title: Hyaluronic acid-serum albumin conjugate-based nanoparticles for targeted cancer therapy.
abstract: Multiple carcinomas including breast, ovarian, colon, lung and stomach cancer, overexpress the hyaluronic acid (HA) receptor, CD44. Overexpression of CD44 contributes to key cancer processes including tumor invasion, metastasis, recurrence, and chemoresistance. Herein, we devised novel targeted nanoparticles (NPs) for delivery of anticancer chemotherapeutics, comprised of self-assembling Maillard reaction-based conjugates of HA and bovine serum albumin (BSA). HA served as the hydrophilic block, and as the ligand for actively targeting cancer cells overexpressing CD44. We demonstrate that Maillard reaction-based covalent conjugates of BSA-HA self-assemble into NPs, which efficiently entrap hydrophobic cytotoxic drugs including paclitaxel and imidazoacridinones. Furthermore, BSA-HA conjugates stabilized paclitaxel and prevented its aggregation and crystallization. The diameter of the NPs was < 15 nm, thus enabling CD44 receptor-mediated endocytosis. These NPs were selectively internalized by ovarian cancer cells overexpressing CD44, but not by cognate cells lacking this HA receptor. Moreover, free HA abolished the endocytosis of drug-loaded BSA-HA conjugates. Consistently, drug-loaded NPs were markedly more cytotoxic to cancer cells overexpressing CD44 than to cells lacking CD44, due to selective internalization, which could be competitively inhibited by excess free HA. Finally, a CD44-targeted antibody which blocks receptor activity, abolished internalization of drug-loaded NPs. In conclusion, a novel cytotoxic drug-loaded nanomedicine platform has been developed, which is based on natural biocompatible biopolymers, capabale of targeting cancer cells with functional surface expression of CD44.
authors.affiliation: Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, 32000, Israel.
authors.forename: Ravit
authors.initials: R
authors.lastname: Edelman
authors.affiliation: Department of Biology, Technion-Israel Institute of Technology, Haifa, 32000, Israel.
authors.forename: Yehuda G
authors.initials: YG
authors.lastname: Assaraf
authors.affiliation: Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, 32000, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Levitzky
authors.affiliation: Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, 32000, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Shahar
authors.affiliation: Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, 32000, Israel.|Russell Berrie Nanotechnology Institute, Technion-Israel Institute of Technology, Haifa, 32000, Israel.
authors.forename: Yoav D
authors.initials: YD
authors.lastname: Livney
mesh_terms: D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000378:metabolism; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000737:chemistry; D008823:Micelles; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D008823:Micelles; D012710:Serum Albumin, Bovine; D006820:Hyaluronic Acid; D017239:Paclitaxel
keywords: Maillard reaction; cancer; hyaluronic acid; nanovehicles; targeted therapy