Cationic Poly-l-lysine Dendrimer Complexes Doxorubicin and Delays Tumor Growth in Vitro and in Vivo
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- 作者：Khuloud T. Al-Jamal ; Wafa鈥?T. Al-Jamal ; Julie T.-W. Wang ; Noelia Rubio ; Joanna Buddle ; David Gathercole ; Mire Zloh ; Kostas Kostarelos
- 刊名：ACS Nano
- 出版年：2013
- 出版时间：March 26, 2013
- 年：2013
- 卷：7
- 期：3
- 页码：1905-1917
- 全文大小：689K
- 年卷期：v.7,no.3(March 26, 2013)
- ISSN：1936-086X
文摘
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鈥揇M complexation was confirmed by florescence polarization measurement, proton nuclear magnetic resonance spectroscopy, and molecular modeling. Enhanced penetration of DOX鈥揇M (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鈥揇M 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 渭M) complexed with DM led to a significant delay in MTS growth compared to untreated MTS or MTS treated with free DOX. DOX鈥揇M 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.