title: Conjugation to Poly(amidoamine) Dendrimers and Pulmonary Delivery Reduce Cardiac Accumulation and Enhance Antitumor Activity of Doxorubicin in Lung Metastasis.
abstract: Lung is one of the most common sites to which almost all other primary tumors metastasize. The major challenges in the chemotherapy of lung metastases include the low drug concentration found in the tumors and high systemic toxicity upon systemic administration. In this study, we combine local lung delivery and the use of nanocarrier-based systems for improving pharmacokinetics and biodistribution of the therapeutics to fight lung metastases. We investigate the impact of the conjugation of doxorubicin (DOX) to carboxyl-terminated poly(amidoamine) dendrimers (PAMAM) through a bond that allows for intracellular-triggered release, and the effect of pulmonary delivery of the dendrimer-DOX conjugate in decreasing tumor burden in a lung metastasis model. The results show a dramatic increase in efficacy of DOX treatment of the melanoma (B16-F10) lung metastasis mouse model upon pulmonary administration of the drug, as indicated by decreased tumor burden (lung weight) and increased survival rates of the animals (male C57BL/6) when compared to iv delivery. Conjugation of DOX further increased the therapeutic efficacy upon lung delivery as indicated by the smaller number of nodules observed in the lungs when compared to free DOX. These results are in agreement with the biodistribution characteristics of the DOX upon pulmonary delivery, which showed a longer lung accumulation/retention compared to iv administration. The distribution of DOX to the heart tissue is also significantly decreased upon pulmonary administration, and further decreased upon conjugation. The results show, therefore, that pulmonary administration of DOX combined to conjugation to PAMAM dendrimer through an intracellular labile bond is a potential strategy to enhance the therapeutic efficacy and decrease systemic toxicity of DOX.
authors.affiliation: Department of Chemical Engineering and Materials Science, College of Engineering, Wayne State University , 5050 Anthony Wayne Drive, Detroit, Michigan 48202, United States.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Department of Chemical Engineering and Materials Science, College of Engineering, Wayne State University , 5050 Anthony Wayne Drive, Detroit, Michigan 48202, United States.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Bielski
authors.affiliation: Department of Chemical Engineering and Materials Science, College of Engineering, Wayne State University , 5050 Anthony Wayne Drive, Detroit, Michigan 48202, United States.
authors.forename: Leonan S
authors.initials: LS
authors.lastname: Rodrigues
authors.affiliation: Department of Chemical Engineering and Materials Science, College of Engineering, Wayne State University , 5050 Anthony Wayne Drive, Detroit, Michigan 48202, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Brown
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University , Brookings, South Dakota 57007, United States.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Reineke
authors.affiliation: Department of Chemical Engineering and Materials Science, College of Engineering, Wayne State University , 5050 Anthony Wayne Drive, Detroit, Michigan 48202, United States.|Department of Pharmaceutics, College of Pharmacy, and Department of Chemical and Life Science Engineering, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Sandro R P
authors.initials: SR
authors.lastname: da Rocha
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry*; D004317:Doxorubicin / Q000737:chemistry* / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D050091:Dendrimers; C104700:PAMAM Starburst; D004317:Doxorubicin
keywords: Polyamidoamine dendrimer; cardiac toxicity; controlled intracellular release; doxorubicin; lung cancer; pulmonary delivery