title: CD133-targeted paclitaxel delivery inhibits local tumor recurrence in a mouse model of breast cancer.
abstract: Expression of the membrane protein CD133 marks a subset of cancer cells with drug resistant phenotype and enhanced tumor initiating ability in xenotransplantation assays. Because drug resistance and tumor relapse are significant problems, approaches to eliminate these cells are urgently needed. As a step towards achieving this goal, we developed polymeric nanoparticles targeting CD133 by conjugating an anti-CD133 monoclonal antibody to nanoparticles formulated using poly(D,L lactide-co-glycolide) polymer. Nanoparticles were loaded with paclitaxel, a microtubule-stabilizing anticancer agent, as well as with 6-coumarin, a fluorescent probe. CD133-targeted nanoparticles (CD133NPs) were efficiently internalized by Caco-2 cells, which abundantly express CD133 (>9-fold higher uptake than non-targeted control nanoparticles). The effectiveness of CD133NPs in reducing tumor initiating cell (TIC) fraction was investigated using mammosphere formation and soft-agar colony formation assays. Free paclitaxel treatment was not effective in decreasing the TIC population relative to untreated control, whereas CD133NPs effectively decreased the number of mammospheres and colonies formed. In vivo studies in the MDA-MB-231 xenograft model showed that free paclitaxel was initially effective in inhibiting tumor growth but the tumors rebounded rapidly once the treatment was stopped. Tumor regrowth was significantly lower when paclitaxel was delivered through CD133NPs (tumor volume was 518.6±228 vs. 1370.9±295mm(3) for free paclitaxel at 63days; P<0.05). Our studies thus show that encapsulation of paclitaxel in CD133NPs results in a significant decrease in the TIC population and improved therapeutic efficacy compared to that with free paclitaxel treatment. These results indicate the potential of targeting anticancer therapeutics to CD133+ cells for reducing tumor recurrence.
authors.affiliation: Department of Pharmaceutics, The University of Minnesota, Minneapolis 55455, USA.
authors.forename: Suresh Kumar
authors.initials: SK
authors.lastname: Swaminathan
authors.forename: Emilie
authors.initials: E
authors.lastname: Roger
authors.forename: Udaya
authors.initials: U
authors.lastname: Toti
authors.forename: Lin
authors.initials: L
authors.lastname: Niu
authors.forename: John R
authors.initials: JR
authors.lastname: Ohlfest
authors.forename: Jayanth
authors.initials: J
authors.lastname: Panyam
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D055910:Antibodies, Immobilized / Q000737:chemistry* / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010455:Peptides / Q000276:immunology*
chemical_list: D000071916:AC133 Antigen; D055910:Antibodies, Immobilized; D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D017239:Paclitaxel
keywords: Cancer initiating cells; Cancer stem cells; Polymeric nanoparticles; Sustained release; Targeted delivery