Cationic poly-L-lysine dendrimer complexes doxorubicin and delays tumor growth in vitro and in vivo

Al-Jamal, Khuloud T, Al-Jamal, Wafa' T, Wang, Julie T-W, Rubio, Noelia, Buddle, Joanna, Gathercole, David, Zloh, Mire and Kostarelos, Kostas (2013) Cationic poly-L-lysine dendrimer complexes doxorubicin and delays tumor growth in vitro and in vivo. ACS Nano, 7 (3). pp. 1905-17. ISSN 1936-086X

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Abstract

We report in this study the complexation of the chemotherapeutic drug doxorubicin (DOX) with the novel sixth-generation cationic poly-l-lysine dendrimer (DM) (MW 8149 kDa), which we previously reported to exhibit systemic antiangiogenic activity in tumor-bearing mice. DOX-DM complexation was confirmed by florescence polarization measurement, proton nuclear magnetic resonance spectroscopy, and molecular modeling. Enhanced penetration of DOX-DM (at 1:10 molar ratio), compared to the free DOX, into prostate 3D multicellular tumor spheroids (MTS) was confirmed by confocal laser scanning microscopy. Furthermore, DOX-DM complexes achieved a significantly higher cytotoxicity in DU145 MTS system compared to the free drug, as shown by growth delay curves. Incubation of MTS with low DOX concentration (1 µM) complexed with DM led to a significant delay in MTS growth compared to untreated MTS or MTS treated with free DOX. DOX-DM complex retention was also achieved in a Calu-6 lung cancer xenograft model in tumor-bearing mice, as shown by live whole animal fluorescence imaging. Therapeutic experiments in B16F10 tumor bearing mice have shown enhanced therapeutic efficacy of DOX when complexed to DM. This study suggests that the cationic poly-l-lysine DM molecules studied here could, in addition to their systemic antiangiogenic property, complex chemotherapeutic drugs such as DOX and improve their accumulation and cytotoxicity into MTS and solid tumors in vivo. Such an approach offers new capabilities for the design of combinatory antiangiogenic/anticancer therapeutics.

Item Type: Article
Uncontrolled Keywords: molecular structure,animals,spheroids, cellular,antineoplastic agents,humans,melanoma, experimental,mice, nude,mice,cell line, tumor,angiogenesis inhibitors,dendrimers,doxorubicin,neoplasms, experimental,nanotechnology,cations,lung neoplasms,polylysine,mice, inbred c57bl,xenograft model antitumor assays,prostatic neoplasms,drug carriers,female,male
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Pure Connector
Date Deposited: 05 Oct 2013 01:54
Last Modified: 16 Oct 2018 17:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/43569
DOI: 10.1021/nn305860k

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