title: Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery.
abstract: Nanoparticle (NP) size has been shown to significantly affect the biodistribution of targeted and non-targeted NPs in an organ specific manner. Herein we have developed NPs from carboxy-terminated poly(d,L-lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG-COOH) polymer and studied the effects of altering the following formulation parameters on the size of NPs: (1) polymer concentration, (2) drug loading, (3) water miscibility of solvent, and (4) the ratio of water to solvent. We found that NP mean volumetric size correlates linearly with polymer concentration for NPs between 70 and 250 nm in diameter (linear coefficient=0.99 for NPs formulated with solvents studied). NPs with desirable size, drug loading, and polydispersity were conjugated to the A10 RNA aptamer (Apt) that binds to the prostate specific membrane antigen (PSMA), and NP and NP-Apt biodistribution was evaluated in a LNCaP (PSMA+) xenograft mouse model of prostate cancer. The surface functionalization of NPs with the A10 PSMA Apt significantly enhanced delivery of NPs to tumors vs. equivalent NPs lacking the A10 PSMA Apt (a 3.77-fold increase at 24h; NP-Apt 0.83%+/-0.21% vs. NP 0.22%+/-0.07% of injected dose per gram of tissue; mean+/-SD, n=4, p=0.002). The ability to control NP size together with targeted delivery may result in favorable biodistribution and development of clinically relevant targeted therapies.
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Cheng
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Teply
authors.forename: Ines
authors.initials: I
authors.lastname: Sherifi
authors.forename: Josephine
authors.initials: J
authors.lastname: Sung
authors.forename: Gaurav
authors.initials: G
authors.lastname: Luther
authors.forename: Frank X
authors.initials: FX
authors.lastname: Gu
authors.forename: Etgar
authors.initials: E
authors.lastname: Levy-Nissenbaum
authors.forename: Aleksandar F
authors.initials: AF
authors.lastname: Radovic-Moreno
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D016503:Drug Delivery Systems; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D051379:Mice; D008956:Models, Chemical; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology / Q000379:methods*; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols