Characterization of high-affinity peptides and their feasibility for use in nanotherapeutics targeting leukemia stem cells

Zhang, Hongyong; Luo, Juntao; Li, Yuanpei; Henderson, Paul T.; Wang, Yanchun; Wachsmann-Hogiu, Sebastian; Zhao, Weixin; Lam, Kit S.; Pan, Chong-xian

doi:10.1016/j.nano.2011.12.004

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Characterization of high-affinity peptides and their feasibility for use in nanotherapeutics targeting leukemia stem cells

Hongyong Zhang, DVM, PhD
- Department of Internal Medicine, Division of Hematology/Oncology, University of California at Davis, Sacramento, California
Juntao Luo, PhD
- Department of Biochemistry and Molecular Medicine, University of California–Davis, Sacramento, California
Yuanpei Li, PhD
- Department of Biochemistry and Molecular Medicine, University of California–Davis, Sacramento, California
Paul T. Henderson, PhD
- Department of Internal Medicine, Division of Hematology/Oncology, University of California at Davis, Sacramento, California
Yanchun Wang, PhD
- Department of Internal Medicine, Division of Hematology/Oncology, University of California at Davis, Sacramento, California
Sebastian Wachsmann-Hogiu, PhD
- Center for Biophotonics Science and Technology, University of California–Davis, Sacramento, California
Weixin Zhao, MD, PhD
- Shanghai Cancer Hospital, Fudan University, Shanghai, China
Kit S. Lam, MD, PhD
- Department of Internal Medicine, Division of Hematology/Oncology, University of California at Davis, Sacramento, California
- Department of Biochemistry and Molecular Medicine, University of California–Davis, Sacramento, California
Chong-xian Pan, MD, PhD
- Department of Internal Medicine, Division of Hematology/Oncology, University of California at Davis, Sacramento, California
- Department of Urology, University of California–Davis, Sacramento, California
- VA Northern California Health Care System, Mather, California
- Corresponding author: University of California–Davis Cancer Center, 4501 X Street, Room 3016, Sacramento, California 95817, USA.

Received 21 February 2011; accepted 11 December 2011. published online 26 December 2011.
Corrected Proof

Abstract

Peptides featuring the LR(S/T) motif were identified that could specifically bind to the C-type lectin-like molecule-1 (CLL1), a protein preferentially expressed on acute myeloid leukemia stem cells (LSCs). Micellar nanoparticles were covalently decorated with CLL1-targeting peptides for targeted drug delivery. The resulting peptide-coated nanoparticles were 13.5 nm in diameter and could be loaded with 5 mg of daunorubicin per 20 mg of telodendrimers. These “targeting nanomicelles” transported the drug load to the interior of cells expressing CLL1 and to LSCs isolated from clinical specimens in vitro, but did not bind to normal blood or normal hematopoietic stem cells. The presence of CLL1-targeting peptides on the surface of the nanomicelles enabled the improved binding and delivery of substantially more daunorubicin into the cells expressing CLL1 and CD34⁺ leukemic cells compared with unmodified nanomicelles. In conclusion, nanomicelles coated with CLL1-targeting peptides are potentially useful for eradicating LSCs and improving leukemia therapy.

Graphical Abstract

A chemotherapeutic drug, drug combinations and/or radioisotopes are loaded inside nanomicelles. Targeting ligands against leukemia stem cell (LSC) surface molecules are decorated on the surface of nanomicelles. After intravenous administration, these targeting nanomicelles can specifically deliver high-concentration therapeutic agents to and eradicate LSC. In addition, the therapeutic agents can diffuse into blood circulation to kill leukemic cells throughout the body. Furthermore, formulation of chemotherapeutic drugs in nanomicelles can decrease therapy-related toxicity and improve treatment outcomes.