Expression of themembrane protein CD133marks 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. Nanoparticleswere loadedwith 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) fractionwas investigated usingmammosphere formation and soft-agar colony formation assays. Free paclitaxel treatmentwas not effective in decreasing the TIC population relative to untreated control, whereas CD133NPs effectively decreased the number ofmammospheres and colonies formed. In vivo studies in the MDA-MB-231 xenograftmodel 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 lowerwhen paclitaxel was delivered through CD133NPs (tumor volume was 518.6 ± 228 vs. 1370.9 ± 295 mm3 for free paclitaxel at 63 days; 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.
Bibliographical noteFunding Information:
We thank the following people at the University of Minnesota: Brenda Koniar and Steve Kalscheuer for help with animal studies; Dr. Deepali Sachdev for help with soft agar colony assay protocol; Colleen Forster for assistance with immunohistochemistry; Dr. David Largaespada for allowing us to use the hematology analyzer. We thank the flow cytometry core facility and the Biological Image Processing Laboratory at the University of Minnesota for their assistance. Funding from Randy Shaver foundation is gratefully acknowledged.
- Cancer initiating cells
- Cancer stem cells
- Polymeric nanoparticles
- Sustained release
- Targeted delivery