Conjugation to Poly(amidoamine) Dendrimers and Pulmonary Delivery Reduce Cardiac Accumulation and Enhance Antitumor Activity of Doxorubicin in Lung Metastasis
Open accessAbstract
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.
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DOX conjugated dendrimers, when administered to mice bearing melanoma (B16-F10), reduced tumor burden through enhanced accumulation and tumor penetration.
“These DOX conjugated dendrimers, when administered to mice bearing melanoma (B16-F10), reduced the tumor burden through enhanced accumulation and tumor penetration.”
From Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles (2019) · cites this paper as [244]
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Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles
Singh, A. P., Biswas, A., Shukla, A., & Maiti, P. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0068-3 · Cited by 645 · see citing works
- Authors
- Zhong, Q., Bielski, E. R., Rodrigues, L. S., Brown, M. R., Reineke, J. J., & da Rocha, S. R. P.
- Affiliations
- Wayne State University (US)
- South Dakota State University (US)
- Department of Chemical Engineering and Materials Science, College of Engineering, Wayne State University, 5050 Anthony Wayne Drive, Detroit, Michigan 48202, United States
- Venue
- Molecular Pharmaceutics
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-06-10
- Volume
- 13
- Issue
- 7
- Pages
- 2363-2375
- ISSN
- 1543-8384 (ISSN-L)
- 1543-8392
- PMC
- PMC6886243
- OpenAlex
- W2415245575
- Cited by
- 88
- References
- 80
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 10 · 2023: 11 · 2022: 9 · 2021: 9 · 2020: 14 · 2019: 9 · 2018: 6 · 2017: 14 · 2016: 1
- FWCI
- 6.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Pharmaceutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Division of Chemical, Bioengineering, Environmental, and Transport Systems (CBET-0933144)
- Wayne State University
- Division of Materials Research (DMR-1508363)
- Topics
- Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Keywords
- doxorubicin, PAMAM dendrimers, lung metastasis, pulmonary drug delivery, melanoma, B16F10, tissue distribution, nanocarriers, anticancer activity, systemic toxicity, drug conjugation
- MeSH terms
- Animals, Doxorubicin, Lung, Lung Neoplasms, Male, Melanoma, Mice, Inbred C57BL, Drug Delivery Systems, Cell Line, Tumor, Dendrimers, Mice
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