title: Anti-metastatic effects of RAPTA-C conjugated polymeric micelles on two-dimensional (2D) breast tumor cells and three-dimensional (3D) multicellular tumor spheroids.
abstract: Macromolecular ruthenium (Ru) complexes are a promising avenue to better, and more selective, chemotherapeutics to treat metastatic cancers. In our previous research, amphiphilic block copolymeric micelles carrying RAPTA-C (RuCl2(p-cymene)(PTA)) were demonstrated to improve the cellular uptake and cytotoxicity of RAPTA-C (Blunden et al., 2013). However, the anti-metastatic effect of RAPTA-C conjugated polymeric micelles is yet to be established. In this work, we investigated the anti-metastatic effects of RAPTA-C conjugated micelles in both 2D and 3D in vitro breast tumor cell models in comparison with free RAPTA-C. RAPTA-C conjugated micelles showed an improved anti-metastatic effect compared with RAPTA-C for 2D cultured breast tumor cells. RAPTA-C micelles selectively targeted the metastatic tumor cells over the nontumorigenic CHO cells. 3D MCTS assays showed that RAPTA-C conjugated micelles showed a cell growth inhibition similar to that of ten times of the free drug. Further improvement of the RAPTA-C delivery vehicle may provide useful tools to harness ruthenium compounds for metastatic cancer therapy.
  
  
  CONCLUSIONS
  The interest in ruthenium drugs stem from their anti-metastatic effect. In contrast to other metal-based drugs that inhibit the growth of tumor cells, ruthenium drugs seem less toxic, but have a pronounce effect on the migration of cancer cells. The ruthenium drug chosen here, RAPTA-C, is capable of inhibiting migration as shown in various assays here. In this publication, we could show for the first time that this effect is enhanced when the drug is delivered using micelles. Important in particular is that the effect is more pronounced in cancerous breast cancer cells while RAPTA-C delivered in micelles does not seem to show any effect on healthy cells. We believe that the presented micelles are suitable carriers for this anti-metastatic drug. The design of the micelle would also allow the encapsulation of other drugs in future studies creating a potentially powerful bullet.
authors.affiliation: Centre for Advanced Macromolecular Design (CAMD), School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Hongxu
authors.initials: H
authors.lastname: Lu
authors.affiliation: Centre for Advanced Macromolecular Design (CAMD), School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia; Cooperative Research Centre (CRC) for Polymers, 8 Redwood Drive, Notting Hill, Victoria 3618, Australia.
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Blunden
authors.affiliation: Centre for Advanced Macromolecular Design (CAMD), School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Scarano
authors.affiliation: Centre for Advanced Macromolecular Design (CAMD), School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Lu
authors.affiliation: Centre for Advanced Macromolecular Design (CAMD), School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: M.stenzel@unsw.edu.au.
authors.forename: Martina H
authors.initials: MH
authors.lastname: Stenzel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018929:Cell Culture Techniques / Q000379:methods*; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D000081007:Cymenes; D005260:Female; D006801:Humans; D008823:Micelles; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D011108:Polymers / Q000737:chemistry*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D000081007:Cymenes; D008823:Micelles; D009942:Organometallic Compounds; D011108:Polymers; C530402:dichloro(4-cymene)(1,3,5-triaza-7-phosphatricyclo(3.3.1.1)decane)ruthenium(II)
keywords: Micelles; Multicellular tumor spheroids; Ruthenium drugs; Tumor metastasis