title: Targeting CD44 expressing cancer cells with anti-CD44 monoclonal antibody improves cellular uptake and antitumor efficacy of liposomal doxorubicin.
abstract: Although liposomes improve the safety and pharmacokinetic properties of free drugs, they have not sufficiently enhanced the therapeutic efficacy compared to them. To address this problem, targeted therapy of tumor cells holds great promise to further enhance therapeutic index and decreases off-target effects compared with non-targeted liposomes. In the context of antibody-mediated targeted cancer therapy, we evaluated the anti-tumor activity and therapeutic efficacy of Doxil, and that of Doxil modified with a monoclonal antibody (mAb) against CD44, which is one of the most well-known surface markers associated with Cancer Stem Cells (CSCs). Flow cytometry analyses and confocal laser scanning microscopy results showed significant enhanced cellular uptake of CD44-targeted Doxil (CD44-Doxil) in CD44-positive C-26 cells compared to Doxil. However, CD44-negative NIH-3T3 cells showed a similar uptake and in vitro cytotoxicity with both CD44-Doxil and non-targeted Doxil. In BALB/c mice bearing C-26 murine carcinoma, CD44-Doxil groups exhibited significantly higher doxorubicin concentration (than Doxil) inside the tumor cells, while their circulation time and distribution profile remained comparable. CD44-Doxil at doses of either 10 or 15 mg/kg resulted in superior tumor growth inhibition and higher inclination to tumor, indicating the potential of anti-CD44 mAb targeting in therapeutic efficacy improvement. This study provides proof-of-principle for actively tumor-targeting concept and merits further investigations.
authors.affiliation: Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran; Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran.
authors.forename: Leila
authors.initials: L
authors.lastname: Arabi
authors.affiliation: Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Badiee
authors.affiliation: Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Mosaffa
authors.affiliation: Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran; Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran. Electronic address: jafarimr@mums.ac.ir.
authors.forename: Mahmoud Reza
authors.initials: MR
authors.lastname: Jaafari
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004339:Drug Compounding; D005260:Female; D018960:Hyaluronan Receptors / Q000276:immunology / Q000378:metabolism*; D018796:Immunoconjugates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D018796:Immunoconjugates; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: CD44; Cancer stem cell; DAPI 2HCL (PubChem CID: 160166); Doxorubicin; Doxorubicin HCl (PubChem CID: 443939); Ethylenediaminetetraacetic acid (PubChem CID: 6049); Glycine (PubChem CID: 750); Isopropanol (PubChem CID: 3776); Ketamine (PubChem CID: 3821); Liposome; Monoclonal antibody; Sucrose (PubChem CID: 5988); Targeted therapy; Xylazine (PubChem CID: 5707)