title: Cationic poly-L-lysine dendrimer complexes doxorubicin and delays tumor growth in vitro and in vivo.
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.
authors.affiliation: Nanomedicine Laboratory, Centre for Drug Delivery Research, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom. khuloud.al-jamal@kcl.ac.uk
authors.forename: Khuloud T
authors.initials: KT
authors.lastname: Al-Jamal
authors.forename: Wafa' T
authors.initials: WT
authors.lastname: Al-Jamal
authors.forename: Julie T-W
authors.initials: JT
authors.lastname: Wang
authors.forename: Noelia
authors.initials: N
authors.lastname: Rubio
authors.forename: Joanna
authors.initials: J
authors.lastname: Buddle
authors.forename: David
authors.initials: D
authors.lastname: Gathercole
authors.forename: Mire
authors.initials: M
authors.lastname: Zloh
authors.forename: Kostas
authors.initials: K
authors.lastname: Kostarelos
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D002412:Cations; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D015394:Molecular Structure; D036103:Nanotechnology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011107:Polylysine / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002412:Cations; D050091:Dendrimers; D004337:Drug Carriers; D011107:Polylysine; D004317:Doxorubicin