoylphosphatidylcholine, albumin and amino acids. By properly choosing
spray-drying parameters and excipient composition, we formulated dry powders with good aerosolization properties and high
fine particle fractions. These powders were shown to enable the pulmonary delivery of therapeutic peptides and proteins
with good efficacy in vivo in the rat.
We study the fate of molecules differing in their physico-chemical properties in the lungs of rodents in vivo in order to
identify parameters and choose formulation strategies that could direct their fate in preferential pathways (Figure 1). In this
regard, we demonstrated that a primary source of elimination of macromolecules following delivery to the lung and prior to
absorption into the bloodstream owed to clearance by alveolar macrophages. Depletion of alveolar macrophages by
liposome-encapsulated dichloromethylene diphosphonate caused several-fold enhancement in systemic absorption of
immunoglobulin G and human chorionic gonadotropin following intratracheal instillation in rats. Large proteins are slowly
transported across the alveolo-capillary barrier and can remain within the airspaces for several hours. This gives time to
alveolar macrophages to engulf them by pinocytosis or cell drinking, the uptake of fluids and soluble compounds. In
contrast to large proteins, no increase in pulmonary absorption of the peptide insulin and of the small protein human growth
hormone was associated with the depletion of alveolar macrophages. Insulin and growth hormone remained in the airspaces
for less than one hour in rats, indicating that these compounds crossed the alveolar epithelium quickly, presumably
preventing major uptake and degradation by alveolar macrophages.

Figure 1. Schematic view of the fate of drugs in the lungs

We investigate the potential of pulmonary vaccination for protection against respiratory pathogens such as influenza virus
and Mycobacterium tuberculosis. We showed that the site of deposition of vaccine antigens within the lung strongly
impacted immune responses with the deeper the deposition within the lung, the stronger the immune response. If one
would like to consider the pulmonary route for delivery of recombinant antigens, one needs to identify safe adjuvants able
to properly orientate immune responses towards protection. Therefore, we assessed the efficacy and safety of different
adjuvants and showed that CpG oligonucleotide and monophosphoryl lipid A were able to promote a Th1-bias immune
response without significant toxicity to the lungs.
Based on the expertise gained on pulmonary vaccination, we currently assess the potential of pulmonary vaccination for
immunotherapy of lung cancer. In addition, new delivery strategies are tested for improving the local delivery of small
molecule and biotech drugs.

10/28/2014 10:45 PM

UCL - Pulmonary Drug Delivery

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http://www.uclouvain.be/en-449742.html

| 24/10/2013 |

10/28/2014 10:45 PM