title: Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers.
abstract: There has been progressively heightened interest in the development of targeted nanoparticles (NPs) for differential delivery and controlled release of drugs. Despite nearly three decades of research, approaches to reproducibly formulate targeted NPs with the optimal biophysicochemical properties have remained elusive. A central challenge has been defining the optimal interplay of parameters that confer molecular targeting, immune evasion, and drug release to overcome the physiological barriers in vivo. Here, we report a strategy for narrowly changing the biophysicochemical properties of NPs in a reproducible manner, thereby enabling systematic screening of optimally formulated drug-encapsulated targeted NPs. NPs were formulated by the self-assembly of an amphiphilic triblock copolymer composed of end-to-end linkage of poly(lactic-co-glycolic-acid) (PLGA), polyethyleneglycol (PEG), and the A10 aptamer (Apt), which binds to the prostate-specific membrane antigen (PSMA) on the surface of prostate cancer (PCa) cells, enabling, respectively, controlled drug release, "stealth" properties for immune evasion, and cell-specific targeting. Fine-tuning of NP size and drug release kinetics was further accomplished by controlling the copolymer composition. By using distinct ratios of PLGA-b-PEG-b-Apt triblock copolymer with PLGA-b-PEG diblock copolymer lacking the A10 Apt, we developed a series of targeted NPs with increasing Apt densities that inversely affected the amount of PEG exposure on NP surface and identified the narrow range of Apt density when the NPs were maximally targeted and maximally stealth, resulting in most efficient PCa cell uptake in vitro and in vivo. This approach may contribute to further development of targeted NPs as highly selective and effective therapeutic modalities.
authors.affiliation: Department of Chemical Engineering, Harvard-MIT Center of Cancer Nanotechnology Excellence, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Gu
authors.forename: Liangfang
authors.initials: L
authors.lastname: Zhang
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Teply
authors.forename: Nina
authors.initials: N
authors.lastname: Mann
authors.forename: Andrew
authors.initials: A
authors.lastname: Wang
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; D044482:Benzeneacetamides / Q000737:chemistry; D055592:Biophysical Phenomena; D001703:Biophysics; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004705:Endocytosis; D006016:Glycolates / Q000737:chemistry*; D006801:Humans; D019344:Lactic Acid; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry*; D010881:Piperidones / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017430:Prostate-Specific Antigen / Q000737:chemistry*; D013499:Surface Properties; D023041:Xenograft Model Antitumor Assays
chemical_list: D044482:Benzeneacetamides; D006016:Glycolates; D008024:Ligands; D010881:Piperidones; C052091:antineoplaston A10; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D017430:Prostate-Specific Antigen