Lanthanide-doped nanoparticles conjugated with an anti-CD33 antibody and a p53-activating peptide for acute myeloid leukemia therapy.

Abstract

Roughly one third of all human cancers are attributable to the functional inhibition of the tumor suppressor protein p53 by its two negative regulators MDM2 and MDMX, making dual-specificity peptide antagonists of MDM2 and MDMX highly attractive drug candidates for anticancer therapy. Two pharmacological barriers, however, remain a major obstacle to the development of peptide therapeutics: susceptibility to proteolytic degradation in vivo and inability to traverse the cell membrane. Here we report the design of a fluorescent lanthanide oxyfluoride nanoparticle (LONp)-based multifunctional peptide drug delivery system for potential treatment of acute myeloid leukemia (AML) that commonly harbors wild type p53, high levels of MDM2 and/or MDMX, and an overexpressed cell surface receptor, CD33. We conjugated to LONp via metal-thiolate bonds a dodecameric peptide antagonist of both MDM2 and MDMX, termed PMI, and a CD33-targeted, humanized monoclonal antibody to allow for AML-specific intracellular delivery of a stabilized PMI. The resultant nanoparticle antiCD33-LONp-PMI, while nontoxic to normal cells, induced apoptosis of AML cell lines and primary leukemic cells isolated from AML patients by antagonizing MDM2 and/or MDMX to activate the p53 pathway. Fluorescent antiCD33-LONp-PMI also enabled real-time visualization of a series of apoptotic events in AML cells, proving a useful tool for possible disease tracking and treatment response monitoring. Our studies shed light on the development of antiCD33-LONp-PMI as a novel class of antitumor agents, which, if further validated, may help targeted molecular therapy of AML.

• Authors: Fan Niu, Jin Yan, Bohan Ma, Shichao Li, Yongping Shao, Pengcheng He, Wanggang Zhang, Wangxiao He, Peter X Ma, Wuyuan Lu
• Journal: Biomaterials (Biomaterials) Vol. 167 Pg. 132-142 (06 2018) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 29571049 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Antineoplastic Agents, Immunological
• CD33 protein, human
• Lanthanoid Series Elements
• Nanoconjugates
• Peptides
• Sialic Acid Binding Ig-like Lectin 3
• Tumor Suppressor Protein p53

Topics

• Antibodies, Monoclonal (administration & dosage, pharmacology)
• Antineoplastic Agents (administration & dosage, pharmacology)
• Antineoplastic Agents, Immunological (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Drug Delivery Systems
• Humans
• Lanthanoid Series Elements (chemistry)
• Leukemia, Myeloid, Acute (drug therapy)
• Models, Molecular
• Nanoconjugates (chemistry)
• Peptides (administration & dosage, pharmacology)
• Sialic Acid Binding Ig-like Lectin 3 (antagonists & inhibitors)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (agonists)