Abstract
Purpose. Delivery of specific antibodies or immunoglobulin constructsto the respiratory tract may be useful for prophylaxis or active treatmentof local or systemic disorders. Therefore, we evaluated the utilityof lipid-based hollow-porous microparticles (PulmoSpheres™) as apotential delivery vehicle for immunoglobulins.
Methods. Lipid-based microparticles loaded with humanimmunoglobulin (hIgG) or control peptide were synthesized by spray drying and testedfor: i) the kinetics of peptide/protein release, using ELISA and bioassays;ii) bioavailability subsequent to nonaqueous liquid instillation into therespiratory tract of BALB/c mice, using ELISA and Western blotting;iii) bioactivity in terms of murine immune response to xenotypic epitopeson human IgG, using ELISA and T cell assays; and iv) mechanismsresponsible for the observed enhancement of immune responses, usingmeasurement of antibodies as well as tagged probes.
Results. Human IgG and the control peptide were both readily releasedfrom the hollow-porous microspheres once added to an aqueousenvironment, although the kinetics depended on the compound. Nonaqueousliquid instillation of hIgG formulated in PulmoSpheres into the upperand lower respiratory tract of BALB/c mice resulted in systemicbiodistribution. The formulated human IgG triggered enhanced local andsystemic immune responses against xenotypic epitopes and wasassociated with receptor-mediated loading of alveolar macrophages.
Conclusions. Formulation of immunoglobulins in hollow-porousmicroparticles is compatible with local and systemic delivery via therespiratory mucosa and may be used as means to trigger or modulateimmune responses.
Article PDF
Similar content being viewed by others
REFERENCES
R. M. Chanock, R. H. Parrott, M. Connors, P. L. Collins, and B. R. Murphy. Serious respiratory tract disease caused by respiratory syncytial virus: prospects for improved therapy and effective immunization. Pediatrics 90:137-143 (1992).
T. Sawa, T. L. Yahr, M. Ohara, K. Kurahasi, M. A. Gropper, J. P. Wiener-Kronish, and D. W. Frank. Active and passive immunization with the Pseudomonas V antigen protects against type III intoxication and lung injury. Nat. Med. 5:392-398 (1999).
F. Ramisse, F. X. Deramoudt, M. Szatanik, A. Bianchi, P. Binder, and C. Hannoun. Effective prophylaxis of influenza A virus pneumonia in mice by topical passive immunotherapy with polyvalent human immunoglobulins or F(ab´)2 fragments. Clin. Exp. Immunol. 111:583-587 (1998).
R. Pirker. Immunotoxins against solid tumors. J. Cancer. Res. Clin. Oncol. 114:385-393 (1988).
A. Biragyn, K. Tani, M. C. Grimm, S. Weeks, and L. W. Kwak. Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity. Nat. Biotech. 17:253-258 (1999).
G. Bergers, K. Javaherian, K.-M. Lo, J. Folkman, and D. Hanahan. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284:808-812 (1999).
P. Lanza, R. Billetta, S. Antonenko, and M. Zanetti. Active immunity against the CD4 receptor by using an antibody antigenized with residues 41-55 of the first extracellular domain. Proc. Natl. Acad. Sci. USA 90:11683-11687 (1993).
H. Zaghouani, R. Steinman, R. Nonacs, H. Shah, W. Gerhard, and C. Bona. Presentation of a viral T cell epitope expressed in the CDR3 region of a self immunoglobulin molecule. Science 259:224-227 (1993).
T. D. Brumeanu, A. Bot, C. A. Bona, P. Dehazya, I. Wolf, and H. Zaghouani. Engineering of doubly antigenized immunoglobulins expressing T and B viral epitopes. Immunotechnology 2: 85-95 (1996).
B. Min, K. L. Legge, C. Pack, and H. Zaghouani. Neonatal exposure to a self-peptide-immunoglobulin chimera circumvents the use of adjuvant and confers resistance to autoimmune disease by a novel mechanism involving interleukin 4 lymph node deviation and interferon gamma-mediated splenic anergy. J. Exp. Med. 188:2007-2017 (1998).
P. A. Rota, B. K. De, M. W. Shaw, R. A. Black, W. C. Gamble, and A. P. Kendal. Comparison of inactivated, live and recombinant DNA vaccines against influenza virus in a mouse model. Virus Res. 16:83-94 (1990).
J. Stein-Streilein, M. Bennet, D. Mann, and V. Kumar. NK cells in mouse lung: surface, phenotype, target preference, and response to local influenza virus infection. J. Immunol. 131:2699-2704 (1983).
A. Bot, S. Bot, and C. A. Bona. Protective role of gamma interferon during the recall response to influenza virus. J. Virol. 72:6637-6645 (1998).
W. Allan, Z. Tabi, A. Cleary, and P. C. Doherty. Cellular events in the lymph node and lung of mice infected with influenza. Consequences of depleting CD4+ T cells. J. Immunol. 144:3980-3986 (1990).
A. Bot, S. Bot, S. Antohi, K. Karjalainen, and C. Bona. Kinetics of generation and persistance on membrane class II molecules of a viral peptide expressed on foreign and self proteins. J. Immunol. 157:3436-3442 (1996).
S. Prokhorova, N. Lavnikova, and D. L. Laskin. Functional characterization of interstitial macrophages and subpopulations of alveolar macrophages from rat lung. J. Leukoc. Biol. 55: 141-146 (1994).
H. Sakakibara, K. Shima, and S. I. Said. Characterization of vasoactive intestinal peptide receptors on rat alveolar macrophages. Am. J. Physiol. 267:L256-262 (1994).
L. Kobzik, S. Huang, J. D. Paulauskis, and J. J. Godleski. Particle opsonization and lung macrophage cytokine response. In vitro and in vivo analysis. J. Immunol. 151:2753-2759.
C. R. Lyons, and M. F. Lipscomb. Alveolar macrophages in pulmonary immune responses. I. Role in the initiation of primary immune responses and in the selective recruitment of T lymphocytes to the lung. J. Immunol. 130:1113-1119 (1983).
J. W. Upham, D. H. Strickland, B. W. Robinson, and P. G. Holt. Selective inhibition of T cell proliferation but not expression function by human alveolar macrophages. Thorax 52:786-795 (1997).
G. C. Kindt, J. G. van de Winkel, S. A. Moore, and C. L. Anderson. Identification and structural characterization of Fc gamma receptors on pulmonary alveolar macrophages. Am. J. Physiol. 260:L403-411 (1991).
D. A. Edwards, J. Hanes, G. Caponetti, J. Hrkach, A. Ben-Jebria, M. L. Eskew, J. Mintzes, D. Deaver, N. Lothan, and R. Langer. Large porous particles for pulmonary drug delivery. Science 276:1868-1871 (1997).
A. Ben-Jebria, D. Chen, M. L. Eskew, R. Vanbever, R. Langer, and D. A. Edwards. Large porous particles for sustained protection from carbachol-induced bronchoconstriction in guinea pigs. Pharm. Res. 16:555-561 (1999).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bot, A.I., Tarara, T.E., Smith, D.J. et al. Novel Lipid-Based Hollow-Porous Microparticles as a Platform for Immunoglobulin Delivery to the Respiratory Tract. Pharm Res 17, 275–283 (2000). https://doi.org/10.1023/A:1007544804864
Issue Date:
DOI: https://doi.org/10.1023/A:1007544804864