1. Cationic poly-L-lysine dendrimer complexes doxorubicin and delays tumor growth in vitro and in vivo
- Author
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Khuloud T. Al-Jamal, Joanna Buddle, Noelia Rubio, Wafa' T Al-Jamal, David Gathercole, Kostas Kostarelos, Julie Tzu-Wen Wang, and Mire Zloh
- Subjects
Male ,Dendrimers ,Materials science ,Lung Neoplasms ,Stereochemistry ,Melanoma, Experimental ,General Physics and Astronomy ,Mice, Nude ,Angiogenesis Inhibitors ,Antineoplastic Agents ,macromolecular substances ,chemistry.chemical_compound ,Mice ,DU145 ,In vivo ,Dendrimer ,Cations ,Cell Line, Tumor ,Spheroids, Cellular ,polycyclic compounds ,medicine ,Animals ,Humans ,Nanotechnology ,General Materials Science ,Doxorubicin ,Polylysine ,Cytotoxicity ,Drug Carriers ,Molecular Structure ,General Engineering ,Prostatic Neoplasms ,Neoplasms, Experimental ,Xenograft Model Antitumor Assays ,In vitro ,carbohydrates (lipids) ,Mice, Inbred C57BL ,chemistry ,Biophysics ,Female ,Drug carrier ,medicine.drug - 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.
- Published
- 2013