Targeting NCAM-expressing neuroblastoma with polymeric precision nanomedicine.
Neural cell adhesion molecule (NCAM) expression is known to be associated with an aggressive biological behavior, increased metastatic capacity and expression of stem-cell markers in several tumor types. NCAM was also found to be expressed on tumor endothelial cells while forming new capillary-like tubes, but not on normal endothelial cells. An NCAM-targeted polymer-drug conjugate can be used both to target tumors expressing high levels of NCAM as well as the angiogenic vessels and cancer stem cells populations characterized by NCAM expression within tumors. Here, we describe the design, synthesis, physico-chemical characterization and the biological evaluation of an NCAM-targeted conjugate of polyglutamic acid with paclitaxel that was developed and evaluated on neuroblastoma, a high NCAM-expressing tumor. This conjugate inhibited tumor growth to a higher extent compared to the control conjugates and was less toxic than free paclitaxel. The dose of the conjugate could be increased at least twice than the maximum tolerated dose of paclitaxel to achieve better activity without aggravating toxicity. This work presents evidence that NCAM targeting can highly increase the efficacy of nanomedicines in the appropriate tumor models.
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Ela
E
Markovsky
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Anat
A
Eldar-Boock
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Dikla
D
Ben-Shushan
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Hemda
H
Baabur-Cohen
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Eilam
E
Yeini
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Evgeni
E
Pisarevsky
Lis Maternity Hospital, Sourasky Medical Center, Tel Aviv, Israel.
Ariel
A
Many
Department of Pathology, Sheba Medical Center, Tel Hashomer 52621, Israel; Talpiot Medical Leadership Program, Sheba Medical Center, Tel Hashomer 52621, Israel.
Sarit
S
Aviel-Ronen
Department of Pathology, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler School of Medicine,Tel Aviv University, Tel Aviv 69978, Israel.
Iris
I
Barshack
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: ronitsf@post.tau.ac.il.
Ronit
R
Satchi-Fainaro
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016513:Mice, SCID; D050997:Nanomedicine; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011099:Polyglutamic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use
D000970:Antineoplastic Agents; D004337:Drug Carriers; D019006:Neural Cell Adhesion Molecules; D010455:Peptides; D011099:Polyglutamic Acid; D017239:Paclitaxel; C509139:paclitaxel poliglumex
Neural cell adhesion molecule; Neuroblastoma; Paclitaxel; Polyglutamic acid; Polymer-drug conjugates; Polymeric nanomedicines