title: Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile.
abstract: We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic.
authors.affiliation: BIND Biosciences Inc., Cambridge, MA 02139, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hrkach
authors.forename: Daniel
authors.initials: D
authors.lastname: Von Hoff
authors.forename: Mir
authors.initials: M
authors.lastname: Mukkaram Ali
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Andrianova
authors.forename: Jason
authors.initials: J
authors.lastname: Auer
authors.forename: Tarikh
authors.initials: T
authors.lastname: Campbell
authors.forename: David
authors.initials: D
authors.lastname: De Witt
authors.forename: Michael
authors.initials: M
authors.lastname: Figa
authors.forename: Maria
authors.initials: M
authors.lastname: Figueiredo
authors.forename: Allen
authors.initials: A
authors.lastname: Horhota
authors.forename: Susan
authors.initials: S
authors.lastname: Low
authors.forename: Kevin
authors.initials: K
authors.lastname: McDonnell
authors.forename: Erick
authors.initials: E
authors.lastname: Peeke
authors.forename: Beadle
authors.initials: B
authors.lastname: Retnarajan
authors.forename: Abhimanyu
authors.initials: A
authors.lastname: Sabnis
authors.forename: Edward
authors.initials: E
authors.lastname: Schnipper
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Song
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Song
authors.forename: Jason
authors.initials: J
authors.lastname: Summa
authors.forename: Douglas
authors.initials: D
authors.lastname: Tompsett
authors.forename: Greg
authors.initials: G
authors.lastname: Troiano
authors.forename: Tina
authors.initials: T
authors.lastname: Van Geen Hoven
authors.forename: Jim
authors.initials: J
authors.lastname: Wright
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Neil H
authors.initials: NH
authors.lastname: Bander
authors.forename: Christopher
authors.initials: C
authors.lastname: Sweeney
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Stephen
authors.initials: S
authors.lastname: Zale
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D051381:Rats; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000954:Antigens, Surface; D011108:Polymers; D043823:Taxoids; D000077143:Docetaxel; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II