Daniela I Staquicini1,2,3, E Magda Barbu4,3, Rachel L Zemans5, Beth K Dray6,7, Fernanda I Staquicini1,8, Prashant Dogra9, Marina Cardó-Vila10,11,12, Cindy K Miranti10,12, Wallace B Baze6, Luisa L Villa13,14, Jorge Kalil15,16, Geetanjali Sharma17,18, Eric R Prossnitz17,18, Zhihui Wang9, Vittorio Cristini9,19,20, Richard L Sidman21, Andrew R Berman22, Reynold A Panettieri23, Rubin M Tuder24, Renata Pasqualini1,2,25,26, Wadih Arap1,27,25. 1. Rutgers Cancer Institute of New Jersey, Newark, NJ 07103, USA. 2. Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA. 3. These authors equally contributed to this work. 4. David H. Koch Center, Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. 5. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA. 6. Michale E. Keeling Center for Comparative Medicine and Research, Department of Comparative Medicine, The University of Texas M. D. Anderson Cancer Center, Bastrop, TX 78602, USA. 7. Current address: Charles River Laboratories, Ashland, OH, USA. 8. Current address: MBrace Therapeutics, Summit, NJ, USA. 9. Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA. 10. The University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA. 11. Department of Otolaryngology - Head & Neck Surgery, University of Arizona College of Medicine, Tucson, AZ 85724, USA. 12. Department of Cellular and Molecular Medicine, University of Arizona College of Medicine, Tucson, AZ 85724, USA. 13. Cancer Institute of São Paulo, University of São Paulo Medical School, São Paulo, SP 01246, Brazil. 14. Department of Radiology and Medical Oncology, University of São Paulo Medical School, São Paulo, SP 01246, Brazil. 15. Laboratory of Immunology, Heart Institute, University of São Paulo Medical School, São Paulo, SP 05403, Brazil. 16. Division of Clinical Immunology and Allergy, Department of Medicine, University of São Paulo Medical School, São Paulo, SP 05403, Brazil. 17. University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131, USA. 18. Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. 19. Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77230, USA. 20. Department of Nanomedicine, Methodist Hospital Research Institute, Houston, TX 77030, USA. 21. Department of Neurology, Harvard Medical School, Boston, MA 02115, USA. 22. Division of Pulmonary, Critical Care Medicine, Allergy & Rheumatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA. 23. Rutgers Institute for Translational Medicine and Science, New Brunswick, NJ 08901, USA. 24. Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. 25. These authors jointly supervised this work. 26. Lead contact. 27. Division of Hematology/Oncology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
Abstract
BACKGROUND: The extensive alveolar capillary network of the lungs is an attractive route for administration of several agents. One key functional attribute is the rapid onset of systemic action due to the absence of first-pass metabolism. METHODS: Here we applied a combinatorial approach for ligand-directed pulmonary delivery as a unique route for systemic targeting in vaccination. FINDINGS: We screened a phage display random peptide library in vivo to select, identify, and validate a ligand (CAKSMGDIVC) that specifically targets and is internalized through its receptor, α3β1 integrin, on the surface of cells lining the lung airways and alveoli and mediates CAKSMGDIVC-displaying phage binding and systemic delivery without compromising lung homeostasis. As a proof-of-concept, we show that the pulmonary delivery of targeted CAKSMGDIVC-displaying phage particles in mice and non-human primates elicit a systemic and specific humoral response. CONCLUSIONS: This broad methodology blueprint represents a robust and versatile platform tool enabling new ligand-receptor discovery with many potential translational applications. FUNDING: Cancer Center Support Grants to the University of Texas M.D. Anderson Cancer Center (CA016672), University of New Mexico Comprehensive Cancer Center (CA118100), Rutgers Cancer Institute of New Jersey (CA072720), research awards from the Gillson Longenbaugh Foundation, and National Institutes of Health (NIH) grant no. 1R01CA226537.
BACKGROUND: The extensive alveolar capillary network of the lungs is an attractive route for administration of several agents. One key functional attribute is the rapid onset of systemic action due to the absence of first-pass metabolism. METHODS: Here we applied a combinatorial approach for ligand-directed pulmonary delivery as a unique route for systemic targeting in vaccination. FINDINGS: We screened a phage display random peptide library in vivo to select, identify, and validate a ligand (CAKSMGDIVC) that specifically targets and is internalized through its receptor, α3β1 integrin, on the surface of cells lining the lung airways and alveoli and mediates CAKSMGDIVC-displaying phage binding and systemic delivery without compromising lung homeostasis. As a proof-of-concept, we show that the pulmonary delivery of targeted CAKSMGDIVC-displaying phage particles in mice and non-human primates elicit a systemic and specific humoral response. CONCLUSIONS: This broad methodology blueprint represents a robust and versatile platform tool enabling new ligand-receptor discovery with many potential translational applications. FUNDING: Cancer Center Support Grants to the University of Texas M.D. Anderson Cancer Center (CA016672), University of New Mexico Comprehensive Cancer Center (CA118100), Rutgers Cancer Institute of New Jersey (CA072720), research awards from the Gillson Longenbaugh Foundation, and National Institutes of Health (NIH) grant no. 1R01CA226537.
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