title: Controlled Multi-functionalization Facilitates Targeted Delivery of Nanoparticles to Cancer Cells.
abstract: A major objective of nanomedicine is to combine in a controlled manner multiple functional entities into a single nanoscale device to target particles with great spatial precision, thereby increasing the selectivity and potency of therapeutic drugs. A multifunctional nanoparticle is described for controlled conjugation of a cytotoxic drug, a cancer cell targeting ligand, and an imaging moiety. The approach is based on the chemical synthesis of polyethylene glycol that at one end is modified by a thioctic acid for controlled attachment to a gold core. The other end of the PEG polymers is modified by a hydrazine, amine, or dibenzocyclooctynol moiety for conjugation with functional entities having a ketone, activated ester, or azide moiety, respectively. The conjugation approach allowed the controlled attachment of doxorubicin through an acid-labile hydrazone linkage, an Alexa Fluor dye through an amide bond, and a glycan-based ligand for the cell surface receptor CD22 of B-cells using strain promoted azide-alkyne cycloaddition. The incorporation of the ligand for CD22 led to rapid entry of the nanoparticle by receptor-mediated endocytosis. Covalent attachment of doxorubicin via hydrazone linkage caused pH-responsive intracellular release of doxorubicin and significantly enhanced the cytotoxicity of nanoparticles. A remarkable 60-fold enhancement in cytotoxicity of CD22 (+) lymphoma cells was observed compared to non- targeted nanoparticles.
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA.|Department of Chemistry, University of Georgia, Athens, GA, 30602, USA.
authors.forename: Manish S
authors.initials: MS
authors.lastname: Hudlikar
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA.
authors.forename: Xiuru
authors.initials: X
authors.lastname: Li
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA.|Department of Chemistry, University of Georgia, Athens, GA, 30602, USA.
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Gagarinov
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA.
authors.forename: Nagesh
authors.initials: N
authors.lastname: Kolishetti
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA.
authors.forename: Margreet A
authors.initials: MA
authors.lastname: Wolfert
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA. gjboons@ccrc.uga.edu.|Department of Chemistry, University of Georgia, Athens, GA, 30602, USA. gjboons@ccrc.uga.edu.
authors.forename: Geert-Jan
authors.identifier: http://orcid.org/0000-0003-3111-5954
authors.initials: GJ
authors.lastname: Boons
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D034242:Cyclooctanes / Q000737:chemistry / Q000378:metabolism; D004317:Doxorubicin / Q000737:chemistry* / Q000494:pharmacology; D004337:Drug Carriers; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis; D006046:Gold / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016393:Lymphoma, B-Cell / Q000737:chemistry* / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D034242:Cyclooctanes; D004337:Drug Carriers; D011108:Polymers; D011092:Polyethylene Glycols; D006046:Gold; D004317:Doxorubicin
keywords: B-cell lymphoma; chemical biology; doxorubicin; drug delivery; nanoparticles