title: Targeted nanoparticles assembled via complexation of boronic-acid-containing targeting moieties to diol-containing polymers.
abstract: The delivery of therapeutics via nanoscaled vehicles for solid cancer treatment can be enhanced by the incorporation of a targeting capability. Here, we describe a new method for assembling a targeted nanoparticle that utilizes the reversible covalent complexation between boronic acids and diols to achieve a targeted nanoparticle for the delivery of the anticancer drug camptothecin (CPT). CPT is conjugated to a biocompatible, hydrophilic copolymer of mucic acid and PEG (MAP). When this polymer-drug conjugate is placed in water, it self-assembles into MAP-CPT nanoparticles of ca. 30 nm (diameter) and slightly negative zeta potential. The antibody Herceptin is attached to a boronic acid via a polyethylene glycol (PEG) spacer, and this boronic acid-containing targeting moiety is complexed with the diol-containing MAP to form a targeted MAP-CPT nanoparticle. The addition of Herceptin targeting agent to the MAP-CPT nanoparticles yields targeted MAP-CPT nanoparticles with increased nanoparticle size to ca. 40 nm (diameter). The main mechanisms of CPT release from MAP-CPT nanoparticles are found by in vitro analysis to be hydrolysis and nanoparticle disruption by fat. Cellular uptake of nanoparticles is enhanced by 70% compared to nontargeted version by the incorporation of a single Herceptin antibody targeting agent per nanoparticle. This single Herceptin antibody targeted MAP-CPT nanoparticle system carries ca. 60 CPT molecules per nanoparticle and shows prolonged plasma circulation with an elimination half-life of 21.2 h and AUC value of 2766 μg.h/mL at a 10 mg CPT/kg tail vein injection in mice.
authors: Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors: Han
authors: H
authors: Han
authors: Mark E
authors: ME
authors: Davis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001775:Blood Circulation / Q000187:drug effects; D001897:Boronic Acids / Q000737:chemistry*; D002166:Camptothecin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D008970:Molecular Weight; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013400:Sugar Acids / Q000737:chemistry*; D013499:Surface Properties
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011108:Polymers; D013400:Sugar Acids; D011092:Polyethylene Glycols; C000090:galactaric acid; D002166:Camptothecin